Patent Application
20230159436
This application claims priorities to, and the benefit of, of Australian application AU 2021903740, filed on of 19 Nov. 2021 and Australian application AU 2022901291, filed on 15 May 2022. The contents of the foregoing applications are hereby incorporated in their entireties by reference into this application for all purposes.
This invention provides methods of synthesizing new compounds for pharmaceutical uses.
This invention provides methods of synthesizing new compounds for pharmaceutical uses. This invention provides methods, compounds and compositions for treating cancer, inhibiting cancer invasion, cell invasion, or cancer cell invasion, wherein the cancers comprise breast, leukocytic, liver, ovarian, bladder, prostatic, skin, bone, brain, leukemia, lung, colon, CNS, melanoma, renal, cervical, esophageal, testicular, splenic, kidney, lymphatic, pancreatic, stomach eye and thyroid cancers.
This invention provides methods of synthesizing new compounds for pharmaceutical uses. This invention provides compounds, compositions, and methods for treating cancer, inhibiting cancer invasion, cell invasion, macromolecular invasion, cancer cell invasion, and metastasis. The active compounds of this invention are triterpenes in form of amine, sulfonamides, amide, and Urea Analogs, providing extremely stable activity in solution. They prolong the activities and duration of drug in a subject. This invention provides a use of compounds, compositions, for manufacturing medicament for treating cancer, inhibiting cancer invasion, macromolecular invasion, virus invasion and metastasis. This invention provides compounds for use as mediator or inhibitor of adhesion protein or angiopoietin, This invention provides compounds for use in a method of modulating attachment or adhesion of cells or angiogenesis, by modulating or inhibiting adhesion protein macromolecules, or angiopoietin, The compounds comprise the structures selected from the formulae in the present application, wherein the compounds are synthesized or isolated, wherein the compounds comprise the saponins, triterpenes, pentacyclic triterpenes, and compounds selected from formulae in the present application, wherein the cancers comprise breast, leukocytic, liver, ovarian, bladder, prostatic, skin, bone, brain, leukemia, lung, colon, CNS, melanoma, renal, cervical, esophageal, testicular, splenic, kidney, lymphatic, pancreatic, stomach and thyroid cancers. This invention provides compounds for use as a mediator for cell circulating, cell moving cell homing and inflammatory diseases. This invention provides compounds for improving blood circulation; soothing stroke; preventing plaque formation and promote their dissipated; improve blood viscosity; reducing cardiovascular; reducing cerebrovascular; reducing thrombosis, arteriosclerosis, coronary heart disease, hypertension, diabetes, thrombocytopenia purpura, hemoptysis, hematemesis; treating blood in the stool, uterine bleeding, traumatic bleeding, abdominal irritation, swelling, fluttering, Blood circulation, swelling, pain; Treating bronchiectasis, tuberculosis and lung abscess caused by too hemoptysis; reducing bleeding, antitussive, expectorant and analgesic effect, dilate blood vessels; reducing blood pressure and the treatment of cerebral arteriosclerosis; elevating blood lipids and reducing cholesterol.
This invention provides a method of synthesizing new active compounds for pharmaceutical uses. The active compounds of this invention are triterpenes in form of amine, sulfonamides, amide, and urea analogs, providing extremely stable activity in solution They prolong the activities and duration of drug in a subject. This invention provides an anti adhesion therapy which uses the compound as a mediator or inhibitor of adhesion proteins and angiopoietins. It inhibits excessive adhesion and inhibits cell viral and macromolecular attachment. It modulates angiogenesis. The compounds also use as mediator of cell viral and macromolecular adhesion receptor(s).
This invention provides compounds or a composition comprising the compounds of triterpenes in form of amine, sulfonamides, amide, and urea analogs, provided in the invention for treating cancers; for inhibiting cancer growth, for inhibiting viruses; for preventing cerebral aging; for improving memory; improving cerebral functions; for curing enuresis, frequent micturition, urinary incontinence; neurodegenerative diseases, dementia, Alzheimer's disease, autism, brain trauma, Parkinson's disease or other diseases caused by cerebral dysfunctions; for treating arthritis, rheumatism, poor circulation, arteriosclerosis, Raynaud's syndrome, angina pectoris, cardiac disorder, coronary heart disease, headache, dizziness, kidney disorder; cerebrovascular disease; inhibiting NF-kappa B activation; for treating brain edema, severe acute respiratory syndrome, respiratory viral diseases, chronic venous insufficiency, hypertension, chronic venous disease, oedema, inflammation, hemonhoids, peripheral edema formation, varicose vein disease, flu, post traumatic edema and postoperative swelling; for inhibiting blood clots, for inhibiting ethanol absorption; for lowering blood sugar; for regulating adrenocorticotropin and corticosterone levels. This invention provides a composition for Anti-MS, anti-aneurysm, anti-asthmatic, anti-oedematous, anti-inflammatory, anti-bradykinic, anti-capillarihemorrhagic, anti-cephalagic, anti-cervicobrachialgic, anti-eclamptic, anti-edemic, anti-encaphalitic, anti-epiglottitic, anti-exudative, anti-flu, anti-fracture, anti-gingivitic, anti-hematomic, anti-herpetic, anti-histaminic, anti-hydrathritic, anti-meningitic, antioxidant, anti-periodontic, anti-phlebitic, anti-pleuritic, anti-raucedo, anti-rhinitic, anti-tonsilitic, anti-ulcer, anti-varicose, anti-vertiginous, cancerostatic, corticosterogenic, diuretic, fungicide, hemolytic, hyaluronidase inhibitor, lymphagogue, natriuretic, pesticide, pituitary stimulant, thymolytic, vasoprotective, inhibiting leishmaniases, modulating adhesion or angiogenesis of cells, anti-parasitic; increase the expression of the genes: ANGPT2, DDIT3, LIF and NFKB1Z, and manufacturing an adjuvant composition and venotonic treatment.
This invention provides compounds, compositions and methods for treating cancer diseases, inhibiting cancer invasion, for inhibiting cancer growth or for inhibiting cancer metastasis, wherein the compounds comprise the structures selected from the formulae of the present application, wherein the compounds can be synthesized or isolated, wherein the compounds comprise the triterpenes, pentacyclic triterpenes, saponins, and compounds selected from formulae in this application, wherein the cancers comprise breast cancer, leukocytic cancer, liver cancer, ovarian cancer, bladder cancer, prostatic cancer, skin cancer, bone cancer, brain cancer, leukemia cancer, lung cancer, colon cancer, CNS cancer, melanoma cancer, renal cancer, cervical cancer, esophageal cancer, testicular cancer, splenic cancer, kidney cancer, lymphatic cancer, pancreatic cancer, stomach cancer, eye cancer and thyroid cancer; wherein the cells comprise breast cell, leukocytic cell, liver cell, ovarian cell, bladder cell, prostatic cell, skin cell, bone cell, brain cell, leukemia cell, lung cell, colon cell, CNS cell, melanoma cell, renal cell, cervical cell, esophageal cell, testicular cell, splenic cell, kidney cell, lymphatic cell, pancreatic cell, stomach cell and thyroid cell.
This invention provides compounds for improving blood circulation; soothing stroke; preventing plaque formation and promote their dissipated; improve blood viscosity; reducing cardiovascular; reducing cerebrovascular; reducing thrombosis, arteriosclerosis, coronary heart disease, hypertension, diabetes, thrombocytopenia purpura, hemoptysis, hematemesis; treating blood in the stool, uterine bleeding, traumatic bleeding, abdominal irritation, swelling, fluttering, Blood circulation, swelling, pain; Treating bronchiectasis, tuberculosis and lung abscess caused by too hemoptysis; reducing bleeding, antitussive, expectorant and analgesic effect, dilate blood vessels; reducing blood pressure and the treatment of cerebral arteriosclerosis; elevating blood lipids and reducing cholesterol.
This invention shows that the presence of group selected from acetyl, angeloyl, tigloyl, senecioyl, Crotonoyl, 3,3-Dimethylartyloyl, Cinnamoyl, Pentenoyl, Hexanoyl, benzoyl, Ethylbutyryl, alkyl, dibenzoyl, benzoyl, methylbutanoyl, methylpropanoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, alkanoyl substituted phenyl, alkenoyl substituted phenyl, aryl, acyl, heterocylic, heteroraryl, alkenylcarbonyl, ethanoyl, propanoyl, propenoyl, butanoyl, butenoyl, pentanoyl, hexenoyl, heptanoyl, heptenoyl, octanoyl, octenoyl, nonanoyl, nonenoyl, decanoyl, decenoyl, propionyl, 2-propenoyl, 2-butenoyl, Isobutyryl, 2-methylpropanoyl, 2-ethylbutyryl, ethylbutanoyl, 2-ethylbutanoyl, butyryl, (E)-2,3-Dimethylacryloyl, (E)-2-Methylcrotonoyl, 3-cis-Methyl-methacryloyl, 3-Methyl-2-butenoyl, 3-Methylcrotonoyl, 4-Pentenoyl, (2E)-2-pentenoyl, Caproyl, 5-Hexenoyl, Capryloyl, Lauroyl, Dodecanoyl, Myristoyl, Tetradecanoyl, Oleoyl, C(2-18) Acyl at carbon position 21, 22, 24 and/or 28 of a pentacyclic triterpene, triterpene, triterpeniod, triterpeniod saponin or compound selected from formulae of the present application, produces inhibition of cancer growth, cancer invasion, cells invasion, cancer cell invasion or macromolecular cell invasion. In an embodiment, the presence of group(s) selected from acetyl, angeloyl, tigloyl, senecioyl, Crotonoyl, 3,3-Dimethylartyloyl, Cinnamoyl, Pentenoyl, Hexanoyl, benzoyl, Ethylbutyryl, alkyl, dibenzoyl, benzoyl, methylbutanoyl, methylpropanoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, alkanoyl substituted phenyl, alkenoyl substituted phenyl, aryl, acyl, heterocylic, heteroraryl, alkenylcarbonyl, ethanoyl, propanoyl, propenoyl, butanoyl, butenoyl, pentanoyl, hexenoyl, heptanoyl, heptenoyl, octanoyl, octenoyl, nonanoyl, nonenoyl, decanoyl, decenoyl, propionyl, 2-propenoyl, 2-butenoyl, Isobutyryl, 2-methylpropanoyl, 2-ethylbutyryl, ethylbutanoyl, 2-ethylbutanoyl, butyryl, (E)-2,3-Dimethylacryloyl, (E)-2-Methylcrotonoyl, 3-cis-Methyl-methacryloyl, 3-Methyl-2-butenoyl, 3-Methylcrotonoyl, 4-Pentenoyl, (2E)-2-pentenoyl, Caproyl, 5-Hexenoyl, Capryloyl, Lauroyl, Dodecanoyl, Myristoyl, Tetradecanoyl, Oleoyl, C(2-18) Acyl at carbon position 2, 3, 8, 15, 21, 22, 23, 24 and/or 28 of a pentacyclic triterpene, triterpeniod, triterpeniod saponin or compound selected from formulae of the present application produces activities including inhibition of cancer growth, cancer invasion, cells invasion, cancer cell invasion, cell adhesion, cell attachment or cell circulating wherein the group may attached with an O, S, NH, CH2O, C(O), C(O)O, N-alkyl, CH2, CH2O, CH2NH, CH2NHCO, CH2NHCONH, or CH2NHSO2 to the carbon of triterpene, triterpeniod, triterpeniod saponin or compound selected from formulae of the present application; The active compounds are triterpene with amine, sulfonamides, amide, or Urea Analogs, providing extremely stable activity in solution. They prolong the activities and duration of drug in a subject. They do not hydrolyzed in plasma by the enzyme, but undergo enzymatic degradation in the liver and excretion in the urine.
In an embodiment, the presence of group at carbon position 24, produces activities. In an embodiment, the presence of group at carbon position 24 and 28 produces activities. In an embodiment, the presence of group at carbon position 24 and 21 produces activities. In an embodiment, the presence of group at carbon position 24, 28 and 21, produces activities. In an embodiment, the presence of group at carbon position 24, 28 and 22 produces activities. In an embodiment, the presence of group at carbon position 24, 28 and 3 produces activities. In an embodiment, the presence of group at carbon position 24, and 3 produces activities. In an embodiment, the presence of group at carbon position 28 and 3 produces activities. In an embodiment, the presence of group at carbon position 3 produces activities. In an embodiment, the presence of group at carbon position 21 and 22 produces activities. In an embodiment, the hemolytic activity of the compound is reduced. In embodiment, the compound is attached a sugar moiety(ies), acid moiety(ies) or alduronic acid. In an embodiment, the presence of group at carbon position 1, produces activities. In an embodiment, the presence of group at carbon position 2, produces activities. In an embodiment, the presence of group at carbon position 3, produces activities. In an embodiment, the presence of group at carbon position 4, produces activities. In an embodiment, the presence of group at carbon position 5, produces activities. In an embodiment, the presence of group at carbon position 6, produces activities. In an embodiment, the presence of group at carbon position 7, produces activities. In an embodiment, the presence of group at carbon position 8, produces activities. In an embodiment, the presence of group at carbon position 9, produces activities. In an embodiment, the presence of group at carbon position 10, produces activities. In an embodiment, the presence of group at carbon position 11, produces activities. In an embodiment, the presence of group at carbon position 12, produces activities. In an embodiment, the presence of group at carbon position 13, produces activities. In an embodiment, the presence of group at carbon position 14, produces activities. In an embodiment, the presence of group at carbon position 15, produces activities. In an embodiment, the presence of group at carbon position 16, produces activities. In an embodiment, the presence of group at carbon position 17, produces activities. In an embodiment, the presence of group at carbon position 18, produces activities. In an embodiment, the presence of group at carbon position 19, produces activities. In an embodiment, the presence of group at carbon position 20, produces activities. In an embodiment, the presence of group at carbon position 21, produces activities. In an embodiment, the presence of group at carbon position 22, produces activities. In an embodiment, the presence of group at carbon position 23, produces activities. In an embodiment, the presence of group at carbon position 24, produces activities. In an embodiment, the presence of group at carbon position 25, produces activities. In an embodiment, the presence of group at carbon position 26, produces activities. In an embodiment, the presence of group at carbon position 27, produces activities. In an embodiment, the presence of group at carbon position 28, produces activities. In an embodiment, the presence of group at carbon position 29, produces activities. In an embodiment, the presence of group at carbon position 30, produces activities. In an embodiment, the activities are for treating cancers, inhibition of cancer growth, cancer invasion, cells invasion, cancer cell invasion; cell adhesion, cell attachment, cell circulating; for treating mad cow disease; treating prion diseases; for inhibiting viruses; for preventing cerebral aging; for improving memory; improving cerebral functions; for curing enuresis, frequent micturition, urinary incontinence; dementia, Alzheimer's disease, autism, brain trauma, Parkinson's disease or other diseases caused by cerebral dysfunctions or neurodegeneration; for treating arthritis, rheumatism, poor circulation, arteriosclerosis, Raynaud's syndrome, angina pectoris, cardiac disorder, coronary heart disease, headache, dizziness, kidney disorder; cerebrovascular diseasea; inhibiting NF-kappa B activation; for treating brain edema, severe acute respiratory syndrome, respiratory viral diseases, chronic venous insufficiency, hypertension, chronic venous disease, oedema, inflammation, hemorrhoids, peripheral edema formation, varicose vein disease, flu, post traumatic edema and postoperative swelling; for inhibiting blood clots, for inhibiting ethanol absorption; for lowering blood sugar; for regulating adrenocorticotropin and corticosterone levels. This invention provides a composition for Anti-MS, anti-aneurysm, anti-asthmatic, anti-oedematous, anti-inflammatory, anti-bradykinic, anti-capillarihemorrhagic, anti-cephalagic, anti-cervicobrachialgic, anti-eclamptic, anti-edemic, anti-encaphalitic, anti-epiglottitic, anti-exudative, anti-flu, anti-fracture, anti-gingivitis, anti-hematomic, anti-herpetic, anti-histaminic, anti-hydrathritic, anti-meningitic, antioxidant, anti-periodontic, anti-phlebitic, anti-pleuritic, anti-raucedo, anti-rhinitic, anti-tonsilitic, anti-ulcer, anti-varicose, anti-vertiginous, cancerostatic, corticosterogenic, diuretic, fungicide, hemolytic, hyaluronidase inhibitor, lymphagogue, natriuretic, pesticide, pituitary stimulant, thymolytic, vasoprotective, inhibiting leishmaniases, modulating adhesion or angiogenesis of cells, anti-parasitic.
In an embodiment, the compound is arresting cells in the S-phase and blocking their entering into the G2/M phase of cell cycle. The compound blocks the DNA synthesis of cancer cell. This application produces synthetic compounds increase the potency and decrease the toxicity. In an embodiment, the compounds are amine, sulfonamides, amide, or urea analogs of triterpene, which provide extremely stable activity in solution They prolong the bio activities and duration of drug in a subject.
Experiments presented in this invention showed that the core compound including E4A, E4D1, E4D which have no effect in inhibiting cancer growth, cancer invasion, cells invasion or cancer cell invasion. The core E4A was obtained by removing the groups from carbon positions 3, 21 and 22 of the active Escin. Further, amination of E4A to give E4D or E4D1 core. The core compound including E4A, E4D, E4D1 E and AKOH have no hemolytic activity and no anti-cancer activity.
This invention showed that functional group attached at carbon position 24 of a pentacyclic triterpene did not produce hemolytic activity, which has bio-activities including inhibiting cancer growth, inhibiting cancer invasion, cells invasion or cancer cell invasion. This invention showed that functional group attached at carbon position 3 of a pentacyclic triterpene did not produce hemolytic activity, which has bio-activities including inhibiting cancer growth, inhibiting cancer invasion, cells invasion or cancer cell invasion. This invention showed that function group(s) attached at carbon position 3 and 1 or 2 or 3 of carbon position 28, 21, 22, 24 of a pentacyclic triterpene did not produce hemolytic activity, which has bio activities including inhibiting cancer growth, inhibiting cancer invasion, cells invasion or cancer cell invasion.
This invention showed that functional group attached at carbon position 2 of a pentacyclic triterpene did not produce hemolytic activity, which has bio activities including inhibiting cancer growth, inhibiting cancer invasion, cells invasion or cancer cell invasion. This invention showed that function group(s) attached at carbon position 2 and 1 or 2 or 3 of carbon position 28, 21, 22, 24 of a pentacyclic triterpene did not produce hemolytic activity, which has bio-activities including inhibiting cancer growth, inhibiting cancer invasion, cells invasion or cancer cell invasion.
This invention provides a pentacyclic triterpene with reduced hemolytic activity for treating diseases, wherein the triterpene comprising a group(s) attached at its core producing bioactivities. This invention provides a pentacyclic triterpene with reduced hemolytic activity comprising a group(s) attached at carbon position 3, or carbon position 24 and 1 or 2 or 3 of of other position(s) of a pantacyclic triterpene, which has bioactivities. This invention provides a triterpene with reduced hemolytic activity comprising a group(s) attached at carbon position 15, 16, 21, 22, 23, 24, 28, 29, 30 and/or 3 of a pentacyclic triterpene, which has bioactivities. This invention provides a composition comprising a triterpene with reduced hemolytic activity comprising a group(s) attached at carbon position 3, or carbon position 24 and 1 or 2 or 3 of of other position(s) of a pentacyclic triterpene, which has bioactivities. This invention provides a method for bio-activities treatment including but not limited to treating cancers, comprising administering to said subject an effective amount of compound, wherein the compound is a pentacyclic triterpene with reduced hemolytic activity comprising a group(s) attached at carbon position 3, or carbon position 24 and 1 or 2 or 3 of of other position(s) of a pentacyclic triterpene, which has bio-activities. The active compounds of this invention are amine, sulfonamides, amide, and urea analogs of triterpene, providing extremely stable activity in solution. They prolong the activities and duration of drug in a subject. They do not hydrolyzed in plasma by the enzyme pseudocholinesterase, but undergo enzymatic degradation in the liver and excretion in the urine.
The compound of the present application can be obtained with the method:
The compound of present application, wherein the core compound is terpene, isoprene, or triterpene core; wherein the core compound is hydroxylated; wherein the core compound was dissolved in pyridine; wherein the acyl chloride including Tigloyl chloride, angeloyl chloride, Acetyl chloride, Crotonoyl chloride, 3,3-Dimethylartyloyl chloride, senecioyl chloride, Cinnamoyl chloride, Pentenoyl chloride, Hexanoyl chloride, benzoyl chloride and Ethylbutyryl chloride; wherein the reaction time for the mixture is stirred for 5 sec, 1 min, 2 min, 5 min, 10 min, 30 min, 1 hr, 2 hr, 18 hr, 2 days or 3 days; wherein the temperature is 0 C, 25 C, 50 C or 75 C temperature; wherein the acid including HCl or the base is a weak base including NaHCO3 is added to the reaction mixture; wherein the solution is then extracted 3 times with ethyl acetate and lyophilization; wherein the reaction product is dissolved in 80% acetonitrile-0.005% Trifluoroacetic acid or DMSO; wherein selecting the HPLC fractions for isolation is according to the cytotoxic activity of the reaction product obtained at a reaction time of 5 sec, 1 min, 2 min, 5 min, 10 min, 30 min, 1 hr, 2 hr, 18 hr, 2 days or 3 days.
This invention showed that functional group attached at carbon position 23 of a pentacyclic triterpene did not produce hemolytic activity, which has bio-activities including inhibiting cancer growth, inhibiting cancer invasion, cells invasion or cancer cell invasion. This invention showed that function group(s) attached at carbon position 24 and 1 or 2 or 3 of carbon position 28, 21, 22 of a pentacyclic triterpene did not produce hemolytic activity, which has bio-activities including inhibiting cancer growth, inhibiting cancer invasion, cells invasion or cancer cell invasion.
This invention showed that functional group attached at carbon position 24 of a pentacyclic triterpene did not produce hemolytic activity, which has bio-activities including inhibiting cancer growth, inhibiting cancer invasion, cells invasion or cancer cell invasion. This invention showed that function group(s) attached at carbon position 24 and 1 or 2 or 3 of carbon position 28, 21, 22 of a pentacyclic triterpene did not produce hemolytic activity, which has bio-activities including inhibiting cancer growth, inhibiting cancer invasion, cells invasion or cancer cell invasion.
This invention provides a triterpene with reduced hemolytic activity for treating diseases, wherein the triterpene comprising a group(s) attached at its core producing bio-activities. This invention provides a pentacyclic triterpene with reduced hemolytic activity comprising a group(s) attached at carbon position 24, or carbon position 24 and 1 or 2 or 3 of of other position(s) of a pentacyclic triterpene, which has bio-activities. This invention provides a composition comprising a pentacyclic triterpene with reduced hemolytic activity comprising a group(s) attached at carbon position 24, or carbon position 24 and 1 or 2 or 3 of of other position(s) of a pentacyclic triterpene, which has bio-activities. This invention provides a method for bio-activities treatment including but not limited to treating cancers, comprising administering to said subject an effective amount of compound, wherein the compound is a triterpene with reduced hemolytic activity comprising a group(s) attached at carbon position 24, or carbon position 24 and 1 or 2 or 3 of of other position(s) of a pentacyclic triterpene, which has bio-activities.
This invention showed that Tig-N, Tig-Q, Tig-R, Tig-T Tig-S and Tig-V do not have hemolytic activity up to 20 ug/ml. The original compound ES lyse 100% red blood cells (RBC) at 5 ug/ml. Compare to Y3, the ACH-Y3 is less potent in hemolytic activity. Tig-R has no hemolytic activity. This invention showed that Tig-N, Tig-Q, Tig-R, Tig-T Tig-S and Tig-V have anti cancer activities. The E4D1-Tig-R, E4D1-Tig-Q, E4D-Tig-R, E4D1-Tig-T E4D1-Tig-S and E4D1-Tig-V in form of amide provide extremely stable activity in solution. They prolong the bio activities and duration of drug in a subject. They do not hydrolyzed in plasma by the enzyme pseudocholinesterase, but undergo enzymatic degradation in the liver and excretion in the urine.
Many saponins and triterpenes have hemolytic characteristic that damage red blood cells. This severe side effect makes people hesitate to use saponins or triterpenes in medicines. This invention produces sythesised saponins and triterpenes with reduced hemolytic characteristic for use as medicament. This invention produces compounds with reduced hemolytic characteristic for use as medicament. The medicament can be used for treating cancer, inhibiting cancer growth, cancer invasion, cells invasion or cancer cell invasion. This application produces synthetic compounds increase the potency and decrease the toxicity.
A compound which has bio-activities including inhibiting cancer growth, inhibiting cancer invasion, cells invasion or cancer cell invasion is called active compound.
This invention provides a use for compounds, compositions, and methods for manufacturing medicament for treating cancers, inhibition of cancer growth, cancer invasion, cells invasion, cancer cell invasion; cell adhesion, cell attachment, cell circulating, or for inhibiting cancer metastasis, wherein the compounds comprise the structures selected from the formulae of the present application, wherein the compounds can be synthesized or isolated, wherein the compounds comprise the pentacyclic triterpenes, wherein the compounds with reduced hemolytic, wherein the cells comprise cancer cells, wherein the cancers comprise breast cancer, leukocytic cancer, liver cancer, ovarian cancer, bladder cancer, prostatic cancer, skin cancer, bone cancer, brain cancer, leukemia cancer, lung cancer, colon cancer, CNS cancer, melanoma cancer, renal cancer, cervical cancer, esophageal cancer, testicular cancer, splenic cancer, kidney cancer, lymphatic cancer, pancreatic cancer, stomach cancer, eye cancer and thyroid cancer. The method of inhibiting cancer invasion, cells invasion or cancer cell invasion activities uses non-cytotoxic drug concentrations. The method of inhibiting metastasis uses non-cytotoxic drug concentrations. There is no noticeable change in cell morphology.
This invention provides triterpene(s) with reduced hemolytic activity for treating diseases, wherein the triterpene can be a pentacyclic triterpene comprising a group(s) attached at its core producing bio-activities. This invention provides a pentacyclic triterpene with reduced hemolytic effect, comprising a group(s) attached at carbon position 24, or carbon position 24 and 1 or 2 or 3 of of other position(s) of a pentacyclic triterpene, which has bio-activities. This invention provides a composition comprising a triterpene with reduced hemolytic activity comprising a group(s) attached at carbon position 24, or carbon position 24 and 1 or 2 or 3 of of other position(s) of a pentacyclic triterpene, which has bio-activities. This invention provides a method for bio-activities treatment including but not limited to treating cancers, comprising administering to said subject an effective amount of compound, wherein the compound is a triterpene with reduced hemolytic activity, comprising a group(s) attached at carbon position 24, or carbon position 24 and 1 or 2 or 3 of of other position(s) of a triterpene, which has bio-activities, wherein a compound selected from AA1-4, BB1-4, CC1-4, DD1-4, EE1-4, GG1-4, HH1-4, II1-4, JJ1-4, KK1-4, LL1-4, MM1-4, PP1-4, QQ1-4, RR1-4, SS1-4, TT1-4, Tig-Sen-n, Tig-Cro-n, Tig-Acy-n, Tig-Pen-n, Tig-Hex-n, Tig-Cin-n, Tig-Ang-n, Tig-Eth-n, Tig-R-Sen-n, Tig-R-Cro-n, Tig-R-Acy-n, Tig-R-Pen-n, Tig-R-Hex-n, Tig-R-Cin-n, Tig-R-Ang-n, Tig-R-Eth-n, wherein n=1 to 6, and a salt, ester, metabolite thereof, or amine, diamine, amide, sulfonamide, urea thereof; wherein the compound(s) is in form in form of powder, liquid or crystal and the compounds selected from formulae 2A, and K; wherein the compound is selected from Tig-N, Tig-Q, Tig-R, Tig-T Tig-S and Tig-V; wherein the compound is selected from E4D1-Tig-R, E4D1-Tig-Q, E4D-Tig-R, E4D1-Tig-T E4D1-Tig-S and E4D1-Tig-V in form of amide.
This invention provides methods for treating cancers, inhibition of cancer growth, cancer invasion, cells invasion, cancer cell invasion; cell adhesion, cell attachment, cell circulating, migration, metastasis or growth of cancers, wherein the methods comprise affecting gene expression, wherein the methods comprise stimulating gene expression, or wherein the methods comprise inhibiting the gene expression, or wherein the methods comprise administering to a subject an effective amount of compounds, compositions in this application. In an embodiment, the method comprises contacting said cell with a compound selected from AA1-4, BB1-4, CC1-4, DD1-4, EE1-4, GG1-4, HH1-4, II1-4, JJ1-4, KK1-4, Xanifolia Y0, Y1, Y2, Y(Y3), Y5, Y7, Y8, Y9, Y10, Xanifolia (x), M10, Escin(bES), Aescin, ACH-Y(Y3), ACH-Y10, ACH-Y2, ACH-Y8, ACH-Y7, ACH-Y0, ACH-X, ACH-Z4, ACH-Z1, ACH-Escin(bES), ACH-M10, Tig-Sen-n, Tig-Cro-n, Tig-Acy-n, Tig-Pen-n, Tig-Hex-n, Tig-Cin-n, Tig-Ang-n, Tig-Eth-n, Tig-R-Sen-n, Tig-R-Cro-n, Tig-R-Acy-n, Tig-R-Pen-n, Tig-R-Hex-n, Tig-R-Cin-n, Tig-R-Ang-n, Tig-R-Eth-n, wherein n=1 to 6, and a salt, ester, metabolite thereof, amine, diamine, amide, sulfonamide, urea thereof; wherein the compound(s) is in form in form of powder, liquid or crystal and the compounds selected from formulae 2A, and K. In vitro studies show that a compound selected from structure (2A) or (K) inhibits cell adhesion to culture flasks. The compound blocks the function of these adhesive molecules on cells. In an embodiment, the selected compound blocks the function of these adhesive molecules on cells. In an embodiment, the selected compound blocks the function of these adhesive molecules on carcinoma cells. In an embodiment, the selected compound blocks the function of these adhesive molecules on the mesothelial cells. This invention provides an anti adhesion therapy which uses the compound as a mediator or inhibitor of adhesion proteins and angiopoietins. It inhibits excess adhesion and inhibits cell attachment. This invention provides compounds for use as a mediator for cell circulating, cell moving and inflammatory diseases. In an embodiment, the selected compound binds to the adhesive proteins (by masking) on the membrane and inhibits the interaction of adhesion proteins with their receptors. In an embodiment, the selected compound's action on the membrane affects adhesion proteins' function in the membrane. The lost of adhesion activity of cancer cells is result from direct or indirect action of the selected compound on membrane proteins.
This invention provides a use of compounds or methods for inhibiting cancer invasion, cell invasion, cancer cell invasion, macromolecular cell invasion, migration, metastasis or growth of cancers, wherein this invention comprises a process and method for administration of the composition, wherein administration is by intravenous injection, intravenous drip, intraperitoneal injection or oral administration; wherein administration is by intravenous drip: 0.003-0.03 mg/kg body weight of compound dissolved in 250 ml of 10% glucose solution or in 250 ml of 0.9% NaCl solution, or by intravenous injection: 0.003-0.03 mg/kg body weight per day of compound dissolved in 10-20 ml of 10% glucose solution or of 0.9% NaCl solution, or 0.01-0.03 mg/kg body weight of compound dissolved in 250 ml of 10% glucose solution or in 250 ml of 0.9% NaCl solution, or by intravenous injection: 0.01-0.03 mg/kg body weight per day of compound dissolved in 10-20 ml of 10% glucose solution or of 0.9% NaCl solution, or 0.01-0.05 mg/kg body weight of compound dissolved in 250 ml of 10% glucose solution or in 250 ml of 0.9% NaCl solution, or by intravenous injection: 0.01-0.05 mg/kg body weight per day of compound dissolved in 10-20 ml of 10% glucose solution or of 0.9% NaCl solution, or 0.05-0.2 mg/kg body weight of compound dissolved in 250 ml of 10% glucose solution or in 250 ml of 0.9% NaCl solution, or by intravenous injection: 0.05-0.2 mg/kg body weight per day of compound dissolved in 10-20 ml of 10% glucose solution or of 0.9% NaCl solution, or by intravenous drip: 0.1-0.2 mg/kg body weight per day of compound dissolved in 250 ml of 10% glucose solution or in 250 ml of 0.9% NaCl solution, or by intravenous injection: 0.1-0.2 mg/kg body weight per day compound dissolved in 10-20 ml of 10% glucose solution or of 0.9% NaCl solution, or by intraperitoneal injection (I.P.): 2.5 mg/kg body weight per day compound dissolved in 10% glucose solution or of 0.9% NaCl solution, or by oral administration wherein the dosage of mammal is 1-10 mg/kg, 10-30 mg/kg, 30-60 mg/kg, or 60-90 mg/kg body weight of compound, or by intravenous injection or intravenous drip wherein the dosage of mammal is 0.01-0.1 mg/kg body weight, 0.1-0.2 mg/kg, 0.2-0.4 mg/kg body weight, or 0.4-0.6 mg/kg body weight of compound, or by intraperitoneal injection (I.P.) wherein the dosage of mammal is 1-3 mg/kg, 3-5 mg/kg, 4-6 mg/kg, or 6-10 mg/kg body weight of compound, or 10-50 mg/kg body weight of compound, or 50-100 mg/kg body weight of compound, or 30-70 mg/kg body weight of compound or 100-150 mg/kg body weight of compound.
This invention provides a use of compounds or methods for treating cancers, inhibition of cancer growth, cancer invasion, cells invasion, cancer cell invasion; macromolecular cell invasion, cell adhesion, cell attachment, cell circulating, migration, metastasis or growth of cancers, infection or re-infection of virus or infectious macromolecules, and cancer cell fusion, wherein the invention comprises a pharmaceutical composition comprising the compound of this invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent, wherein said compound is present in a concentration of 0.01 ug/ml to 65 ug/ml, or wherein said compound is present in a concentration of 0.01 ug/ml to 40 ug/ml, or wherein said compound is present in a concentration of 0.01 ug/ml to 30 ug/ml, or wherein said compound is present in a concentration of 0.01 ug/ml to 10 ug/ml, or wherein said compound is present in a concentration of 0.01 ug/ml to 5 ug/ml, or wherein said compound is present in a concentration of 5 ug/ml to 10 ug/ml, or wherein said compound is present in a concentration of 0.1 ug/ml to 5 ug/ml, or wherein said compound is present in a concentration of 0.1 ug/ml to 7.5 ug/ml, or wherein said compound is present in a concentration of 0.1 ug/ml to 10 ug/ml, or wherein said compound is present in a concentration of 0.1 ug/ml to 15 ug/ml, or wherein said compound is present in a concentration of 0.1 ug/ml to 20 ug/ml, or wherein said compound is present in a concentration of 0.1 ug/ml to 30 ug/ml, or wherein said compound is present in a concentration of 1 ug/ml to 5 ug/ml, or wherein said compound is present in a concentration of 1 ug/ml to 7.5 ug/ml, or wherein said compound is present in a concentration of 1 ug/ml to 10 ug/ml, or wherein said compound is present in a concentration of 1 ug/ml to 15 ug/ml, or wherein said compound is present in a concentration of 1 ug/ml to 20 ug/ml, or wherein said compound is present in a concentration of 1 ug/ml to 30 ug/ml, or wherein said compound is present in a concentration of 3 ug/ml to 5 ug/ml, or wherein said compound is present in a concentration of 3 ug/ml to 7.5 ug/ml, or wherein said compound is present in a concentration of 3 ug/ml to 10 ug/ml, or wherein said compound is present in a concentration of 3 ug/ml to 15 ug/ml, or wherein said compound is present in a concentration of 3 ug/ml to 20 ug/ml, or wherein said compound is present in a concentration of 3 ug/ml to 30 ug/ml, or wherein said compound is present in a concentration of 4 ug/ml to 5 ug/ml, or wherein said compound is present in a concentration of 4 ug/ml to 7.5 ug/ml, or wherein said compound is present in a concentration of 4 ug/ml to 10 ug/ml, or wherein said compound is present in a concentration of 4 ug/ml to 15 ug/ml, or wherein said compound is present in a concentration of 4 ug/ml to 20 ug/ml, or wherein said compound is present in a concentration of 4 ug/ml to 30 ug/ml, or wherein said compound is present in a concentration of 5 ug/ml to 8 ug/ml, or wherein said compound is present in a concentration of 5 ug/ml to 9 ug/ml, or wherein said compound is present in a concentration of 5 ug/ml to 10 ug/ml, or wherein said compound is present in a concentration of 5 ug/ml to 15 ug/ml, or wherein said compound is present in a concentration of 5 ug/ml to 20 ug/ml, or wherein said compound is present in a concentration of 5 ug/ml to 30 ug/ml, or wherein said compound is present in a concentration of 7 ug/ml to 8 ug/ml, or wherein said compound is present in a concentration of 7 ug/ml to 9 ug/ml, or wherein said compound is present in a concentration of 7 ug/ml to 10 ug/ml, or wherein said compound is present in a concentration of 7 ug/ml to 15 ug/ml, or wherein said compound is present in a concentration of 7 ug/ml to 20 ug/ml, or wherein said compound is present in a concentration of 7 ug/ml to 30 ug/ml, or wherein said compound is present in a concentration of 30 ug/ml to 70 ug/ml or wherein said compound is present in a concentration of 70 ug/ml to 100 ug/ml or wherein said compound is present in a concentration of 100 ug/ml to 150 ug/ml. In an embodiment, the compound(s) is(are) in form in form of powder, liquid or crystal.
This invention provides a use of compounds or methods for treating cancers, inhibition of cancer growth, cancer invasion, cells invasion, cancer cell invasion; macromolecular cell invasion, cell adhesion, cell attachment, cell circulating, migration, metastasis or growth of cancers, infection or re-infection of virus or infectious macromolecules, and cancer cell fusion, wherein the invention comprises a pharmaceutical composition comprising the compound of this invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent, wherein said compound is present in a concentration of 0.008 uM to 80 uM, or wherein said compound is present in a concentration of 0.01 uM to 60 uM, or wherein said compound is present in a concentration of 0.01 uM to 50 uM, or wherein said compound is present in a concentration of 0.01 uM to 40 uM, or wherein said compound is present in a concentration of 0.01 uM to 30 uM, or wherein said compound is present in a concentration of 0.01 uM to 20 uM, or wherein said compound is present in a concentration of 0.01 uM to 10 uM, or wherein said compound is present in a concentration of 5 uM to 10 uM, or wherein said compound is present in a concentration of 0.1 uM to 5 uM, or wherein said compound is present in a concentration of 0.1 uM to 7.5 uM, or wherein said compound is present in a concentration of 0.1 uM to 10 uM, or wherein said compound is present in a concentration of 0.1 uM to 15 uM, or wherein said compound is present in a concentration of 0.1 uM to 20 uM, or wherein said compound is present in a concentration of 0.1 uM to 30 uM or wherein said compound is present in a concentration of 0.1 uM to 40 uM, or wherein said compound is present in a concentration of 0.1 uM to 50 uM or wherein said compound is present in a concentration of 0.1 uM to 60 uM, or wherein said compound is present in a concentration of 0.1 uM to 80 uM, or wherein said compound is present in a concentration of 1 uM to 5 uM, or wherein said compound is present in a concentration of 1 uM to 7.5 uM, or wherein said compound is present in a concentration of 1 uM to 10 uM, or wherein said compound is present in a concentration of 1 uM to 15 uM, or wherein said compound is present in a concentration of 1 uM to 20 uM, or wherein said compound is present in a concentration of 1 uM to 30 uM or wherein said compound is present in a concentration of 1 uM to 40 uM, or wherein said compound is present in a concentration of 1 uM to 50 uM or wherein said compound is present in a concentration of 1 uM to 60 uM, or wherein said compound is present in a concentration of 1 uM to 80 uM, or wherein said compound is present in a concentration of 3 uM to 5 uM, or wherein said compound is present in a concentration of 3 uM to 7.5 uM, or wherein said compound is present in a concentration of 3 uM to 10 uM, or wherein said compound is present in a concentration of 3 uM to 15 uM, or wherein said compound is present in a concentration of 3 uM to 20 uM, or wherein said compound is present in a concentration of 3 uM to 30 uM or wherein said compound is present in a concentration of 3 uM to 40 uM, or wherein said compound is present in a concentration of 3 uM to 50 uM or wherein said compound is present in a concentration of 3 uM to 60 uM, or wherein said compound is present in a concentration of 3 uM to 80 uM, or wherein said compound is present in a concentration of 5 uM to 8 uM, or wherein said compound is present in a concentration of 5 uM to 10 uM, or wherein said compound is present in a concentration of 5 uM to 15 uM, or wherein said compound is present in a concentration of 5 uM to 20 uM, or wherein said compound is present in a concentration of 5 uM to 30 uM or wherein said compound is present in a concentration of 5 uM to 40 uM, or wherein said compound is present in a concentration of 5 uM to 50 uM or wherein said compound is present in a concentration of 5 uM to 60 uM, or wherein said compound is present in a concentration of 5 uM to 80 uM. or wherein said compound is present in a concentration of 7 uM to 8 uM, or wherein said compound is present in a concentration of 7 uM to 10 uM, or wherein said compound is present in a concentration of 7 uM to 15 uM, or wherein said compound is present in a concentration of 7 uM to 20 uM, or wherein said compound is present in a concentration of 7 uM to 30 uM or wherein said compound is present in a concentration of 7 uM to 40 uM, or wherein said compound is present in a concentration of 7 uM to 50 uM or wherein said compound is present in a concentration of 7 uM to 60 uM, or wherein said compound is present in a concentration of 7 uM to 80 uM or wherein said compound is present in a concentration of 70 uM to 100 uM, or wherein said compound is present in a concentration of 90 uM to 120 uM.
The invention will be better understood by reference to the Experimental Details which follow, but those skilled in the art will readily appreciate that the specific experiments detailed are only illustrative, and are not meant to limit the invention as described herein, which is defined by the claims which follow thereafter.
Disclosures of these references or publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains.
It is to be noted that the transitional term “comprising”, which is synonymous with “including”, “containing” or “characterized by”, is inclusive or open-ended and does not exclude additional, un-recited elements or method steps.
The active compound, cellulose, and a portion of the corn starch are mixed and granulated to 10% corn starch paste. The resulting granulation is sieved, dried and blended with the remainder of the corn starch and the magnesium stearate. The resulting granulation is then compressed into tablets containing 1, 5, 10, 20, 30 mg, respectively of active ingredient per tablet.
An intravenous dosage form of the active compound is prepared as follows:
Active compound 1-10 ug
Sodium citrate 5-50 mg
Citric acid 1-15 mg
Sodium chloride 1-8 mg
Water for injection (USP) q.s. to 1 mL
Utilizing the above quantities, the active compound is dissolved at room temperature in a prepared solution of sodium chloride, citric acid, and sodium citrate in water for injection.
0.25-2.5 mg compound dissolved in 250 ml of 10% glucose solution or in 250 ml of 0.9% NaCl solution.
Intravenous drip preparation: 1-2. mg compound dissolved in 250 ml of 10% glucose solution or in 250 ml of 0.9% NaCl solution
Treatment of angelic acid with one of the many standard chlorinating reagents including phosphorus ocychloride, phosphorus trichloride and thionyl chloride produces tigloyl chloride. Oxalyl chloride produces a 2:1 ratio of angeloyl chloride to tigloyl chloride. Treatment of potassium salt in diethyl ether with oxalyl chloride and catalytic DMF for 2 hr at 0 C produces pure angeloyl chloride.
Acid Hydrolysis of the Following Compounds:
a) Xanifolia (Y),
or chemical name: 3-O-[β-D-galactopyranosyl (1→2)]-α-L-arabinofuranosy (1→3)-β-D-glucuronopyranosyl-21,22-O-diangeloyl-3β,15α,16α,21β,22α,28-hexahydroxyolean-12-ene;
c) Xanifolia (Y2),
or chemical name: 3-O-[β-D-glucopyranosyl-(1→2)]-α-L-arabinofuranosy (1→3)-β-D-glucuronopyranosyl-21,22-O-diangeloyl-3β,15α,16α,21β,22α,24β,28-heptahydroxyolean-12-ene;
d) Xanifolia (Y8),
or chemical name: 3-O-[β-glucopyranosyl (1→2)]-α-arabinofuranosyl (1→3)-β-glucuronopyranosyl-21,22-O-diangeloyl-3β,16α,21β,22α,24β,28-hexahydroxyolean-12-ene;
m) structure (bES):
After acid hydrolysis of the above, an isolated, purified or synthesized compound is produced having a structure (ACH) selected from following:
ACH-n3; ACH-n3
The composition comprises bioactive compounds from natural plants or synthesis.
The program is based on the purification methods and biological assays including the MTT assay as described in International Application No. PCT/US05/31900, filed Sep. 7, 2005, U.S. Ser. No. 11/289,142, filed Nov. 28, 2005, and U.S. Ser. No. 11/131,551, filed May 17, 2005, and PCT/US2008/002086, 1188-ALA-PCT, filed Feb. 15, 2008, Ser. No. 12/344,682, 1020-B1-US, filed Dec. 29, 2008, US009499577B2, filed Jun. 24, 2014. The details of Analysis of gene expression of ES2 cells after Y-treatment by Microarray, Data Analysis Methods and Western blot in PCT/US2008/002086, 1188-ALA-PCT, filed Feb. 15, 2008, and the cell invasion experiments methods in International Application PCT/US2010/0042240, filed Jul. 16, 2010.
The Haemolytic Assay
Erythrocytes (RBC) were isolated from human blood (EDTA whole blood, collected randomly). 50 ul of the 10% RBC suspension (in PBS) was added to 2 ml of sample solutions (concentration range from 0.1 ug/ml to 400 ug/ml) in PBS. The mixture was vortexed briefly and sat for 60 min at room temperature. The mixture was spun at 3K for 10 min and the relative amounts of lysed hemoglobin in the supernatant were measured at 540 nm. The synthetic compounds of present application were tested with this method.
Acid Hydrolysis of Saponin
15 mg Xanifolia-Y was dissolved in 1 ml of methanol. 1 ml of 2N HCl was then added. The mixture was refluxed in 80 C water bath for 5 hours. The solution was then neutralized by adding 2 ml of 1N NaOH (to final pH 4-6). The aglycone was then extracted with ethylacetate 3 ml×2. The extracts were collected and pooled. Further isolation of aglycone (ACH-Y) was achieved by HPLC with isocratic elution of 80-100% acetonitrile. Repeating the experiment with compounds Z4, Y10, Y2, Y8, Y7, Y0, X, M10 and ESCIN (bES) gives the following compounds respectively: ACH-Z4, ACH-Y10, ACH-Y2, ACH-Y8, ACH-Y7, ACH-Y0, ACH-X, ACH-E, ACH-Z5, ACH-M10 and ACH-bES.
Removal of the Acyl Group by Alkaline Hydrolysis
20 mg of Xanifolia-Y was dissolved in 0.5 ml of 1N NaOH. The solution was incubated in 80 C water bath for 4 hours. It was cooled to room temperature before being neutralized with 0.5 ml 1N HCl (adjust pH to about 3). The mixture was extracted with 2 ml 1-butanol 3 times. The butanol fractions were collected and lyophilized. The hydrolyzed saponin was further purified with HPLC in a C-18 column eluted with 25% acetonitrile.
Compounds AKOH-Y and AKOH-M10 do not show the ability to inhibit cancer growth, cancer invasion, cells invasion or cancer cell invasion.
Core Compound
A core compound or pentacyclic triterpenes, hydroxylated triterpenes is obtained by acid and alkaline hydroysis of saponin from natural sources. A pentacyclic triterpene can also be obtained by synthetic methods. A method for synthesizing the core compound is as follows:
Beta-Escin, dissolved in 1M NaOH (20 mg/ml) was incubated at 70 C for 5 hours. The hydrolyzed solution was neutralized with HCl and the water was evaporated by lyophilization. The product was dissolved in 50% methanol and 1N HCl. The mixture was incubated at 70 C for 5 hours. The solution was neutralized with NaOH. The hydrolyzed product was extracted with ethylacetate, which was subsequently removed by evaporation. Further purification of the hydrolyzed product of core compounds including (E4A) were archived with FPLC chromatography in a C18 column equilibrated with 70% acetonitrile/TFA at the flow rate of 1 ml/min. The core compound are obtained.
To a solution of compound E4A (2 mmol) in tetrahydrofuran (THF, 10 mL) were added methanesulfonyl chloride (Ms-Cl, 2.2 mmol) and triethylamine (TEA, 3 mmol) at 0° C. and the resulting mixture was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (EtOAc) and washed with water. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in 10 mL of dimethylformamide (DMF), and then sodium azide (NaN3, 6 mmol) was added. After overnight stirring at 60° C., the reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Then, the obtained compound was dissolved in methanol (MeOH), and 10% palladium on carbon (Pd—C, 0.2 mmol) was added. After overnight stirring under hydrogen atmosphere, the reaction mixture was filtered, washed with methanol and concentrated under reduced pressure to provide the desired 24,28-diamine (E4D).
Further, Amination primary and secondary alcohol of core compound E4A to give E4D1
The core compounds do not show the ability to inhibit cancer growth, cancer invasion, or cell adhesion. The structures of core compounds:
also named as bES-core, E IV A, ES4A, E4A or (E4);
wherein R1, R2, R5, R8 represent OH; R3 represents OH, H or absent; R4, R10 represent CH3 or CH2OH; R9, R11, R12, R13, R14, R15 represent CH3;
wherein R1, R2, R5, R8, R17, R18 represent OH or NH2; R3 represents NH2, OH, H or absent; R9, R11, R12, R13, R14, R15 represent CH3.
A typical numbering 1 to 30 of carbon positions of a pentacyclic triterpene.
wherein R1, R2, R5, R8, R17, R18 represent OH; R9, R11, R12, R13, R14, R15 represent CH3, also named E4A or (E).
wherein R1, R2, R3, R4, R5, R8, R9, R10, R11, R12, R13, R14, R15, R16 R17 represent H, OH, CH2OH, COOH, OR CH3, named as (P1), (P2).
This invention provides a method of synthesizing new active compounds. A method of attaching functional groups to the core compounds including but not limited to (A), (B), (C), (D1), (D2), (E), (F), (G), (H1), (H2), (J), E4A, E4A2Y, E6A, (P1), P(2),] involves esterification or methods of present invention of core compounds with acyl halide, wherein the halide including chloride, bromide, fluoride and iodide, wherein the acyl halide comprises acyl chloride, wherein acyl chloride including but not limited to Tigloyl chloride, angeloyl chloride, Acetyl chloride, Crotonoyl chloride, 3,3-Dimethylartyloyl chloride, senecioyl chloride, Cinnamoyl chloride, Pentenoyl chloride, Hexanoyl chloride, benzoyl chloride, Ethylbutyryl chloride, Propionyl chloride, 2-Propenoyl chloride, Isobutyryl chloride, Butyryl chloride, (2E)-2-pentenoyl chloride, 4-Pentenoyl chloride, 5-Hexenoyl chloride, Heptanoyl chloride, Octanoyl chloride, Nonanoyl chloride, Decanoyl chloride, Lauroyl chloride, Myristoyl chloride, Oleoyl chloride for 5 sec, 1 min, 2 min, 5 min, 10 min, 30 min, 1 hr, 2 hr, 18 hr, 2 days or 3 days at 0 C, 25 C or 75 C temperature. At the end of reaction, 5 ml of 2N HCl or 1M NaHCO3 is added to the reaction mixture. The solution is then extracted 3 times with 10 ml of ethyl acetate which is then evaporated under vacuum and at 45 C and lyophilization. The reaction product is dissolved in 80% acetonitrile-0.005% Trifluoroacetic acid. The active esterification products are purified with HPLC. MTT activity was performed to test the activity of acyl chloride, solution after the reaction, individual fractions, and individual compounds. The core compounds are synthetic, semi synthetic or from natural source. The core compounds are including terpene, isoprene, triterpenes, and hydroxylated triterpenes.
MTT activity of acylation of core compounds in different reaction time period of (ASAP) 5 sec, 1 min, 2 min, 5 min, 10 min, 30 min, 1 hr, 2 hrs., 18 hrs., 2 days or 3 days at 0 C, 25 C or 75 C temperature were studied. HPLC profiles of esterification or methods of present application, products of core compound E4A with acyl halide, wherein the halide comprise chloride, bromide, fluoride and iodide, wherein the acyl halide comprise acyl chloride, wherein acyl chloride comprise tigloyl chloride, angeloyl chloride, acetyl chloride, crotonoyl chloride, 3,3-dimethylartyloyl chloride, senecioyl chloride, cinnamoyl chloride, pentenoyl chloride, hexanoyl chloride, benzoyl chloride, ethylbutyryl chloride, propionyl chloride, 2-propenoyl chloride, isobutyryl chloride, butyryl chloride, (2E) pentenoyl chloride, 4-Pentenoyl chloride, 5-hexenoyl chloride, heptanoyl chloride, octanoyl chloride, nonanoyl chloride, decanoyl chloride, Lauroyl chloride, myristoyl chloride, oleoyl chloride show that the compounds vary in composition when the time or temperature of the reaction is changed.
The peaks, fractions and compounds are selected according to the activities of times studies and the changes of peaks. Selecting the HPLC fractions for isolation is according to the cytotoxic activity of the reaction product obtained at a specific time. The compounds having strong to weak activities are selected and isolated. Selecting the HPLC fractions for isolation may be according to the cytotoxic activity of times studies and the change of peaks. The anti cancer activities are the MTT studies of bone (U2OS), lung (H460), bladder (HTB-9), ovary (ES2), colon (HCT116), pancreas (Capan), ovary (OVCAR3), prostate (DU145), skin (SK-Mel-5), mouth (KB), kidney (A498), breast (MCF-7), liver (HepG2), brain (T98G), luekemia (K562), cervix (HeLa).
Amidation of core compound E4D or E4D1 with Tigloyl or Tigloyl chloride and isolation of the compounds with HPLC give the following compounds: wherein Tig=Tigloyl
Amidation of core compound E4D or E4D1 with Angeloyl or Angeloyl chloride and isolation of the compounds with HPLC give the following compounds: wherein Ang=Angeloyl
Amidation of core compound E4D or E4D1 with senecioyl or senecioyl chloride and isolation of the compounds with HPLC give the following compounds:
Wherein Sen=senecioyl
Amidation of core compound E4D, or E4D1 with Pentenoyl or 4-Pentenoyl chloride and isolation of the compounds with HPLC give the following compounds: wherein Pen=4-Pentenoyl
Amidation of core compound E4D, or E4D1 with Hexanoyl or Hexanoyl chloride and isolation of the compounds with HPLC give the following compounds: wherein Hex=Hexanoyl
Amidation of core compound E4D or E4D1 with2-Ethylbutyryl or 2-Ethylbutyryl chloride and isolation of the compounds with HPLC give the following compounds: wherein Eth=2-Ethylbutyryl
Amidation of core compound E4D or E4D1 with Acetyl chloride (H) and isolation of the compounds with HPLC give the following compounds: wherein Acy=Acetyl
Amidation of core compound E4D or E4D1 with Crotonoyl or Crotonoyl chloride and isolation of the compounds with HPLC give the following compounds: wherein Cro=Crotonoyl
Amidation of core compound E4D or E4D1 with Cinnamoyl or Cinnamoyl chloride and isolation of the compounds with HPLC give the following compounds: wherein Cin=Cinnamoyl
Amidation of core compound E4D or E4D1 with benzoyl or benzoyl chloride and isolation of the compounds with HPLC give the following compounds: wherein Ben=benzoyl
Amidation of core compound E4D OR E4D1 with Propionyl or Propionyl chloride and isolation of the compounds with HPLC give the following compounds: wherein Ppi=Propionyl
Amidation of core compound E4D OR E4D1 with 2-propenoyl or 2-propenoyl chloride and isolation of the compounds with HPLC give the following compounds: wherein Ppe=Propenoyl
Amidation of core compound E4D or E4D1 with Isobutyryl or Isobutyryl chloride and isolation of the compounds with HPLC give the following compounds: wherein Iso=Isobutyryl
Amidation of core compound E4D or E4D1 with Butyryl or Butyryl chloride and isolation of the compounds with HPLC give the following compounds: wherein But=Butyryl
Amidation of core compound E4D or E4D1 with(2E)-2-pentenoyl or (2E)-2-pentenoyl chloride and isolation of the compounds with HPLC give the following compounds: wherein 2pe=2-pentenoyl
Amidation of core compound E4D of E4D1 with Octanoyl or Octanoyl chloride and isolation of the compounds with HPLC give the following compounds: wherein Oct=Octanoyl
Amidation of core compound E4D or E4D1 with Decanoyl or Decanoyl chloride and isolation of the compounds with HPLC give the following compounds: wherein Dec=Decanoyl
Amidation of core compound E4D or E4D1 with Myristoyl or Myristoyl chloride and isolation of the compounds with HPLC give the following compounds: wherein Myr=Myristoyl
Esterification, amidation, amination, or sulfonamidation of compound (A), (B), (C), (D1), (D2), (E), (F), (G), (H1), (H2), E4A, E4A2Y, E4D, E4D1, (P1), P(2), terpene, isoprene, triterpenes, hydroxylated triterpenes, with acyl halide, wherein the halide comprise chloride, bromide, fluoride and iodide, wherein the acyl halide comprise acyl chloride, wherein acyl chloride comprise tigloyl chloride, angeloyl chloride, acetyl chloride, crotonoyl chloride, 3,3-dimethylartyloyl chloride, senecioyl chloride, cinnamoyl chloride, pentenoyl chloride, hexanoyl chloride, benzoyl chloride, ethylbutyryl chloride, propionyl chloride, 2-propenoyl chloride, isobutyryl chloride, butyryl chloride, (2E)-2-pentenoyl chloride, 4-Pentenoyl chloride, 5-hexenoyl chloride, heptanoyl chloride, octanoyl chloride, nonanoyl chloride, decanoyl chloride, Lauroyl chloride, myristoyl chloride, oleoyl chloride. The compounds vary in composition when the time or temperature of the reaction is changed. The peaks, fractions and compounds are selected according to the activities of times studies and the changes of peaks. The compounds having strong to weak activities are selected and isolated. The anti cancer activities (Cytotoxic Assay) are the MTT studies of bone (U2OS), lung (H460), bladder (HTB-9), ovary (ES2), colon (HCT116), pancreas (Capan), ovary (OVCAR3), prostate (DU145), skin (SK-Mel-5), mouth (KB), kidney (A498), breast (MCF-7), liver (HepG2), brain (T98G), luekemia (K562), cervix (HeLa). The active esterification, amidation, amination, or sulfonamidation products are purified with HPLC. The reaction product of mixtures and individual compounds are tested with MTT Cytotoxic Assay. Details of method are in Experiment 3 of the present application. A second esterification of compound can be selected from the above experiment results to produce new active compounds. A partial esterification compound is selected from the above experiments to perform a second or repeated with a third esterification with different acyl chloride in order to produce new active compounds with the experiments in the present application. The active compounds of this invention are triterpenes in form of amine, sulfonamides, amide, and urea analogs, providing extremely stable activity in solution. They prolong the activities and duration of drug in a subject.
A method is 1) Dissolving core compound or triterpenes core, hydroxylated triterpenes core, in pyridine; 2) Adding acyl halide or acyl chloride; 3, The mixture is stirred for length of time including 5 sec, 10 sec, 20 sec, 30 sec, 40 sec, 1 min, 2 min, 5 min, 10 min, 30 min, 1 hr, 2 hr, 18 hr, 2 days or 3 days at different temperature; 4) At the end of reaction, aqueous solution of acid or weak base, or water is added to the reaction mixture; 5) The solution is then extracted of ethyl acetate and ethyl acetate is removed by evaporation and lyophilization; 6) Dissolving the reaction product in acetonitrile with Trifluoroacetic acid or DMSO; 7) Testing the reaction product of mixtures and individual fractions with MTT cytotoxic assay; 8) Selecting the HPLC fractions for isolation is according to the cytotoxic activity of the reaction product obtained at a specific reaction time; 10) Purifiing the active esterification products with HPLC; 11) Collecting the products; 12) Testing the products; wherein the core compound is terpene, isoprene, or triterpene core or hydroxylated triterpenes core; wherein the core compound was dissolved in pyridine; wherein the acyl chloride including Tigloyl chloride, angeloyl chloride, Acetyl chloride, Crotonoyl chloride, 3,3-Dimethylartyloyl chloride, senecioyl chloride, Cinnamoyl chloride, Pentenoyl chloride, Hexanoyl chloride, benzoyl chloride, Ethylbutyryl chloride, Propionyl chloride, 2-Propenoyl chloride, Isobutyryl chloride, Butyryl chloride, (2E)-2-pentenoyl chloride, 4-Pentenoyl chloride, 5-Hexenoyl chloride, Heptanoyl chloride, Octanoyl chloride, Nonanoyl chloride, Decanoyl chloride, Lauroyl chloride, Myristoyl chloride, and Oleoyl chloride; wherein the reaction time for the mixture is stirred for 5 sec, 10 sec, 20 sec, 30 sec, 40 sec, 1 min, 2 min, 5 min, 10 min, 30 min, 1 hr, 2 hrs., 18 hrs., 2 days or 3 days; wherein the temperature is 0 C, 25 C, 50 C or 75 C temperature; wherein the acid including HCl or the base including NaHCO3 is added to the reaction mixture; wherein the solution is then extracted 3 times with ethyl acetate and lyophilization; wherein the reaction product is dissolved in 80% acetonitrile-0.005% Trifluoroacetic acid or DMSO; wherein selecting the HPLC fractions for isolation is according to the cytotoxic activity of the reaction product obtained at a reaction time of 5 sec, 10 sec, 20 sec, 30 sec, 40 sec, 1 min, 2 min, 5 min, 10 min, 30 min, 1 hr, 2 hr, 18 hr, 2 days or 3 days. In an embodiment, the reaction time may be over 3 days. In an embodiment, the experiment may be performed under 0 C. In an embodiment, the experiment may be performed over 75 C.
The anti-cancer activities of Tig-R compound: IC50 of bone (U2OS) is 4.5 ug/ml, lung (H460) is 4.8 ug/ml, bladder (HTB-9) is 2.5 ug/ml, ovary (ES2) is 2.8 ug/ml, colon (HCT116) is 5.2 ug/ml, pancreas (Capan) 2.4 ug/ml, ovary (OVCAR3) is 5.8, prostate (DU145) is 3.6 ug/ml, skin (SK-Mel-5) is 5.1 ug/ml, mouth (KB) is 3 ug/ml, kidney (A498) is 3.5 ug/ml, breast (MCF-7) is 4.5 ug/ml, liver (HepG2) is 6 ug/ml, brain (T98G) is 8 ug/ml), leukemia (K562) is 2 ug/ml, cervix (HeLa) is 5 ug/ml.
The anti-cancer activities of Tig-V compound: IC50 of bone (U2OS) is 7 ug/ml, lung (H460) is 6.8 ug/ml, bladder (HTB-9) is 4 ug/ml, ovary (ES2) is 2 ug/ml, colon (HCT116) is 8 ug/ml, pancreas (Capan) 5 ug/ml, ovary (OVCAR3) is 9, prostate (DU145) is 4 ug/ml, skin (SK-Mel-5) is 6 ug/ml, mouth (KB) is 4.5 ug/ml, kidney (A498) is 4.8 ug/ml, breast (MCF-7) is 9 ug/ml, liver (HepG2) is 12 ug/ml, brain (T98G) is 14 ug/ml), leukemia (K562) is 4 ug/ml, cervix (HeLa) is 7 ug/ml.
The anti-cancer activities of Tig-N compound: IC50 of bone (U2OS) is 15 ug/ml, lung (H460) is 13 ug/ml, bladder (HTB-9) is 7.5 ug/ml, ovary (ES2) is 9 ug/ml, colon (HCT116) is 15 ug/ml, pancreas (Capan) 8 ug/ml, ovary (OVCAR3) is 18, prostate (DU145) is 4.8 ug/ml, skin (SK-Mel-5) is 15 ug/ml, mouth (KB) is 9 ug/ml, kidney (A498) is 11 ug/ml, breast (MCF-7) is 13 ug/ml, liver (HepG2) is 18 ug/ml, brain (T98G) is 19 ug/ml), leukemia (K562) is 6 ug/ml, cervix (HeLa) is 15 ug/ml.
The anti-cancer activities of Tig-Q compound: IC50 of bone (U2OS) is 20 ug/ml, lung (H460) is 18 ug/ml, bladder (HTB-9) is 10 ug/ml, ovary (ES2) is 12 ug/ml, colon (HCT116) is 22 ug/ml, pancreas (Capan) 9 ug/ml, ovary (OVCAR3) is 23, prostate (DU145) is 15 ug/ml, skin (SK-Mel-5) is 20 ug/ml, mouth (KB) is 12 ug/ml, kidney (A498) is 13 ug/ml, breast (MCF-7) is 18 ug/ml, liver (HepG2) is 24 ug/ml, brain (T98G) is 29 ug/ml), leukemia (K562) is 6 ug/ml, cervix (HeLa) is 20 ug/ml.
The anti-cancer activities of Tig-T compound: IC50 of bone (U2OS) is 20 ug/ml, lung (H460) is 21 ug/ml, bladder (HTB-9) is 12 ug/ml, ovary (ES2) is 14 ug/ml, colon (HCT116) is 23 ug/ml, pancreas (Capan) 10 ug/ml, ovary (OVCAR3) is 25, prostate (DU145) is 16 ug/ml, skin (SK-Mel-5) is 22 ug/ml, mouth (KB) is 13 ug/ml, kidney (A498) is 15 ug/ml, breast (MCF-7) is 20 ug/ml, liver (HepG2) is 26 ug/ml, brain (T98G) is 26 ug/ml), leukemia (K562) is 9 ug/ml, cervix (HeLa) is 18 ug/ml.
The anti-cancer activities of Tig-S compound: IC50 of bone (U2OS) is 5.2 ug/ml, lung (H460) is 5.6 ug/ml, bladder (HTB-9) is 3.5 ug/ml, ovary (ES2) is 0.1 ug/ml, colon (HCT116) is 6.6 ug/ml, pancreas (Capan) 2.9 ug/ml, ovary (OVCAR3) is 6.5, prostate (DU145) is 4.3 ug/ml, skin (SK-Mel-5) is 5.8 ug/ml, mouth (KB) is 4 ug/ml, kidney (A498) is 4.8 ug/ml, breast (MCF-7) is 6.3 ug/ml, liver (HepG2) is 8.5 ug/ml, brain (T98G) is 9 ug/ml), leukemia (K562) is 4.3 ug/ml, cervix (HeLa) is 7 ug/ml.
The anti-cancer activities of Tig-U compound: IC50 of bone (U2OS) is 23 ug/ml, lung (H460) is 19 ug/ml, bladder (HTB-9) is 15 ug/ml, ovary (ES2) is 17 ug/ml, colon (HCT116) is 26 ug/ml, pancreas (Capan) 9 ug/ml, ovary (OVCAR3) is 27, prostate (DU145) is 15 ug/ml, skin (SK-Mel-5) is 24 ug/ml, mouth (KB) is 16 ug/ml, kidney (A498) is 18 ug/ml, breast (MCF-7) is 25 ug/ml, liver (HepG2) is 23 ug/ml, brain (T98G) is 22 ug/ml), leukemia (K562) is 10 ug/ml, cervix (HeLa) is 17 ug/ml.
The IC50 of Tig-R in normal human fibroblast cells (WI38) is about 10-15 ug/ml. This IC50 value is 3 times higher than those in ovary ES2 (2.8 ug/ml) and lung (H460) is 4.8 ug/ml.
Swiss3T3 cells are mouse normal fibroblast which were used in this experiment to compare with ES2 (human ovarian cancer) in Tig-R cytotoxicity determination. The preliminary results indicate that the IC50 of Tig-R in SW3T3 cells is above 20 ug/ml while the corresponding IC50 in ES2 cells is about 2.8 ug/ml.
This invention provides compounds, methods, or uses of a compound for the manufacture of a medicament, or uses of a compound for medicament selected from formula (2A), K, 3K, 3K2, T1, T2, T3, T4, T5, T6, T7, T8, T9,T10, T11, T12, T13, T14, T15, T16, T17, T18, T19, T20, T21, T22, T23, T24, T25, T26, T27 for treating cancers, inhibition of cancer growth, cancer invasion, cells invasion, cancer cell invasion; cell adhesion, cell attachment, cell circulating; for treating mad cow disease; treating prion diseases; for inhibiting viruses; for preventing cerebral aging; for improving memory; improving cerebral functions; for curing enuresis, frequent micturition, urinary incontinence; dementia, Alzheimer's disease, autism, brain trauma, Parkinson's disease or other diseases caused by cerebral dysfunctions or neurodegeneration; for treating arthritis, rheumatism, poor blood circulation, arteriosclerosis, Raynaud's syndrome, angina pectoris, cardiac disorder, coronary heart disease, headache, dizziness, kidney disorder; cerebrovascular diseases; inhibiting NF-kappa B activation; for treating brain edema, severe acute respiratory syndrome, respiratory viral diseases, chronic venous insufficiency, hypertension, chronic venous disease, oedema, inflammation, hemorrhoids, peripheral edema formation, varicose vein disease, flu, post traumatic edema and postoperative swelling; for inhibiting blood clots, for inhibiting ethanol absorption; for lowering blood sugar; for regulating adrenocorticotropin and corticosterone levels; for Anti-MS, anti-aneurysm, anti-asthmatic, anti-oedematous, anti-inflammatory, anti-bradykinic, anti-capillarihemorrhagic, anti-cephalagic, anti-cervicobrachialgic, anti-eclamptic, anti-edemic, anti-encaphalitic, anti-epiglottitic, anti-exudative, anti-flu, anti-fracture, anti-gingivitic, anti-hematomic, anti-herpetic, anti-histaminic, anti-hydrathritic, anti-meningitic, antioxidant, anti-periodontic, anti-phlebitic, anti-pleuritic, anti-raucedo, anti-rhinitic, anti-tonsilitic, anti-ulcer, anti-varicose, anti-vertiginous, cancerostatic, corticosterogenic, diuretic, fungicide, hemolytic, hyaluronidase inhibitor, lymphagogue, natriuretic, pesticide, pituitary stimulant, thymolytic, vasoprotective, inhibiting leishmaniases, modulating adhesion or angiogenesis of cells, anti-parasitic; for improving blood circulation; soothing stroke; preventing plaque formation and promote their dissipated; improve blood viscosity; reducing cardiovascular; reducing cerebrovascular; reducing thrombosis, arteriosclerosis, coronary heart disease, hypertension, diabetes, thrombocytopenia purpura, hemoptysis, hematemesis; treating blood in the stool, uterine bleeding, traumatic bleeding, abdominal irritation, swelling, fluttering, Blood circulation, swelling, pain; treating bronchiectasis, tuberculosis and lung abscess caused by too hemoptysis; reducing bleeding; antitussive; reducing expectorant; reducing analgesic effect; dilate blood vessels; reducing blood pressure; treatment of cerebral arteriosclerosis; elevating blood lipids; reducing cholesterol; manufacturing an adjuvant composition for treatment.
In an embodiment, the cancers comprise breast cancer, leukocytic cancer, liver cancer, ovarian cancer, bladder cancer, prostatic cancer, skin cancer, bone cancer, brain cancer, leukemia cancer, lung cancer, colon cancer, CNS cancer, melanoma cancer, renal cancer, cervical cancer, esophageal cancer, testicular cancer, splenic cancer, kidney cancer, lymphatic cancer, pancreatic cancer, stomach cancer, eye cancer and thyroid cancer; wherein the cells comprise breast cell, leukocytic cell, liver cell, ovarian cell, bladder cell, prostatic cell, skin cell, bone cell, brain cell, leukemia cell, lung cell, colon cell, CNS cell, melanoma cell, renal cell, cervical cell, esophageal cell, testicular cell, splenic cell, kidney cell, lymphatic cell, pancreatic cell, stomach cell and thyroid cell.
In an embodiment, the compound is selected from the structure:
With the experiments in present application, the compound is selected from the structures:
R1, R2, R3, R4, R5, R8, R9, R10, R11, R12, R13, R14, R15, R16 are independently selected from the group of H, O, OH, NH2, CH2NH2, NH-angeloyl, CH2NH-angeloyl, CH2NHCO-angeloyl, CH2NHCONH-angeloyl, CH2NHSO2-angeloyl, CH3, CH2OH, COOH, hydrogen, hydroxyl, methyl, O-angeloyl, O-tigloyl, O-senecioyl, O-acetyl, O-Crotonoyl, O-3,3-Dimethylartyloyl, O-Cinnamoyl, O-Pentenoyl, O-Hexanoyl, O-benzoyl, O-Ethylbutyryl, O-alkyl, O-dibenzoyl, O-benzoyl, O-alkanoyl, O-alkenoyl, O-benzoyl alkyl substituted O-alkanoyl, O-alkanoyl substituted phenyl, O-alkenoyl substituted phenyl, O-aryl, O-acyl, O-heterocylic, O-heteroraryl, O-alkenylcarbonyl, O-alkane, O-alkene, O-sugar moiety, O-acid moiety, O-ethanoyl, O-propanoyl, O-propenoyl, O-butanoyl, O-butenoyl, O-pentanoyl, O-hexenoyl, O-heptanoyl, O-heptenoyl, O-octanoyl, O-octenoyl, O-nonanoyl, O-nonenoyl, O-decanoyl, O-decenoyl, O-propionyl, O-2-propenoyl, O-2-butenoyl, -Isobutyryl, O-2-methylpropanoyl, O-2-ethylbutyryl, O-ethylbutanoyl, O-2-ethylbutanoyl, O-butyryl, O-(E)-2,3-Dimethylacryloyl, O-(E)-2-Methylcrotonoyl, O-3-cis-Methyl-methacryloyl, O-3-Methyl-2-butenoyl, O-3-Methylcrotonoyl, O-4-Pentenoyl, O-(2E)-2-pentenoyl, O-Caproyl, O-5-Hexenoyl, O-Capryloyl, O-Lauroyl, O-Dodecanoyl, O-Myristoyl, O-Tetradecanoyl, O-Oleoyl, O—C(2-18) Acyl, COO-angeloyl, COO-tigloyl, COO-senecioyl, COO-acetyl, COO-Crotonoyl, COO-3,3-Dimethylartyloyl, COO-Cinnamoyl, COO-Pentenoyl, COO-Hexanoyl, COO-benzoyl, COO-Ethylbutyryl, COO-alkyl, COO-dibenzoyl, COO-benzoyl, COO-alkanoyl, CH2O-alkenoyl, COO-benzoyl alkyl substituted O-alkanoyl, COO-alkanoyl substituted phenyl, COO-alkenoyl substituted phenyl, COO-aryl, COO-acyl, COO-heterocylic, COO-heteroraryl, COO-alkenylcarbonyl, COO-alkane, COO-alkene, COO-sugar moiety, COO-acid moiety, COO-ethanoyl, COO-propanoyl, COO-propenoyl, COO-butanoyl, COO-butenoyl, COO-pentanoyl, COO-hexenoyl, COO-heptanoyl, COO-heptenoyl, COO-octanoyl, COO-octenoyl, COO-nonanoyl, COO-nonenoyl, COO-decanoyl, COO-decenoyl, COO-propionyl, COO-2-propenoyl, COO-2-butenoyl, COO-Isobutyryl, COO-2-methylpropanoyl, COO-2-ethylbutyryl, COO-ethylbutanoyl, COO-2-ethylbutanoyl, COO-butyryl, COO-(E)-2,3-Dimethylacryloyl, COO-(E)-2-Methylcrotonoyl, COO-3-cis-Methyl-methacryloyl, COO-3-Methyl-2-butenoyl, COO-3-Methylcrotonoyl, COO-4-Pentenoyl, COO-(2E)-2-pentenoyl, COO-Caproyl, COO-5-Hexenoyl, COO-Capryloyl, COO-Lauroyl, COO-Dodecanoyl, COO-Myristoyl, COO-Tetradecanoyl, COO-Oleoyl, COO—C(2-18) Acyl, CH2O-angeloyl, CH2O-tigloyl, CH2O-senecioyl, CH2O-acetyl, CH2O-Crotonoyl, CH2O-3,3-Dimethylartyloyl, CH2O-Cinnamoyl, CH2O-Pentenoyl, CH2O-Hexanoyl, CH2O-benzoyl, CH2O-Ethylbutyryl, CH2O-alkyl, CH2O-dibenzoyl, CH2O-benzoyl, CH2O-alkanoyl, CH2O-alkenoyl, CH2O-benzoyl alkyl substituted O-alkanoyl, CH2O-alkanoyl substituted phenyl, CH2O-alkenoyl substituted phenyl, CH2O-aryl, CH2O-acyl, CH2O-heterocylic, CH2O-heteroraryl, CH2O-alkenylcarbonyl, CH2O-alkane, CH2O-alkene and CH2O-sugar moiety, CH2O-angeloyl, CH2O-tigloyl, CH2O-senecioyl, CH2O-acetyl, CH2O-Crotonoyl, CH2O-3,3-Dimethylartyloyl, CH2O-Cinnamoyl, CH2O-Pentenoyl, CH2O-Hexanoyl, CH2O-benzoyl, CH2O-Ethylbutyryl, CH3, CH2OH, CH2O-alkyl, CH2O-dibenzoyl, CH2O-benzoyl, CH2O-alkanoyl, CH2O-alkenoyl, CH2O-benzoyl alkyl substituted O-alkanoyl, CH2O-alkanoyl substituted phenyl, CH2O-alkenoyl substituted phenyl, CH2O-aryl, CH2O-acyl, CH2O-heterocylic, CH2O-heteroraryl, CH2O-alkenylcarbonyl, CH2O-ethanoyl, CH2O-propanoyl, CH2O-propenoyl, CH2O-butanoyl, CH2O-butenoyl, CH2O-pentanoyl, CH2O-hexenoyl, CH2O-heptanoyl, CH2O-heptenoyl, CH2O-octanoyl, CH2O-octenoyl, CH2O-nonanoyl, CH2O-nonenoyl, CH2O-decanoyl, CH2O-decenoyl, CH2O-propionyl, CH2O-2-propenoyl, CH2O-2-butenoyl, CH2O-Isobutyryl, CH2O-2-methylpropanoyl, CH2O-2-ethylbutyryl, CH2O-ethylbutanoyl, CH2O-2-ethylbutanoyl, CH2O-butyryl, CH2O-(E)-2,3-Dimethylacryloyl, CH2O-(E)-2-Methylcrotonoyl, CH2O-3-cis-Methyl-methacryloyl, CH2O-3-Methyl-2-butenoyl, CH2O-3-Methylcrotonoyl, CH2O-4-Pentenoyl, CH2O-(2E)-2-pentenoyl, CH2O-Caproyl, CH2O-5-Hexenoyl, CH2O-Capryloyl, CH2O-Lauroyl, CH2O-Dodecanoyl, CH2O-Myristoyl, CH2O-Tetradecanoyl, CH2O-Oleoyl, CH2O—C(2-18) Acyl, (CnH2n)O-angeloyl, (CnH2n)O-tigloyl, (CnH2n)O-senecioyl, (CnH2n)O-acetyl, (CnH2n)O-Crotonoyl, (CnH2n)O-3,3-Dimethylartyloyl, (CnH2n)O-Cinnamoyl, (CnH2n)O-Pentenoyl, (CnH2n)O-Hexanoyl, (CnH2n)O-benzoyl, (CnH2n)O-Ethylbutyryl, (CnH2n)O-alkyl, (CnH2n)O-dibenzoyl, (CnH2n)O-benzoyl, (CnH2n)O-alkanoyl, (CnH2n)O-alkenoyl, (CnH2n)O-benzoyl alkyl substituted O-alkanoyl, (CnH2n)O-alkanoyl substituted phenyl, (CnH2n)O-alkenoyl substituted phenyl, (CnH2n)O-aryl, (CnH2n)O-acyl, (CnH2n)O-heterocylic, (CnH2n)O-heteroraryl, (CnH2n)O-alkenylcarbonyl, (CnH2n)O-alkane, (CnH2n)O-alkene and (CnH2n)O-sugar moiety and (CnH2n)O-acid moiety, wherein n is 1 or 2 or 3 or 4 or over 5 or derivatives thereof; wherein the sugar moiety(ies) is/are selected from a group of glucose, galactose, rhamnose, arabinose, xylose, fucose, allose, altrose, gulose, idose, lyxose, mannose, psicose, ribose, sorbose, tagatose, talose, fructose, alduronic acid, glucuronic acid, galacturonic acid, and derivatives or combinations thereof; or wherein any 1 or 2 or 3 or 4 of R1, R2, R3, R4, R5, R8, R16 and R10 are independently attached an O-angeloyl, O-tigloyl, O-senecioyl, O-acetyl, O-Crotonoyl, O-3,3-Dimethylartyloyl, O-Cinnamoyl, O-Pentenoyl, O-Hexanoyl, O-benzoyl, O-Ethylbutyryl, O-alkyl, O-dibenzoyl, O-benzoyl, O-alkanoyl, O-alkenoyl, O-benzoyl alkyl substituted O-alkanoyl, O-alkanoyl substituted phenyl, O-alkenoyl substituted phenyl, O-aryl, O-acyl, O-heterocylic, O-heteroraryl, O-alkenylcarbonyl, O-ethanoyl, O-propanoyl, O-propenoyl, O-butanoyl, O-butenoyl, O-pentanoyl, O-hexenoyl, O-heptanoyl, O-heptenoyl, O-octanoyl, O-octenoyl, O-nonanoyl, O-nonenoyl, O-decanoyl, O-decenoyl, O-propionyl, O-2-propenoyl, O-2-butenoyl, O-Isobutyryl, O-2-methylpropanoyl, O-2-ethylbutyryl, O-ethylbutanoyl, O-2-ethylbutanoyl, O-butyryl, O-(E)-2,3-Dimethylacryloyl, O-(E)-2-Methylcrotonoyl, O-3-cis-Methyl-methacryloyl, O-3-Methyl-2-butenoyl, O-3-Methylcrotonoyl, O-4-Pentenoyl, O-(2E)-2-pentenoyl, O-Caproyl, O-5-Hexenoyl, O-Capryloyl, O-Lauroyl, O-Dodecanoyl, O-Myristoyl, O-Tetradecanoyl, O-Oleoyl, O—C(2-18) Acyl, CH2O-angeloyl, CH2O-tigloyl, CH2O-senecioyl, CH2O-acetyl, CH2O-Crotonoyl, CH2O-3,3-Dimethylartyloyl, CH2O-Cinnamoyl, CH2O-Pentenoyl, CH2O-Hexanoyl, CH2O-benzoyl, CH2O-Ethylbutyryl, CH3, CH2OH, CH2O-alkyl, CH2O-dibenzoyl, CH2O-benzoyl, CH2O-alkanoyl, CH2O-alkenoyl, CH2O-benzoyl alkyl substituted O-alkanoyl, CH2O-alkanoyl substituted phenyl, CH2O-alkenoyl substituted phenyl, CH2O-aryl, CH2O-acyl, CH2O-heterocylic, CH2O-heteroraryl, CH2O-alkenylcarbonyl, CH2O-ethanoyl, CH2O-propanoyl, CH2O-propenoyl, CH2O-butanoyl, CH2O-butenoyl, CH2O-pentanoyl, CH2O-hexenoyl, CH2O-heptanoyl, CH2O-heptenoyl, CH2O-octanoyl, CH2O-octenoyl, CH2O-nonanoyl, CH2O-nonenoyl, CH2O-decanoyl, CH2O-decenoyl, CH2O-propionyl, CH2O-2-propenoyl, CH2O-2-butenoyl, CH2O-Isobutyryl, CH2O-2-methylpropanoyl, CH2O-2-ethylbutyryl, CH2O-ethylbutanoyl, CH2O-2-ethylbutanoyl, CH2O-butyryl, CH2O-(E)-2,3-Dimethylacryloyl, CH2O-(E)-2-Methylcrotonoyl, CH2O-3-cis-Methyl-methacryloyl, CH2O-3-Methyl-2-butenoyl, CH2O-3-Methylcrotonoyl, CH2O-4-Pentenoyl, CH2O-(2E)-2-pentenoyl, CH2O-Caproyl, CH2O-5-Hexenoyl, CH2O-Capryloyl, CH2O-Lauroyl, CH2O-Dodecanoyl, CH2O-Myristoyl, CH2O-Tetradecanoyl, CH2O-Oleoyl, CH2O—C(2-18) Acyl;
NH-tigloyl, NH-senecioyl, NH-acetyl, NH-Crotonoyl, NH-3,3-Dimethylartyloyl, NH-Cinnamoyl, NH-Pentenoyl, NH-Hexanoyl, NH-benzoyl, NH-Ethylbutyryl, NH-alkyl, NH-dibenzoyl, NH-benzoyl, NH-alkanoyl, NH-alkenoyl, NH-benzoyl alkyl substituted NH-alkanoyl, NH-alkanoyl substituted phenyl, NH-alkenoyl substituted phenyl, NH-aryl, NH-acyl, NH-heterocylic, NH-heteroraryl, NH-alkenylcarbonyl, NH-alkane, NH-alkene, NH-sugar moiety, NH-acid moiety, NH-ethanoyl, NH-propanoyl, NH-propenoyl, NH-butanoyl, NH-butenoyl, NH-pentanoyl, NH-hexenoyl, NH-heptanoyl, NH-heptenoyl, NH-octanoyl, H-octenoyl, NH-nonanoyl, NH-nonenoyl, NH-decanoyl, NH-decenoyl, NH-propionyl, NH-2-propenoyl, NH-2-butenoyl, NH-Isobutyryl, NH-2-methylpropanoyl, NH-2-ethylbutyryl, NH-ethylbutanoyl, NH-2-ethylbutanoyl, NH-butyryl, NH-(E)-2,3-Dimethylacryloyl, NH-(E)-2-Methylcrotonoyl, NH-3-cis-Methyl-methacryloyl, NH-3-Methyl-2-butenoyl, NH-3-Methylcrotonoyl, NH-4-Pentenoyl, NH-(2E)-2-pentenoyl, NH-Caproyl, NH-5-Hexenoyl, NH-Capryloyl, NH-Lauroyl, NH-Dodecanoyl, NH-Myristoyl, NH-Tetradecanoyl, NH-Oleoyl, NH—C(2-18) Acyl, NH-ethanyl, NH-propanyl, NH-propenyl, NH-butanyl, NH-butenyl, NH-pentanyl, NH-hexenyl, NH-heptanyl, NH-heptenyl, NH-octanyl, NH-octenyl, NH-nonanyl, NH-nonenyl, NH-decanyl, NH-decenyl, NH-alkyl, NH-haloalkyl, NH-alkenyl, NH-alkynyl, NH-hydroxyalkyl, NH-alkylene-O-alkyl, NH-aryl, NH-alkylene-aryl, NH-heteroaryl, NH-alkylene-heteroaryl, NH-cycloalkyl, NH-heterocyclyl, and NH-alkylene-heterocyclyl,
CH2NH-tigloyl, CH2NH-senecioyl, CH2NH-acetyl, CH2NH-Crotonoyl, CH2NH-3,3-Dimethylartyloyl, CH2NH-Cinnamoyl, CH2NH-Pentenoyl, CH2NH-Hexanoyl, CH2NH-benzoyl, CH2NH-Ethylbutyryl, CH2NH-alkyl, CH2NH-dibenzoyl, CH2NH-benzoyl, CH2NH-alkanoyl, CH2NH-alkenoyl, CH2NH-benzoyl alkyl substituted CH2NH-alkanoyl, CH2NH-alkanoyl substituted phenyl, CH2NH-alkenoyl substituted phenyl, CH2NH-aryl, CH2NH-acyl, CH2NH-heterocylic, CH2NH-heteroraryl, CH2NH-alkenylcarbonyl, CH2NH-alkane, CH2NH-alkene, CH2NH-sugar moiety, CH2NH-acid moiety, CH2NH-ethanoyl, CH2NH-propanoyl, CH2NH-propenoyl, CH2NH-butanoyl, CH2NH-butenoyl, CH2NH-pentanoyl, CH2NH-hexenoyl, CH2NH-heptanoyl, CH2NH-heptenoyl, CH2NH-octanoyl, CH2NH-octenoyl, CH2NH-nonanoyl, CH2NH-nonenoyl, CH2NH-decanoyl, CH2NH-decenoyl, CH2NH-propionyl, CH2NH-2-propenoyl, CH2NH-2-butenoyl, CH2NH-Isobutyryl, CH2NH-2-methylpropanoyl, CH2NH-2-ethylbutyryl, CH2NH-ethylbutanoyl, CH2NH-2-ethylbutanoyl, CH2NH-butyryl, CH2NH-(E)-2,3-Dimethylacryloyl, CH2NH-(E)-2-Methylcrotonoyl, CH2NH-3-cis-Methyl-methacryloyl, CH2NH-3-Methyl-2-butenoyl, CH2NH-3-Methylcrotonoyl, CH2NH-4-Pentenoyl, CH2NH-(2E)-2-pentenoyl, CH2NH-Caproyl, CH2NH-5-Hexenoyl, CH2NH-Capryloyl, CH2NH-Lauroyl, CH2NH-Dodecanoyl, CH2NH-Myristoyl, CH2NH-Tetradecanoyl, CH2NH-Oleoyl, CH2NH—C(2-18) Acyl, CH2NH-ethanyl, CH2NH-propanyl, CH2NH-propenyl, CH2NH-butanyl, CH2NH-butenyl, CH2NH-pentanyl, CH2NH-hexenyl, CH2NH-heptanyl, CH2NH-heptenyl, CH2NH-octanyl, CH2NH-octenyl, CH2NH-nonanyl, CH2NH-nonenyl, CH2NH-decanyl, CH2NH-decenyl, CH2NH-alkyl, CH2NH-haloalkyl, CH2NH-alkenyl, CH2NH-alkynyl, CH2NH-hydroxyalkyl, CH2NH-alkylene-O-alkyl, CH2NH-aryl, CH2NH-alkylene-aryl, CH2NH-heteroaryl, CH2NH-alkylene-heteroaryl, CH2NH-cycloalkyl, CH2NH-heterocyclyl, and CH2NH-alkylene-heterocyclyl, CH2NHCH2-tigloyl, CH2NHCH2-angeloyl, CH2NHCH2-senecioyl, CH2NHCH2-acetyl, CH2NHCH2-Crotonoyl, CH2NHCH2-3,3-Dimethylartyloyl, CH2NHCH2-Cinnamoyl, CH2NHCH2-Pentenoyl, CH2NHCH2-Hexanoyl, CH2NHCH2-benzoyl, CH2NHCH2-Ethylbutyryl, CH2NHCH2-alkyl, CH2NHCH2-dibenzoyl, CH2NHCH2-benzoyl, CH2NHCH2-alkanoyl, CH2NHCH2-alkenoyl, CH2NHCH2-benzoyl alkyl substituted CH2NHCH2-alkanoyl, CH2NHCH2-alkanoyl substituted phenyl, CH2NHCH2-alkenoyl substituted phenyl, CH2NHCH2-aryl, CH2NHCH2-acyl, CH2NHCH2-heterocylic, CH2NHCH2-heteroraryl, CH2NHCH2-alkenylcarbonyl, CH2NHCH2-alkane, CH2NHCH2-alkene, CH2NHCH2-sugar moiety, CH2NHCH2-acid moiety, CH2NHCH2-ethanoyl, CH2NHCH2-propanoyl, CH2NHCH2-propenoyl, CH2NHCH2-butanoyl, CH2NHCH2-butenoyl, CH2NHCH2-pentanoyl, CH2NHCH2-hexenoyl, CH2NHCH2-heptanoyl, CH2NHCH2-heptenoyl, CH2NHCH2-octanoyl, CH2NHCH2-octenoyl, CH2NHCH2-nonanoyl, CH2NHCH2-nonenoyl, CH2NHCH2-decanoyl, CH2NH-decenoyl, CH2NHCH2-propionyl, CH2NHCH2-2-propenoyl, CH2NHCH2-2-butenoyl, CH2NHCH2-Isobutyryl, CH2NHCH2-2-methylpropanoyl, CH2NHCH2-2-ethylbutyryl, CH2NHCH2-ethylbutanoyl, CH2NHCH2-2-ethylbutanoyl, CH2NHCH2-butyryl, CH2NHCH2-(E)-2,3-Dimethylacryloyl, CH2NHCH2-(E)-2-Methylcrotonoyl, CH2NHCH2-3-cis-Methyl-methacryloyl, CH2NHCH2-3-Methyl-2-butenoyl, CH2NHCH2-3-Methylcrotonoyl, CH2NHCH2-4-Pentenoyl, CH2NHCH2-(2E)-2-pentenoyl, CH2NHCH2-Caproyl, CH2NHCH2-5-Hexenoyl, CH2NHCH2-Capryloyl, CH2NHCH2-Lauroyl, CH2NHCH2-Dodecanoyl, CH2NHCH2-Myristoyl, CH2NHCH2-Tetradecanoyl, CH2NHCH2-Oleoyl, CH2NHCH2-C(2-18) Acyl, CH2NHCH2-ethanyl, CH2NHCH2-propanyl, CH2NHCH2-propenyl, CH2NHCH2-butanyl, CH2NHCH2-butenyl, CH2NHCH2-pentanyl, CH2NHCH2-hexenyl, CH2NHCH2-heptanyl, CH2NHCH2-heptenyl, CH2NHCH2-octanyl, CH2NHCH2-octenyl, CH2NHCH2-nonanyl, CH2NHCH2-nonenyl, CH2NHCH2-decanyl, CH2NHCH2-decenyl, CH2NHCH2-alkyl, haloalkyl, CH2NHCH2-alkenyl, CH2NHCH2-alkynyl, CH2NHCH2-hydroxyalkyl, -alkylene-O-alkyl, CH2NHCH2-aryl, CH2NHCH2-alkylene-aryl, CH2NHCH2-heteroaryl, CH2NHCH2-alkylene-heteroaryl, CH2NHCH2-cycloalkyl, CH2NHCH2-heterocyclyl, and CH2NHCH2-alkylene-heterocyclyl,
CH2NHCO-tigloyl, CH2NHCO-senecioyl, CH2NHCO-acetyl, CH2NHCO-Crotonoyl, CH2NHCO-3,3-Dimethylartyloyl, CH2NHCO-Cinnamoyl, CH2NHCO-Pentenoyl, CH2NHCO-Hexanoyl, CH2NHCO-benzoyl, CH2NHCO-Ethylbutyryl, CH2NHCO-alkyl, CH2NHCO-dibenzoyl, CH2NHCO-benzoyl, CH2NHCO-alkanoyl, CH2NHCO-alkenoyl, CH2NHCO-benzoyl alkyl substituted CH2NHCO-alkanoyl, CH2NHCO-alkanoyl substituted phenyl, CH2NHCO-alkenoyl substituted phenyl, CH2NHCO-aryl, CH2NHCO-acyl, CH2NHCO-heterocylic, CH2NHCO-heteroraryl, CH2NHCO-alkenylcarbonyl, CH2NHCO-alkane, CH2NHCO-alkene, CH2NHCO-sugar moiety, CH2NHCO-acid moiety, CH2NHCO-ethanoyl, CH2NHCO-propanoyl, CH2NHCO-propenoyl, CH2NHCO-butanoyl, CH2NHCO-butenoyl, CH2NHCO-pentanoyl, CH2NHCO-hexenoyl, CH2NHCO-heptanoyl, CH2NHCO-heptenoyl, CH2NHCO-octanoyl, CH2NHCO-octenoyl, CH2NHCO-nonanoyl, CH2N HCO-nonenoyl, CH2NHCO-decanoyl, CH2NHCO-decenoyl, CH2NHCO-propionyl, CH2NHCO-2-propenoyl, CH2NHCO-2-butenoyl, CH2NHCO-Isobutyryl, CH2NHCO-2-methylpropanoyl, CH2NHCO-2-ethylbutyryl, CH2NHCO-ethylbutanoyl, CH2NHCO-2-ethylbutanoyl, CH2NHCO-butyryl, CH2NHCO-(E)-2,3-Dimethylacryloyl, CH2NHCO-(E)-2-Methylcrotonoyl, CH2NHCO-3-cis-Methyl-methacryloyl, CH2NHCO-3-Methyl-2-butenoyl, CH2NHCO-3-Methylcrotonoyl, CH2NHCO-4-Pentenoyl, CH2NHCO-(2E)-2-pentenoyl, CH2NHCO-Caproyl, CH2NHCO-5-Hexenoyl, CH2NHCO-Capryloyl, CH2NHCO-Lauroyl, CH2NHCO-Dodecanoyl, CH2NHCO-Myristoyl, CH2NHCO-Tetradecanoyl, CH2NHCO-Oleoyl, CH2NHCO—C(2-18) Acyl, CH2NHCO-ethanyl, CH2NHCO-propanyl, CH2NHCO-propenyl, CH2NHCO-butanyl, CH2NHCO-butenyl, CH2NHCO-pentanyl, CH2NHCO-hexenyl, CH2NHCO-heptanyl, CH2NHCO-heptenyl, CH2NHCO-octanyl, CH2NHCO-octenyl, CH2NHCO-nonanyl, CH2NHCO-nonenyl, CH2NHCO-decanyl, CH2NHCO-decenyl, CH2NHCO-alkyl, CH2NHCO-haloalkyl, alkenyl, CH2NHCO-alkynyl, CH2NHCO-hydroxyalkyl, CH2NHCO-alkylene-O-alkyl, CH2NHCO-aryl, CH2NHCO-alkylene-aryl, CH2NHCO-heteroaryl, CH2NHCO-alkylene-heteroaryl, CH2NHCO-cycloalkyl, CH2NHCO-heterocyclyl, and CH2NHCO-alkylene-heterocyclyl,
CH2NHCONH-tigloyl, CH2NHCONH-senecioyl, CH2NHCONH-acetyl, CH2NHCONH-Crotonoyl, CH2NHCONH-3,3-Dimethylartyloyl, CH2NHCONH-Cinnamoyl, CH2NHCONH-Pentenoyl, CH2NHCONH-Hexanoyl, CH2NHCONH-benzoyl, CH2NHCONH-Ethylbutyryl, CH2NHCONH-alkyl, CH2NHCONH-dibenzoyl, CH2NHCONH-benzoyl, CH2NHCONH-alkanoyl, CH2NHCONH-alkenoyl, CH2NHCONH-benzoyl alkyl substituted CH2NHCONH-alkanoyl, CH2NHCONH-alkanoyl substituted phenyl, CH2NHCONH-alkenoyl substituted phenyl, CH2NHCONH-aryl, CH2NHCONH-acyl, CH2NHCONH-heterocylic, CH2NHCONH-heteroraryl, CH2NHCONH-alkenylcarbonyl, CH2NHCONH-alkane, CH2NHCONH-alkene, CH2NHCONH-sugar moiety, CH2NHCONH-acid moiety, CH2NHCONH-ethanoyl, CH2NHCONH-propanoyl, CH2NHCONH-propenoyl, CH2NHCONH-butanoyl, CH2NHCONH-butenoyl, CH2NHCONH-pentanoyl, CH2NHCONH-hexenoyl, CH2NHCONH-heptanoyl, CH2NHCONH-heptenoyl, CH2NHCONH-octanoyl, CH2NHCONH-octenoyl, CH2NHCONH-nonanoyl, CH2NHCONH-nonenoyl, CH2NHCONH-decanoyl, CH2NHCONH-decenoyl, CH2NHCONH-propionyl, CH2NHCONH-2-propenoyl, CH2NHCONH-2-butenoyl, CH2NHCONH-Isobutyryl, CH2NHCONH-2-methylpropanoyl, CH2NHCONH-2-ethylbutyryl, CH2NHCONH-ethylbutanoyl, CH2NHCONH-2-ethylbutanoyl, CH2NHCONH-butyryl, CH2NHCONH-(E)-2,3-Dimethylacryloyl, CH2NHCONH-(E)-2-Methylcrotonoyl, CH2NHCONH-3-cis-Methyl-methacryloyl, CH2NHCONH-3-Methyl-2-butenoyl, CH2NHCONH-3-Methylcrotonoyl, CH2NHCONH-4-Pentenoyl, CH2NHCONH-(2E)-2-pentenoyl, CH2NHCONH-Caproyl, CH2NHCONH-5-Hexenoyl, CH2NHCONH-Capryloyl, CH2NHCONH-Lauroyl, CH2NHCONH-Dodecanoyl, CH2NHCONH-Myristoyl, CH2NHCONH-Tetradecanoyl, CH2NHCONH-Oleoyl, CH2NHCONH—C(2-18) Acyl, CH2NHCONH-ethanyl, CH2NHCONH-propanyl, CH2NHCONH-propenyl, CH2NHCONH-butanyl, CH2NHCONH-butenyl, CH2NHCONH-pentanyl, CH2NHCONH-hexenyl, CH2NHCONH-heptanyl, CH2NHCONH-heptenyl, CH2NHCONH-octanyl, CH2NHCONH-octenyl, CH2NHCONH-nonanyl, CH2NHCONH-nonenyl, CH2NHCONH-decanyl, CH2NHCONH-decenyl, NH—CO—NH-ethyl, NH—CO—NH—(Z)-1-(2-methylbut-2-en-1-yl), NH—CO—NH-(E)-1-(2-methylbut-2-en-1-yl), NH—CO—NH-1-(3-methylbut-2-en-1-yl), NH—CO—NH-(E)-1-(but-2-en-1-yl), NH—CO—NH-1-cinnamyl, NH—CO—NH-1-(but-3-en-1-yl), NH—CO—NH-(E)-1-(4-(dimethylamino)but-3-en-1-yl),
CH2NHSO2-tigloyl, CH2NHSO2-senecioyl, CH2NHSO2-acetyl, CH2NHSO2-Crotonoyl, CH2NHSO2-3,3-Dimethylartyloyl, CH2NHSO2-Cinnamoyl, CH2NHSO2-Pentenoyl, CH2NHSO2-Hexanoyl, CH2NHSO2-benzoyl, CH2NHSO2-Ethylbutyryl, CH2NHSO2-alkyl, CH2NHSO2-dibenzoyl, CH2NHSO2-benzoyl, CH2NHSO2-alkanoyl, CH2NHSO2-alkenoyl, CH2NHSO2-benzoyl alkyl substituted CH2NHSO2-alkanoyl, CH2NHSO2-alkanoyl substituted phenyl, CH2NHSO2-alkenoyl substituted phenyl, CH2NHSO2-aryl, CH2NHSO2-acyl, CH2NHSO2-heterocylic, CH2NHSO2-heteroraryl, CH2NHSO2-alkenylcarbonyl, CH2NHSO2-alkane, CH2NHSO2-alkene, CH2NHSO2-sugar moiety, CH2NHSO2-acid moiety, CH2NHSO2-ethanoyl, CH2NHSO2-propanoyl, CH2NHSO2-propenoyl, CH2NHSO2-butanoyl, CH2NHSO2-butenoyl, CH2NHSO2-pentanoyl, CH2NHSO2-hexenoyl, CH2NHSO2-heptanoyl, CH2NHSO2-heptenoyl, CH2NHSO2-octanoyl, CH2NHSO2-octenoyl, CH2NHSO2-nonanoyl, CH2NHSO2-nonenoyl, CH2NHSO2-decanoyl, CH2NHSO2-decenoyl, CH2NHSO2-propionyl, CH2NHSO2-2-propenoyl, CH2NHSO2-2-butenoyl, CH2NHSO2-Isobutyryl, CH2NHSO2-2-methylpropanoyl, CH2NHSO2-2-ethylbutyryl, CH2NHSO2-ethylbutanoyl, CH2NHSO2-2-ethylbutanoyl, CH2NHSO2-butyryl, CH2NHSO2-(E)-2,3-Dimethylacryloyl, CH2NHSO2-(E)-2-Methylcrotonoyl, CH2NHSO2-3-cis-Methyl-methacryloyl, CH2NHSO2-3-Methyl-2-butenoyl, CH2NHSO2-3-Methylcrotonoyl, CH2NHSO2-4-Pentenoyl, CH2NHSO2-(2E)-2-pentenoyl, CH2NHSO2-Caproyl, CH2NHSO2-5-Hexenoyl, CH2NHSO2-Capryloyl, CH2NHSO2-Lauroyl, CH2NHSO2-Dodecanoyl, CH2NHSO2-Myristoyl, CH2NHSO2-Tetradecanoyl, CH2NHSO2-Oleoyl, CH2NHSO2-C(2-18) Acyl, CH2NHSO2-ethanyl, CH2NHSO2-propanyl, CH2NHSO2-propenyl, CH2NHSO2-butanyl, CH2NHSO2-butenyl, CH2NHSO2-pentanyl, CH2NHSO2-hexenyl, CH2NHSO2-heptanyl, CH2NHSO2-heptenyl, CH2NHSO2-octanyl, CH2NHSO2-octenyl, CH2NHSO2-nonanyl, CH2NHSO2-nonenyl, CH2NHSO2-decanyl, CH2NHSO2-decenoyl, CH2NHSO2-alkyl, CH2NHSO2-haloalkyl, CH2NHSO2-alkenyl, CH2NHSO2-alkynyl, CH2NHSO2-hydroxyalkyl, CH2NHSO2-alkylene-O-alkyl, CH2NHSO2-aryl, CH2NHSO2-alkylene-aryl, CH2NHSO2-heteroaryl, CH2NHSO2-alkylene-heteroaryl, CH2NHSO2-cycloalkyl, CH2NHSO2-heterocyclyl, and CH2NHSO2-alkylene-heterocyclyl, CH2NHSO2-ethyl, CH2NHSO2-(Z)-(2-methylbut-2-en-1-yl), CH2NHSO2-(E)-prop-1-enyl, CH2NHSO2-(E)-2-phenylethenyl, CH2NHSO2-but-3-enyl;
NH-ethyl, NH—(Z)-(2-methylbut-2-en-1-yl), NH-(E)-(2-methylbut-2-en-1-yl), NH-(3-methylbut-2-en-1-yl, NH-(E)-(but-2-en-1-yl, NH-cinnamyl, NH-pent-4-en-1-yl, NH-(E)-3-((4-(dimethylamino)but-2-en-1-yl, NH-acetyl, NH-angeloyl, NH-tigloyl, NH-senecioyl, NH-Crotonoyl, NH-Cinnamoyl, NH-Pentenoyl, NH-4-(dimethylamino)-2-methylbut-2-enoyl, NH-4-[(2-methoxyethyl)amino]-2-methyl-4oxobut-2-enoyl, NHSO2-ethyl, NHSO2-(Z)-(2-methylbut-2-en-1-yl), NHSO2-(E)-prop-1-enyl, NHSO2-(E)-2-phenylethenyl, NHSO2-but-3-enyl, NH—CO—NH-ethyl, NH—CO—NH—(Z)-1-(2-methylbut-2-en-1-yl), NH—CO—NH-(E)-1-(2-methylbut-2-en-1-yl), NH—CO—NH-1-(3-methylbut-2-en-1-yl), NH—CO—NH-(E)-1-(but-2-en-1-yl), NH—CO—NH-1-cinnamyl, NH—CO—NH-1-(but-3-en-1-yl), NH—CO—NH-(E)-1-(4-(dimethylamino)but-3-en-1-yl);
or wherein R9, R11, R12, R13, R14, R15, are independently attached a CH3; or wherein R10 is attached CH2NH-tigloyl, CH2NH-senecioyl, CH2NH-acetyl, CH2NH-Crotonoyl, CH2NH-3,3-Dimethylartyloyl, CH2NH-Cinnamoyl, CH2NH-Pentenoyl, CH2NH-Hexanoyl, CH2NH-benzoyl, CH2NH-Ethylbutyryl, CH2NH-alkyl, CH2NH-dibenzoyl, CH2NH-benzoyl, CH2NH-alkanoyl, CH2NH-alkenoyl, CH2NH-benzoyl alkyl substituted CH2NH-alkanoyl, CH2NH-alkanoyl substituted phenyl, CH2NH-alkenoyl substituted phenyl, CH2NH-aryl, CH2NH-acyl, CH2NH-heterocylic, CH2NH-heteroraryl, CH2NH-alkenylcarbonyl, CH2NH-alkane, CH2NH-alkene, CH2NH-sugar moiety, CH2NH-acid moiety, CH2NH-ethanoyl, CH2NH-propanoyl, CH2NH-propenoyl, CH2NH-butanoyl, CH2NH-butenoyl, CH2NH-pentanoyl, CH2NH-hexenoyl, CH2NH-heptanoyl, CH2NH-heptenoyl, CH2NH-octanoyl, CH2NH-octenoyl, CH2NH-nonanoyl, CH2NH-nonenoyl, CH2NH-decanoyl, CH2NH-decenoyl, CH2NH-propionyl, CH2NH-2-propenoyl, CH2NH-2-butenoyl, CH2NH-Isobutyryl, CH2NH-2-methylpropanoyl, CH2NH-2-ethylbutyryl, CH2NH-ethylbutanoyl, CH2NH-2-ethylbutanoyl, CH2NH-butyryl, CH2NH-(E)-2,3-Dimethylacryloyl, CH2NH-(E)-2-Methylcrotonoyl, CH2NH-3-cis-Methyl-methacryloyl, CH2NH-3-Methyl-2-butenoyl, CH2NH-3-Methylcrotonoyl, CH2NH-4-Pentenoyl, CH2NH-(2E)-2-pentenoyl, CH2NH-Caproyl, CH2NH-5-Hexenoyl, CH2NH-Capryloyl, CH2NH-Lauroyl, CH2NH-Dodecanoyl, CH2NH-Myristoyl, CH2NH-Tetradecanoyl, CH2NH-Oleoyl, CH2NH—C(2-18) Acyl,
or wherein R4 and/or R10 are independently attached an O-angeloyl, O-tigloyl, O-senecioyl, O-acetyl, O-Crotonoyl, O-3,3-Dimethylartyloyl, O-Cinnamoyl, O-Pentenoyl, O-Hexanoyl, O-benzoyl, O-Ethylbutyryl, O-alkyl, O-dibenzoyl, O-benzoyl, O-alkanoyl, O-alkenoyl, O-benzoyl alkyl substituted O-alkanoyl, O-alkanoyl substituted phenyl, O-alkenoyl substituted phenyl, O-aryl, O-acyl, O-heterocylic, O-heteroraryl, O-alkenylcarbonyl, O-ethanoyl, O-propanoyl, O-propenoyl, O-butanoyl, O-butenoyl, O-pentanoyl, O-hexenoyl, O-heptanoyl, O-heptenoyl, O-octanoyl, O-octenoyl, O-nonanoyl, O-nonenoyl, O-decanoyl, O-decenoyl, O-propionyl, O-2-propenoyl, O-2-butenoyl, O-Isobutyryl, O-2-methyl propanoyl, O-2-ethylbutyryl, O-ethylbutanoyl, O-2-ethylbutanoyl, O-butyryl, O-(E)-2,3-Dimethylacryloyl, O-(E)-2-Methylcrotonoyl, O-3-cis-Methyl-methacryloyl, O-3-Methyl-2-butenoyl, O-3-Methylcrotonoyl, O-4-Pentenoyl, O-(2E)-2-pentenoyl, O-Caproyl, O-5-Hexenoyl, O-Capryloyl, O-Lauroyl, O-Dodecanoyl, O-Myristoyl, O-Tetradecanoyl, O-Oleoyl, O—C(2-18) Acyl, CH2O-angeloyl, CH2O-tigloyl, CH2O-senecioyl, CH2O-acetyl, CH2O-Crotonoyl, CH2O-3,3-Dimethylartyloyl, CH2O-Cinnamoyl, CH2O-Pentenoyl, CH2O-Hexanoyl, CH2O-benzoyl, CH2O-Ethylbutyryl, CH3, CH2OH, CH2O-alkyl, CH2O-dibenzoyl, CH2O-benzoyl, CH2O-alkanoyl, CH2O-alkenoyl, CH2O-benzoyl alkyl substituted O-alkanoyl, CH2O-alkanoyl substituted phenyl, CH2O-alkenoyl substituted phenyl, CH2O-aryl, CH2O-acyl, CH2O-heterocylic, CH2O-heteroraryl, CH2O-alkenylcarbonyl, CH2O-ethanoyl, CH2O-propanoyl, CH2O-propenoyl, CH2O-butanoyl, CH2O-butenoyl, CH2O-pentanoyl, CH2O-hexenoyl, CH2O-heptanoyl, CH2O-heptenoyl, CH2O-octanoyl, CH2O-octenoyl, CH2O-nonanoyl, CH2O-nonenoyl, CH2O-decanoyl, CH2O-decenoyl, CH2O-propionyl, CH2O-2-propenoyl, CH2O-2-butenoyl, CH2O-Isobutyryl, CH2O-2-methylpropanoyl, CH2O-2-ethylbutyryl, CH2O-ethylbutanoyl, CH2O-2-ethylbutanoyl, CH2O-butyryl, CH2O-(E)-2,3-Dimethylacryloyl, CH2O-(E)-2-Methylcrotonoyl, CH2O-3-cis-Methyl-methacryloyl, CH2O-3-Methyl-2-butenoyl, CH2O-3-Methylcrotonoyl, CH2O-4-Pentenoyl, CH2O-(2E)-2-pentenoyl, CH2O-Caproyl, CH2O-5-Hexenoyl, CH2O-Capryloyl, CH2O-Lauroyl, CH2O-Dodecanoyl, CH2O-Myristoyl, CH2O-Tetradecanoyl, CH2O-Oleoyl, CH2O—C(2-18) Acyl;
NH-tigloyl, NH-senecioyl, NH-acetyl, NH-Crotonoyl, NH-3,3-Dimethylartyloyl, NH-Cinnamoyl, NH-Pentenoyl, NH-Hexanoyl, NH-benzoyl, NH-Ethylbutyryl, NH-alkyl, NH-dibenzoyl, NH-benzoyl, NH-alkanoyl, NH-alkenoyl, NH-benzoyl alkyl substituted NH-alkanoyl, NH-alkanoyl substituted phenyl, NH-alkenoyl substituted phenyl, NH-aryl, NH-acyl, NH-heterocylic, NH-heteroraryl, NH-alkenylcarbonyl, NH-alkane, NH-alkene, NH-sugar moiety, NH-acid moiety, NH-ethanoyl, NH-propanoyl, NH-propenoyl, NH-butanoyl, NH-butenoyl, NH-pentanoyl, NH-hexenoyl, NH-heptanoyl, NH-heptenoyl, NH-octanoyl, NH-octenoyl, NH-nonanoyl, NH-nonenoyl, NH-decanoyl, NH-decenoyl, NH-propionyl, NH-2-propenoyl, NH-2-butenoyl, NH-Isobutyryl, NH-2-methylpropanoyl, NH-2-ethylbutyryl, NH-ethylbutanoyl, NH-2-ethylbutanoyl, NH-butyryl, NH-(E)-2,3-Dimethylacryloyl, NH-(E)-2-Methylcrotonoyl, NH-3-cis-Methyl-methacryloyl, NH-3-Methyl-2-butenoyl, NH-3-Methylcrotonoyl, NH-4-Pentenoyl, NH-(2E)-2-pentenoyl, NH-Caproyl, NH-5-Hexenoyl, NH-Capryloyl, NH-Lauroyl, NH-Dodecanoyl, NH-Myristoyl, NH-Tetradecanoyl, NH-Oleoyl, NH—C(2-18) Acyl, NH-ethanyl, NH-propanyl, NH-propenyl, NH-butanyl, NH-butenyl, NH-pentanyl, NH-hexenyl, NH-heptanyl, NH-heptenyl, NH-octanyl, NH-octenyl, NH-nonanyl, NH-nonenyl, NH-decanyl, NH-decenyl, NH-alkyl, NH-haloalkyl, NH-alkenyl, NH-alkynyl, NH-hydroxyalkyl, NH-alkylene-O-alkyl, NH-aryl, NH-alkylene-aryl, NH-heteroaryl, NH-alkylene-heteroaryl, NH-cycloalkyl, NH-heterocyclyl, and NH-alkylene-heterocyclyl,
CH2NH-tigloyl, CH2NH-senecioyl, CH2NH-acetyl, CH2NH-Crotonoyl, CH2NH-3,3-Dimethylartyloyl, CH2NH-Cinnamoyl, CH2NH-Pentenoyl, CH2NH-Hexanoyl, CH2NH-benzoyl, CH2NH-Ethylbutyryl, CH2NH-alkyl, CH2NH-dibenzoyl, CH2NH-benzoyl, CH2NH-alkanoyl, CH2NH-alkenoyl, CH2NH-benzoyl alkyl substituted CH2NH-alkanoyl, CH2NH-alkanoyl substituted phenyl, CH2NH-alkenoyl substituted phenyl, CH2NH-aryl, CH2NH-acyl, CH2NH-heterocylic, CH2NH-heteroraryl, CH2NH-alkenylcarbonyl, CH2NH-alkane, CH2NH-alkene, CH2NH-sugar moiety, CH2NH-acid moiety, CH2NH-ethanoyl, CH2NH-propanoyl, CH2NH-propenoyl, CH2NH-butanoyl, CH2NH-butenoyl, CH2NH-pentanoyl, CH2NH-hexenoyl, CH2NH-heptanoyl, CH2NH-heptenoyl, CH2NH-octanoyl, CH2NH-octenoyl, CH2NH-nonanoyl, CH2NH-nonenoyl, CH2NH-decanoyl, CH2NH-decenoyl, CH2NH-propionyl, CH2NH-2-propenoyl, CH2NH-2-butenoyl, CH2NH-Isobutyryl, CH2NH-2-methylpropanoyl, CH2NH-2-ethylbutyryl, CH2NH-ethylbutanoyl, CH2NH-2-ethylbutanoyl, CH2NH-butyryl, CH2NH-(E)-2,3-Dimethylacryloyl, CH2NH-(E)-2-Methylcrotonoyl, CH2NH-3-cis-Methyl-methacryloyl, CH2NH-3-Methyl-2-butenoyl, CH2NH-3-Methylcrotonoyl, CH2NH-4-Pentenoyl, CH2NH-(2E)-2-pentenoyl, CH2NH-Caproyl, CH2NH-5-Hexenoyl, CH2NH-Capryloyl, CH2NH-Lauroyl, CH2NH-Dodecanoyl, CH2NH-Myristoyl, CH2NH-Tetradecanoyl, CH2NH-Oleoyl, CH2NH—C(2-18) Acyl, CH2NH-ethanyl, CH2NH-propanyl, CH2NH-propenyl, CH2NH-butanyl, CH2NH-butenyl, CH2NH-pentanyl, CH2NH-hexenyl, CH2NH-heptanyl, CH2NH-heptenyl, CH2NH-octanyl, CH2NH-octenyl, CH2NH-nonanyl, CH2NH-nonenyl, CH2NH-decanyl, CH2NH-decenyl, CH2NH-alkyl, CH2NH-haloalkyl, CH2NH-alkenyl, CH2NH-alkynyl, CH2NH-hydroxyalkyl, CH2NH-alkylene-O-alkyl, CH2NH-aryl, CH2NH-alkylene-aryl, CH2NH-heteroaryl, CH2NH-alkylene-heteroaryl, CH2NH-cycloalkyl, CH2NH-heterocyclyl, and CH2NH-alkylene-heterocyclyl,
CH2NHCH2-tigloyl, CH2NHCH2-angeloyl, CH2NHCH2-senecioyl, CH2NHCH2-acetyl, CH2NHCH2-Crotonoyl, CH2NHCH2-3,3-Dimethylartyloyl, CH2NHCH2-Cinnamoyl, CH2NHCH2-Pentenoyl, CH2NHCH2-Hexanoyl, CH2NHCH2-benzoyl, CH2NHCH2-Ethylbutyryl, CH2NHCH2-alkyl, CH2NHCH2-dibenzoyl, CH2NHCH2-benzoyl, CH2NHCH2-alkanoyl, CH2NHCH2-alkenoyl, CH2NHCH2-benzoyl alkyl substituted CH2NHCH2-alkanoyl, CH2NHCH2-alkanoyl substituted phenyl, CH2NHCH2-alkenoyl substituted phenyl, CH2NHCH2-aryl, CH2NHCH2-acyl, CH2NHCH2-heterocylic, CH2NHCH2-heteroraryl, CH2NHCH2-alkenylcarbonyl, CH2NHCH2-alkane, CH2NHCH2-alkene, CH2NHCH2-sugar moiety, CH2NHCH2-acid moiety, CH2NHCH2-ethanoyl, CH2NHCH2-propanoyl, CH2NHCH2-propenoyl, CH2NHCH2-butanoyl, CH2NHCH2-butenoyl, CH2NHCH2-pentanoyl, CH2NHCH2-hexenoyl, CH2NHCH2-heptanoyl, CH2NHCH2-heptenoyl, CH2NHCH2-octanoyl, CH2NHCH2-octenoyl, CH2NHCH2-nonanoyl, CH2NHCH2-nonenoyl, CH2NHCH2-decanoyl, CH2NH-decenoyl, CH2NHCH2-propionyl, CH2NHCH2-2-propenoyl, CH2NHCH2-2-butenoyl, CH2NHCH2-Isobutyryl, CH2NHCH2-2-methylpropanoyl, CH2NHCH2-2-ethylbutyryl, CH2NHCH2-ethylbutanoyl, CH2NHCH2-2-ethylbutanoyl, CH2NHCH2-butyryl, CH2NHCH2-(E)-2,3-Dimethylacryloyl, CH2NHCH2-(E)-2-Methylcrotonoyl, CH2NHCH2-3-cis-Methyl-methacryloyl, CH2NHCH2-3-Methyl-2-butenoyl, CH2NHCH2-3-Methylcrotonoyl, CH2NHCH2-4-Pentenoyl, CH2NHCH2-(2E)-2-pentenoyl, CH2NHCH2-Caproyl, CH2NHCH2-5-Hexenoyl, CH2NHCH2-Capryloyl, CH2NHCH2-Lauroyl, CH2NHCH2-Dodecanoyl, CH2NHCH2-Myristoyl, CH2NHCH2-Tetradecanoyl, CH2NHCH2-Oleoyl, CH2NHCH2-C(2-18) Acyl, CH2NHCH2-ethanyl, CH2NHCH2-propanyl, CH2NHCH2-propenyl, CH2NHCH2-butanyl, CH2NHCH2-butenyl, CH2NHCH2-pentanyl, CH2NHCH2-hexenyl, CH2NHCH2-heptanyl, CH2NHCH2-heptenyl, CH2NHCH2-octanyl, CH2NHCH2-octenyl, CH2NHCH2-nonanyl, CH2NHCH2-nonenyl, CH2NHCH2-decanyl, CH2NHCH2-decenyl, CH2NHCH2-alkyl, haloalkyl, CH2NHCH2-alkenyl, CH2NHCH2-alkynyl, CH2NHCH2-hydroxyalkyl, -alkylene-O-alkyl, CH2NHCH2-aryl, CH2NHCH2-alkylene-aryl, CH2NHCH2-heteroaryl, CH2NHCH2-alkylene-heteroaryl, CH2NHCH2-cycloalkyl, CH2NHCH2-heterocyclyl, and CH2NHCH2-alkylene-heterocyclyl,
CH2NHCO-tigloyl, CH2NHCO-senecioyl, CH2NHCO-acetyl, CH2NHCO-Crotonoyl, CH2NHCO-3,3-Dimethylartyloyl, CH2NHCO-Cinnamoyl, CH2NHCO-Pentenoyl, CH2NHCO-Hexanoyl, CH2NHCO-benzoyl, CH2NHCO-Ethylbutyryl, CH2NHCO-alkyl, CH2NHCO-dibenzoyl, CH2NHCO-benzoyl, CH2NHCO-alkanoyl, CH2NHCO-alkenoyl, CH2NHCO-benzoyl alkyl substituted CH2NHCO-alkanoyl, CH2NHCO-alkanoyl substituted phenyl, CH2NHCO-alkenoyl substituted phenyl, CH2NHCO-aryl, CH2NHCO-acyl, CH2NHCO-heterocylic, CH2NHCO-heteroraryl, CH2NHCO-alkenylcarbonyl, CH2NHCO-alkane, CH2NHCO-alkene, CH2NHCO-sugar moiety, CH2NHCO-acid moiety, CH2NHCO-ethanoyl, CH2NHCO-propanoyl, CH2NHCO-propenoyl, CH2NHCO-butanoyl, CH2NHCO-butenoyl, CH2NHCO-pentanoyl, CH2NHCO-hexenoyl, CH2NHCO-heptanoyl, CH2NHCO-heptenoyl, CH2NHCO-octanoyl, CH2NHCO-octenoyl, CH2NHCO-nonanoyl, CH2NHCO-nonenoyl, CH2NHCO-decanoyl, CH2NHCO-decenoyl, CH2NHCO-propionyl, CH2NHCO-2-propenoyl, CH2NHCO-2-butenoyl, CH2NHCO-Isobutyryl, CH2NHCO-2-methylpropanoyl, CH2NHCO-2-ethylbutyryl, CH2NHCO-ethylbutanoyl, CH2NHCO-2-ethylbutanoyl, CH2NHCO-butyryl, CH2NHCO-(E)-2,3-Dimethylacryloyl, CH2NHCO-(E)-2-Methylcrotonoyl, CH2NHCO-3-cis-Methyl-methacryloyl, CH2NHCO-3-Methyl-2-butenoyl, CH2NHCO-3-Methylcrotonoyl, CH2NHCO-4-Pentenoyl, CH2NHCO-(2E)-2-pentenoyl, CH2NHCO-Caproyl, CH2NHCO-5-Hexenoyl, CH2NHCO-Capryloyl, CH2NHCO-Lauroyl, CH2NHCO-Dodecanoyl, CH2NHCO-Myristoyl, CH2NHCO-Tetradecanoyl, CH2NHCO-Oleoyl, CH2NHCO—C(2-18) Acyl, CH2NHCO-ethanyl, CH2NHCO-propanyl, CH2NHCO-propenyl, CH2NHCO-butanyl, CH2NHCO-butenyl, CH2NHCO-pentanyl, CH2NHCO-hexenyl, CH2NHCO-heptanyl, CH2NHCO-heptenyl, CH2NHCO-octanyl, CH2NHCO-octenyl, CH2NHCO-nonanyl, CH2NHCO-nonenyl, CH2NHCO-decanyl, CH2NHCO-decenyl, CH2NHCO-alkyl, CH2NHCO-haloalkyl, alkenyl, CH2NHCO-alkynyl, CH2NHCO-hydroxyalkyl, CH2NHCO-alkylene-O-alkyl, CH2NHCO-aryl, CH2NHCO-alkylene-aryl, CH2NHCO-heteroaryl, CH2NHCO-alkylene-heteroaryl, CH2NHCO-cycloalkyl, CH2NHCO-heterocyclyl, and CH2NHCO-alkylene-heterocyclyl,
CH2NHCONH-tigloyl, CH2NHCONH-senecioyl, CH2NHCONH-acetyl, CH2NHCONH-Crotonoyl, CH2NHCONH-3,3-Dimethylartyloyl, CH2NHCONH-Cinnamoyl, CH2NHCONH-Pentenoyl, CH2NHCONH-Hexanoyl, CH2NHCONH-benzoyl, CH2NHCONH-Ethylbutyryl, CH2NHCONH-alkyl, CH2NHCONH-dibenzoyl, CH2NHCONH-benzoyl, CH2NHCONH-alkanoyl, CH2NHCONH-alkenoyl, CH2NHCONH-benzoyl alkyl substituted CH2NHCONH-alkanoyl, CH2NHCONH-alkanoyl substituted phenyl, CH2NHCONH-alkenoyl substituted phenyl, CH2NHCONH-aryl, CH2NHCONH-acyl, CH2NHCONH-heterocylic, CH2NHCONH-heteroraryl, CH2NHCONH-alkenylcarbonyl, CH2NHCONH-alkane, CH2NHCONH-alkene, CH2NHCONH-sugar moiety, CH2NHCONH-acid moiety, CH2NHCONH-ethanoyl, CH2NHCONH-propanoyl, CH2NHCONH-propenoyl, CH2NHCONH-butanoyl, CH2NHCONH-butenoyl, CH2NHCONH-pentanoyl, CH2NHCONH-hexenoyl, CH2NHCONH-heptanoyl, CH2NHCONH-heptenoyl, CH2NHCONH-octanoyl, CH2NHCONH-octenoyl, CH2NHCONH-nonanoyl, CH2NHCONH-nonenoyl, CH2NHCONH-decanoyl, CH2NHCONH-decenoyl, CH2NHCONH-propionyl, CH2NHCONH-2-propenoyl, CH2NHCONH-2-butenoyl, CH2NHCONH-Isobutyryl, CH2NHCONH-2-methylpropanoyl, CH2NHCONH-2-ethylbutyryl, CH2NHCONH-ethylbutanoyl, CH2NHCONH-2-ethylbutanoyl, CH2NHCONH-butyryl, CH2NHCONH-(E)-2,3-Dimethylacryloyl, CH2NHCONH-(E)-2-Methylcrotonoyl, CH2NHCONH-3-cis-Methyl-methacryloyl, CH2NHCONH-3-Methyl-2-butenoyl, CH2NHCONH-3-Methylcrotonoyl, CH2NHCONH-4-Pentenoyl, CH2NHCONH-(2E)-2-pentenoyl, CH2NHCONH-Caproyl, CH2NHCONH-5-Hexenoyl, CH2NHCONH-Capryloyl, CH2NHCONH-Lauroyl, CH2NHCONH-Dodecanoyl, CH2NHCONH-Myristoyl, CH2NHCONH-Tetradecanoyl, CH2NHCONH-Oleoyl, CH2NHCONH—C(2-18) Acyl, CH2NHCONH-ethanyl, CH2NHCONH-propanyl, CH2NHCONH-propenyl, CH2NHCONH-butanyl, CH2NHCONH-butenyl, CH2NHCONH-pentanyl, CH2NHCONH-hexenyl, CH2NHCONH-heptanyl, CH2NHCONH-heptenyl, CH2NHCONH-octanyl, CH2NHCONH-octenyl, CH2NHCONH-nonanyl, CH2NHCONH-nonenyl, CH2NHCONH-decanyl, CH2NHCONH-decenyl, NH—CO—NH-ethyl, NH—CO—NH—(Z)-1-(2-methylbut-2-en-1-yl), NH—CO—NH-(E)-1-(2-methylbut-2-en-1-yl), NH—CO—NH-1-(3-methylbut-2-en-1-yl), NH—CO—NH-(E)-1-(but-2-en-1-yl), NH—CO—NH-1-cinnamyl, NH—CO—NH-1-(but-3-en-1-yl), NH—CO—NH-(E)-1-(4-(dimethylamino)but-3-en-1-yl);
CH2NHSO2-tigloyl, CH2NHSO2-senecioyl, CH2NHSO2-acetyl, CH2NHSO2-Crotonoyl, CH2NHSO2-3,3-Dimethylartyloyl, CH2NHSO2-Cinnamoyl, CH2NHSO2-Pentenoyl, CH2NHSO2-Hexanoyl, CH2NHSO2-benzoyl, CH2NHSO2-Ethylbutyryl, CH2NHSO2-alkyl, CH2NHSO2-dibenzoyl, CH2NHSO2-benzoyl, CH2NHSO2-alkanoyl, CH2NHSO2-alkenoyl, CH2NHSO2-benzoyl alkyl substituted CH2NHSO2-alkanoyl, CH2NHSO2-alkanoyl substituted phenyl, CH2NHSO2-alkenoyl substituted phenyl, CH2NHSO2-aryl, CH2NHSO2-acyl, CH2NHSO2-heterocylic, CH2NHSO2-heteroraryl, CH2NHSO2-alkenylcarbonyl, CH2NHSO2-alkane, CH2NHSO2-alkene, CH2NHSO2-sugar moiety, CH2NHSO2-acid moiety, CH2NHSO2-ethanoyl, CH2NHSO2-propanoyl, CH2NHSO2-propenoyl, CH2NHSO2-butanoyl, CH2NHSO2-butenoyl, CH2NHSO2-pentanoyl, CH2NHSO2-hexenoyl, CH2NHSO2-heptanoyl, CH2NHSO2-heptenoyl, CH2NHSO2-octanoyl, CH2NHSO2-octenoyl, CH2NHSO2-nonanoyl, CH2NHSO2-nonenoyl, CH2NHSO2-decanoyl, CH2NHSO2-decenoyl, CH2NHSO2-propionyl, CH2NHSO2-2-propenoyl, CH2NHSO2-2-butenoyl, CH2NHSO2-Isobutyryl, CH2NHSO2-2-methylpropanoyl, CH2NHSO2-2-ethylbutyryl, CH2NHSO2-ethylbutanoyl, CH2NHSO2-2-ethylbutanoyl, CH2NHSO2-butyryl, CH2NHSO2-(E)-2,3-Dimethylacryloyl, CH2NHSO2-(E)-2-Methylcrotonoyl, CH2NHSO2-3-cis-Methyl-methacryloyl, CH2NHSO2-3-Methyl-2-butenoyl, CH2NHSO2-3-Methylcrotonoyl, CH2NHSO2-4-Pentenoyl, CH2NHSO2-(2E)-2-pentenoyl, CH2NHSO2-Caproyl, CH2NHSO2-5-Hexenoyl, CH2NHSO2-Capryloyl, CH2NHSO2-Lauroyl, CH2NHSO2-Dodecanoyl, CH2NHSO2-Myristoyl, CH2NHSO2-Tetradecanoyl, CH2NHSO2-Oleoyl, CH2NHSO2-C(2-18) Acyl, CH2NHSO2-ethanyl, CH2NHSO2-propanyl, CH2NHSO2-propenyl, CH2NHSO2-butanyl, CH2NHSO2-butenyl, CH2NHSO2-pentanyl, CH2NHSO2-hexenyl, CH2NHSO2-heptanyl, CH2NHSO2-heptenyl, CH2NHSO2-octanyl, CH2NHSO2-octenyl, CH2NHSO2-nonanyl, CH2NHSO2-nonenyl, CH2NHSO2-decanyl, CH2NHSO2-decenoyl, CH2NHSO2-alkyl, CH2NHSO2-haloalkyl, CH2NHSO2-alkenyl, CH2NHSO2-alkynyl, CH2NHSO2-hydroxyalkyl, CH2NHSO2-alkylene-O-alkyl, CH2NHSO2-aryl, CH2NHSO2-alkylene-aryl, CH2NHSO2-heteroaryl, CH2NHSO2-alkylene-heteroaryl, CH2NHSO2-cycloalkyl, CH2NHSO2-heterocyclyl, and CH2NHSO2-alkylene-heterocyclyl, CH2NHSO2-ethyl, CH2NHSO2-(Z)-(2-methylbut-2-en-1-yl), CH2NHSO2-(E)-prop-1-enyl, CH2NHSO2-(E)-2-phenylethenyl, CH2NHSO2-but-3-enyl,
wherein R3 is OH or H or NH2 or others; wherein R1, R2, R3, R5, R8, R16 are OH or H or NH2 or others; or wherein an O were attached to the above structures with double bond; wherein R9, R11, R12, R13, R14, and R15 are CH3; or wherein R1, R2, R5, R8 represent NH2 or OH; R3 represents NH2 or OH, H or absent; or wherein R4, R10 represent CH2Oangeloyl or CH2NH-angeloyl or CH2NH-tigloyl; R9, R11, R12, R13, R14, R15 represent CH3; or wherein R1, R2, R5, R8 represent OH, NH2, NH-tigloyl, or O-tigloyl; R3 represents OH, H, or absent; or wherein R4, R10 represent NH-tigloyl or CH2O tigloyl; R9, R11, R12, R13, R14, R15 represent CH3; wherein the group attaching to the core compound selected from acetyl, angeloyl, tigloyl, senecioyl, Crotonoyl, 3,3-Dimethylartyloyl, Cinnamoyl, Pentenoyl, Hexanoyl, benzoyl, Ethylbutyryl, alkyl, dibenzoyl, benzoyl, methylbutanoyl, methylpropanoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, alkanoyl substituted phenyl, alkenoyl substituted phenyl, aryl, acyl, heterocylic, heteroraryl, alkenylcarbonyl, ethanoyl, propanoyl, propenoyl, butanoyl, butenoyl, pentanoyl, hexenoyl, heptanoyl, heptenoyl, octanoyl, octenoyl, nonanoyl, nonenoyl, decanoyl, decenoyl, propionyl, 2-propenoyl, 2-butenoyl, Isobutyryl, 2-methylpropanoyl, 2-ethylbutyryl, ethylbutanoyl, 2-ethylbutanoyl, butyryl, (E)-2,3-Dimethylacryloyl, (E)-2-Methylcrotonoyl, 3-cis-Methyl-methacryloyl, 3-Methyl-2-butenoyl, 3-Methylcrotonoyl, 4-Pentenoyl, (2E)-2-pentenoyl, Caproyl, 5-Hexenoyl, Capryloyl, Lauroyl, Dodecanoyl, Myristoyl, Tetradecanoyl, Oleoyl, C(2-18) Acyl are interchangeable; wherein the attached group can be the same group or in combination thereof; wherein the connecting group between the core compound and attached group may be O, S, S(O), S(O)2, C(O), C(O)O, NH, N-alkyl, CH2 or CH2O. In an embodiment, R4 is attached an O-angeloyl, O-tigloyl, O-senecioyl, O-acetyl, O-Crotonoyl, O-3,3-Dimethylartyloyl, O-Cinnamoyl, O-Pentenoyl, O-Hexanoyl, O-benzoyl, O-Ethylbutyryl, O-alkyl, O-dibenzoyl, O-benzoyl, O-alkanoyl, O-alkenoyl, O-benzoyl alkyl substituted O-alkanoyl, O-alkanoyl substituted phenyl, O-alkenoyl substituted phenyl, O-aryl, O-acyl, O-heterocylic, O-heteroraryl, O-alkenylcarbonyl, O-ethanoyl, O-propanoyl, O-propenoyl, O-butanoyl, O-butenoyl, O-pentanoyl, O-hexenoyl, O-heptanoyl, O-heptenoyl, O-octanoyl, O-octenoyl, O-nonanoyl, O-nonenoyl, O-decanoyl, O-decenoyl, O-propionyl, O-2-propenoyl, O-2-butenoyl, O-Isobutyryl, O-2-methylpropanoyl, O-2-ethylbutyryl, O-ethylbutanoyl, O-2-ethylbutanoyl, O-butyryl, O-(E)-2,3-Dimethylacryloyl, O-(E)-2-Methylcrotonoyl, O-3-cis-Methyl-methacryloyl, O-3-Methyl-2-butenoyl, O-3-Methylcrotonoyl, O-4-Pentenoyl, O-(2E)-2-pentenoyl, O-Caproyl, O-5-Hexenoyl, O-Capryloyl, O-Lauroyl, O-Dodecanoyl, O-Myristoyl, O-Tetradecanoyl, O-Oleoyl, O—C(2-18) Acyl, CH2O-angeloyl, CH2O-tigloyl, CH2O-senecioyl, CH2O-acetyl, CH2O-Crotonoyl, CH2O-3,3-Dimethylartyloyl, CH2O-Cinnamoyl, CH2O-Pentenoyl, CH2O-Hexanoyl, CH2O-benzoyl, CH2O-Ethylbutyryl, CH3, CH2OH, CH2O-alkyl, CH2O-dibenzoyl, CH2O-benzoyl, CH2O-alkanoyl, CH2O-alkenoyl, CH2O-benzoyl alkyl substituted O-alkanoyl, CH2O-alkanoyl substituted phenyl, CH2O-alkenoyl substituted phenyl, CH2O-aryl, CH2O-acyl, CH2O-heterocylic, CH2O-heteroraryl, CH2O-alkenylcarbonyl, CH2O-ethanoyl, CH2O-propanoyl, CH2O-propenoyl, CH2O-butanoyl, CH2O-butenoyl, CH2O-pentanoyl, CH2O-hexenoyl, CH2O-heptanoyl, CH2O-heptenoyl, CH2O-octanoyl, CH2O-octenoyl, CH2O-nonanoyl, CH2O-nonenoyl, CH2O-decanoyl, CH2O-decenoyl, CH2O-propionyl, CH2O-2-propenoyl, CH2O-2-butenoyl, CH2O-Isobutyryl, CH2O-2-methylpropanoyl, CH2O-2-ethylbutyryl, CH2O-ethylbutanoyl, CH2O-2-ethylbutanoyl, CH2O-butyryl, CH2O-(E)-2,3-Dimethylacryloyl, CH2O-(E)-2-Methylcrotonoyl, CH2O-3-cis-Methyl-methacryloyl, CH2O-3-Methyl-2-butenoyl, CH2O-3-Methylcrotonoyl, CH2O-4-Pentenoyl, CH2O-(2E)-2-pentenoyl, CH2O-Caproyl, CH2O-5-Hexenoyl, CH2O-Capryloyl, CH2O-Lauroyl, CH2O-Dodecanoyl, CH2O-Myristoyl, CH2O-Tetradecanoyl, CH2O-Oleoyl, CH2O—C(2-18) Acyl, In an embodiment, the connecting group between the functional group of angeloyl, tigloyl, senecioyl, acetyl, Crotonoyl, 3,3-Dimethylartyloyl, Cinnamoyl, Pentenoyl, Hexanoyl, benzoyl, Ethylbutyryl, alkyl, dibenzoyl, benzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, alkanoyl substituted phenyl, alkenoyl substituted phenyl, aryl, acyl, heterocylic, heteroraryl, and alkenylcarbonyl ethanoyl, propanoyl, propenoyl, butanoyl, butenoyl, pentanoyl, hexenoyl, heptanoyl, heptenoyl, octanoyl, octenoyl, nonanoyl, nonenoyl, decanoyl, decenoyl, propionyl, 2-propenoyl, 2-butenoyl, Isobutyryl, 2-methylpropanoyl, 2-ethylbutyryl, ethylbutanoyl, 2-ethylbutanoyl, butyryl, (E)-2,3-Dimethylacryloyl, (E)-2-Methylcrotonoyl, 3-cis-Methyl-methacryloyl, 3-Methyl-2-butenoyl, 3-Methylcrotonoyl, 4-Pentenoyl, (2E)-2-pentenoyl, Caproyl, 5-Hexenoyl, Capryloyl, Lauroyl, Dodecanoyl, Myristoyl, Tetradecanoyl, Oleoyl, or C(2-18) Acyl, can be O, S, S(O), S(O)2, C(O), C(O)O, NH, N-alkyl, CH2 or CH2O. In an embodiment, the compound(s) is(are) in form in form of powder, liquid or crystal.
In an embodiment, any 1 or 2 or 3 or 4 or 5 or 6 of R1, R2, R3, R4, R5, R8, R9, R10, R11, R12, R13, R14, R15, R16 are independently selected from the group of A-B, wherein A can be O, S, S(O), S(O)2, C(O), C(O)O, NH, N-alkyl, CH2 or CH2O, CH2NH, CH2NHCH2, CH2NHCO, CH2NHCONH, CH2NHSO2;
wherein B is selected from the group of acetyl, angeloyl, tigloyl, senecioyl, Crotonoyl, 3,3-Dimethylartyloyl, Cinnamoyl, Pentenoyl, Hexanoyl, benzoyl, Ethylbutyryl, alkyl, dibenzoyl, benzoyl, methylbutanoyl, methylpropanoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, alkanoyl substituted phenyl, alkenoyl substituted phenyl, aryl, acyl, heterocylic, heteroraryl, alkenylcarbonyl, ethanoyl, propanoyl, propenoyl, butanoyl, butenoyl, pentanoyl, hexenoyl, heptanoyl, heptenoyl, octanoyl, octenoyl, nonanoyl, nonenoyl, decanoyl, decenoyl, propionyl, 2-propenoyl, 2-butenoyl, Isobutyryl, 2-methylpropanoyl, 2-ethylbutyryl, ethylbutanoyl, 2-ethylbutanoyl, butyryl, (E)-2,3-Dimethylacryloyl, (E)-2-Methylcrotonoyl, 3-cis-Methyl-methacryloyl, 3-Methyl-2-butenoyl, 3-Methylcrotonoyl, 4-Pentenoyl, (2E)-2-pentenoyl, Caproyl, 5-Hexenoyl, Capryloyl, Lauroyl, Dodecanoyl, Myristoyl, Tetradecanoyl, Oleoyl and C(2-18) Acyl. In an embodiment, R1 is A-B. In an embodiment, R2 is A-B. In an embodiment, R3 is A-B. In an embodiment, R4 is A-B. In an embodiment, R5 is A-B. In an embodiment, R6 is A-B. In an embodiment, R7 is A-B. In an embodiment, R8 is A-B. In an embodiment, R9 is A-B. In an embodiment, R10 is A-B. In an embodiment, R11 is A-B. In an embodiment, R12 is A-B. In an embodiment, R13 is A-B. In an embodiment, R14 is A-B. In an embodiment, R15 is A-B. In an embodiment, the compound(s) is(are) in form in form of powder, liquid or crystal. In an embodiment, this invention provides compounds of the above to improve blood circulation; soothing stroke; Prevent plaque formation and promote their dissipated; improve blood viscosity; reduce cardiovascular; reduce cerebrovascular; reduce thrombosis, arteriosclerosis, coronary heart disease, hypertension, diabetes, thrombocytopenia purpura, hemoptysis, hematemesis; treating blood in the stool, uterine bleeding, traumatic bleeding, abdominal irritation, swelling, flutter, Blood circulation, swelling, pain; Treating bronchiectasis, tuberculosis and lung abscess caused by too hemoptysis; reducing bleeding, antitussive, expectorant and analgesic effect, dilate blood vessels; reducing blood pressure and the treatment of cerebral arteriosclerosis; elevated blood lipids and reduced cholesterol. The R1, R2, R3, R4, R5, R8, R9, R10, R11, R12, R13, R14, R15, R16 bonds of (3K2) can be alpha or beta.
R1, R2, R3, R4, R5, R8, R9, R10, R11, R12, R13, R14, R15, R16 are independently selected from the group of O, hydrogen, hydroxyl, methyl, O-angeloyl, O-tigloyl, O-senecioyl, O-acetyl, O-Crotonoyl, O-3,3-Dimethylartyloyl, O-Cinnamoyl, O-Pentenoyl, O-Hexanoyl, O-benzoyl, O-Ethylbutyryl, O-alkyl, O-dibenzoyl, O-benzoyl, O-alkanoyl, O-alkenoyl, O-benzoyl alkyl substituted O-alkanoyl, O-alkanoyl substituted phenyl, O-alkenoyl substituted phenyl, O-aryl, O-acyl, O-heterocylic, O-heteroraryl, O-alkenylcarbonyl, O-ethanoyl, O-propanoyl, O-propenoyl, O-butanoyl, O-butenoyl, O-pentanoyl, O-hexenoyl, O-heptanoyl, O-heptenoyl, O-octanoyl, O-octenoyl, O-nonanoyl, O-nonenoyl, O-decanoyl, O-decenoyl, O-propionyl, O-2-propenoyl, O-2-butenoyl, O-Isobutyryl, O-2-methylpropanoyl, O-2-ethylbutyryl, O-ethylbutanoyl, O-2-ethylbutanoyl, O-butyryl, O-(E)-2,3-Dimethylacryloyl, O-(E)-2-Methylcrotonoyl, O-3-cis-Methyl-methacryloyl, O-3-Methyl-2-butenoyl, O-3-Methylcrotonoyl, O-4-Pentenoyl, O-(2E)-2-pentenoyl, O-Caproyl, O-5-Hexenoyl, O-Capryloyl, O-Lauroyl, O-Dodecanoyl, O-Myristoyl, O-Tetradecanoyl, O-Oleoyl In an embodiment, the compound(s) is(are) in form in form of powder, liquid or crystal.
In embodiment the core having structures:
wherein R1, R2, R3, R4, R5, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, of T1, T2, T3, T4, T5, T6, T7, T8, T9,T10, T11, T12, T13, T14, T15, T16, T17, T18, T19, T20, T21, T22, T23, T24, T25, T26, T27 represent H, OH, O, CH2OH, COOH or CH3. The bonds can be in forms of alpha or beta or in combinations. In an embodiment, the compound(s) is in form in form of powder, liquid or crystal
With experiments and methods in present application or esterification the above core compound with acyl halide, wherein the halide comprise chloride, bromide, fluoride and iodide, wherein the acyl halide comprise acyl chloride, wherein acyl chloride comprise tigloyl chloride, angeloyl chloride, acetyl chloride, crotonoyl chloride, 3,3-dimethylartyloyl chloride, senecioyl chloride, cinnamoyl chloride, pentenoyl chloride, hexanoyl chloride, benzoyl chloride, ethylbutyryl chloride, propionyl chloride, 2-propenoyl chloride, isobutyryl chloride, butyryl chloride, (2E)-2-pentenoyl chloride, 4-Pentenoyl chloride, 5-hexenoyl chloride, heptanoyl chloride, octanoyl chloride, nonanoyl chloride, decanoyl chloride, Lauroyl chloride, myristoyl chloride, oleoyl chloride. The compounds vary in composition when the time or temperature of the reaction is changed. The peaks, fractions and compounds are selected according to the activities of times studies and the changes of peaks. The compounds having strong to weak activities are selected and isolated. The anti cancer activities (Cytotoxic Assay) are the MTT studies of bone (U2OS), lung (H460), bladder (HTB-9), ovary (ES2), colon (HCT116), pancreas (Capan), ovary (OVCAR3), prostate (DU145), skin (SK-Mel-5), mouth (KB), kidney (A498), breast (MCF-7), liver (HepG2), brain (T98G), luekemia (K562), cervix (HeLa). The active esterification products are purified with HPLC. The reaction product of mixtures and individual compounds are tested with MTT Cytotoxic Assay. Details of method are in Experiment 3 of the present application. A second esterification of compound can be selected from the above experiment results to produce new active compounds. A partial esterification compound is selected from the above experiments to perform a second or repeated with a third esterification with different acyl chloride in order to produce new active compounds with the experiments in the present application.
A method is 1) Dissolving core compound or triterpenes core, hydroxylated triterpenes core, in pyridine; 2) Adding acyl halide or acyl chloride; 3, The mixture is stirred for length of time including 5 sec, 10 sec, 20 sec, 30 sec, 40 sec, 1 min, 2 min, 5 min, 10 min, 30 min, 1 hr, 2 hr, 18 hr, 2 days or 3 days at different temperature; 4) At the end of reaction, aqueous solution of acid or weak base, or water is added to the reaction mixture; 5) The solution is then extracted of ethyl acetate and ethyl acetate is removed by evaporation and lyophilization; 6) Dissolving the reaction product in acetonitrile with Trifluoroacetic acid or DMSO; 7) Testing the reaction product of mixtures and individual fractions with MTT cytotoxic assay; 8) Selecting the HPLC fractions for isolation is according to the cytotoxic activity of the reaction product obtained at a specific reaction time; 10) Purifying the active esterification products with HPLC; 11) Collecting the products; 12) Testing the products; wherein the core compound is terpene, isoprene, or triterpene core or hydroxylated triterpenes core; wherein the core compound was dissolved in pyridine; wherein the acyl chloride including Tigloyl chloride, angeloyl chloride, Acetyl chloride, Crotonoyl chloride, 3,3-Dimethylartyloyl chloride, senecioyl chloride, Cinnamoyl chloride, Pentenoyl chloride, Hexanoyl chloride, benzoyl chloride, Ethylbutyryl chloride, Propionyl chloride, 2-Propenoyl chloride, Isobutyryl chloride, Butyryl chloride, (2E)-2-pentenoyl chloride, 4-Pentenoyl chloride, 5-Hexenoyl chloride, Heptanoyl chloride, Octanoyl chloride, Nonanoyl chloride, Decanoyl chloride, Lauroyl chloride, Myristoyl chloride, and Oleoyl chloride; wherein the reaction time for the mixture is stirred for 5 sec, 10 sec, 20 sec, 30 sec, 40 sec, 1 min, 2 min, 5 min, 10 min, 30 min, 1 hr, 2 hr, 18 hr, 2 days or 3 days; wherein the temperature is 0 C, 25 C, 50 C or 75 C temperature; wherein the acid including HCl or the base including NaHCO3 is added to the reaction mixture; wherein the solution is then extracted 3 times with ethyl acetate and lyophilization; wherein the reaction product is dissolved in 80% acetonitrile-0.005% Trifluoroacetic acid or DMSO; wherein selecting the HPLC fractions for isolation is according to the cytotoxic activity of the reaction product obtained at a reaction time of 5 sec, 10 sec, 20 sec, 30 sec, 40 sec, 1 min, 2 min, 5 min, 10 min, 30 min, 1 hr, 2 hrs, 18 hrs, 2 days or 3 days. In an embodiment, the reaction time may be over 3 days. In an embodiment, the experiment may be performed under 0 C. In an embodiment, the experiment may be performed over 75° C.
In embodiment, the attachment of sugar moiety(ies) can be biosynthesized.
A method is to a solution of core (2 mmol) in THF (10 mL) were added Ms-Cl (2.2 mmol) and triethylamine (3 mmol) at 0° C. and the resulting mixture was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate and washed with water. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in 10 mL of DMF, and then NaN3 (6 mmol) was added. After overnight stirring at 60° C., the reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Then, the obtained compound was dissolved in methanol, and 10% Pd—C (0.2 mmol) was added. After overnight stirring under hydrogen atmosphere, the reaction mixture was filtered, washed with methanol and concentrated under reduced pressure to provide products.
This invention provide the compound having structures of T1, T2, T3, T4, T5, T6, T7, T8, T9, T10, T11, T12, T13, T14, T15, T16, T17; T18, T19, T20, T21, T22, T23, T24, T25, T26, T27 wherein the R1, R2, R3, R4, R5, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18 are independently selected from the group of hydrogen, hydroxyl, methyl, O,O-angeloyl, O-tigloyl, O-senecioyl, O-acetyl, O-Crotonoyl, O-3,3-Dimethylartyloyl, O-Cinnamoyl, O-Pentenoyl, O-Hexanoyl, O-benzoyl, O-Ethylbutyryl, O-alkyl, O-dibenzoyl, O-benzoyl, O-alkanoyl, O-alkenoyl, O-benzoyl alkyl substituted O-alkanoyl, O-alkanoyl substituted phenyl, O-alkenoyl substituted phenyl, O-aryl, O-acyl, O-heterocylic, O-heteroraryl, O-alkenylcarbonyl, O-ethanoyl, O-propanoyl, O-propenoyl, O-butanoyl, O-butenoyl, O-pentanoyl, O-hexenoyl, O-heptanoyl, O-heptenoyl, O-octanoyl, O-octenoyl, O-nonanoyl, O-nonenoyl, O-decanoyl, O-decenoyl, O-propionyl, O-2-propenoyl, O-2-butenoyl, O-Isobutyryl, O-2-methyl propanoyl, O-2-ethylbutyryl, O-ethylbutanoyl, O-2-ethylbutanoyl, O-butyryl, O-(E)-2,3-Dimethylacryloyl, O-(E)-2-Methylcrotonoyl, O-3-cis-Methyl-methacryloyl, O-3-Methyl-2-butenoyl, O-3-Methylcrotonoyl, O-4-Pentenoyl, O-(2E)-2-pentenoyl, O-Caproyl, O-5-Hexenoyl, O-Capryloyl, O-Lauroyl, O-Dodecanoyl, O-Myristoyl, O-Tetradecanoyl, O-Oleoyl, O—C(2-18) Acyl, O-4-(dimethylamino)-2-methylbut-2-enoyl, O-4-[(2-methoxyethyl)amino]-2-methyl-4oxobut-2-enoyl, O-sugar moiety(ies), O-acid moiety(ies), CH2O-angeloyl, CH2O-tigloyl, CH2O-senecioyl, CH2O-acetyl, CH2O-Crotonoyl, CH2O-3,3-Dimethylartyloyl, CH2O-Cinnamoyl, CH2O-Pentenoyl, CH2O-Hexanoyl, CH2O-benzoyl, CH2O-Ethylbutyryl, CH3, CH2OH, CH2O-alkyl, CH2O-dibenzoyl, CH2O-benzoyl, CH2O-alkanoyl, CH2O-alkenoyl, CH2O-benzoyl alkyl substituted O-alkanoyl, CH2O-alkanoyl substituted phenyl, CH2O-alkenoyl substituted phenyl, CH2O-aryl, CH2O-acyl, CH2O-heterocylic, CH2O-heteroraryl, CH2O-alkenylcarbonyl, CH2O-ethanoyl, CH2O-propanoyl, CH2O-propenoyl, CH2O-butanoyl, CH2O-butenoyl, CH2O-pentanoyl, CH2O-hexenoyl, CH2O-heptanoyl, CH2O-heptenoyl, CH2O-octanoyl, CH2O-octenoyl, CH2O-nonanoyl, CH2O-nonenoyl, CH2O-decanoyl, CH2O-decenoyl, CH2O-propionyl, CH2O-2-propenoyl, CH2O-2-butenoyl, CH2O-Isobutyryl, CH2O-2-methylpropanoyl, CH2O-2-ethylbutyryl, CH2O-ethylbutanoyl, CH2O-2-ethylbutanoyl, CH2O-butyryl, CH2O-(E)-2,3-Dimethylacryloyl, CH2O-(E)-2-Methylcrotonoyl, CH2O-3-cis-Methyl-methacryloyl, CH2O-3-Methyl-2-butenoyl, CH2O-3-Methylcrotonoyl, CH2O-4-Pentenoyl, CH2O-(2E)-2-pentenoyl, CH2O-Caproyl, CH2O-5-Hexenoyl, CH2O-Capryloyl, CH2O-Lauroyl, CH2O-Dodecanoyl, CH2O-Myristoyl, CH2O-Tetradecanoyl, CH2O-Oleoyl, CH2O—C(2-18) Acyl, CH2O-4-(dimethylamino)-2-methylbut-2-enoyl, CH2O-4-[(2-methoxyethyl)amino]-2-methyl-4oxobut-2-enoyl, alkane, alkene and derivatives thereof. In an embodiment, the compound(s) is(are) in form in form of powder, liquid or crystal.
In an embodiment, the compound is attached a sugar moiety(ies), acid moiety(ies) or alduronic acid, wherein the sugar moiety(ies) is/are selected from a group of glucose, galactose, rhamnose, arabinose, xylose, fucose, allose, altrose, gulose, idose, lyxose, mannose, psicose, ribose, sorbose, tagatose, talose, fructose, alduronic acid, glucuronic acid, galacturonic acid, and derivatives or combinations thereof. In an embodiment, the compound is attached a group selected from (CnH2n)O-angeloyl, (CnH2n)O-tigloyl, (CnH2n)O-senecioyl, (CnH2n)O-acetyl, (CnH2n)O-Crotonoyl, (CnH2n)O-3,3-Dimethylartyloyl, (CnH2n)O-Cinnamoyl, (CnH2n)O-Pentenoyl, (CnH2n)O-Hexanoyl, (CnH2n)O-benzoyl, (CnH2n)O-Ethylbutyryl, (CnH2n)O-alkyl, (CnH2n)O-dibenzoyl, (CnH2n)O-benzoyl, (CnH2n)O-alkanoyl, (CnH2n)O-alkenoyl, (CnH2n)O-benzoyl alkyl substituted O-alkanoyl, (CnH2n)O-alkanoyl substituted phenyl, (CnH2n)O-alkenoyl substituted phenyl, (CnH2n)O-aryl, (CnH2n)O-acyl, (CnH2n)O-heterocylic, (CnH2n)O-heteroraryl, (CnH2n)O-alkenylcarbonyl, (CnH2n)O-alkane, (CnH2n)O-alkene and (CnH2n)O-sugar moiety and (CnH2n)O-acid moiety; wherein the sugar moiety(ies) is/are included but not limited to a group of glucose, galactose, rhamnose, arabinose, xylose, fucose, allose, altrose, gulose, idose, lyxose, mannose, psicose, ribose, sorbose, tagatose, talose, fructose, alduronic acid, glucuronic acid, galacturonic acid, and derivatives or combinations thereof; wherein n is 1 or 2 or 3 or 4 or over 5.
In an embodiment with experiments in the invention, any 1 or 2 or 3 or 4 or 5 or 6 of R1, R2, R3, R4, R5, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18 are independently selected from the group of A-B, wherein A can be O, S, S(O), S(O)2, C(O), C(O)O, NH, N-alkyl, CH2, CH2O, CH2NH, CH2NHCH2, CH2NHCO, CH2NHCONH, or CH2NHSO2;
wherein B is selected from the group of H, acetyl, angeloyl, tigloyl, senecioyl, Crotonoyl, 3,3-Dimethylartyloyl, Cinnamoyl, Pentenoyl, Hexanoyl, benzoyl, Ethylbutyryl, alkyl, dibenzoyl, benzoyl, methylbutanoyl, methylpropanoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, alkanoyl substituted phenyl, alkenoyl substituted phenyl, aryl, acyl, heterocylic, heteroraryl, alkenylcarbonyl, ethanoyl, propanoyl, propenoyl, butanoyl, butenoyl, pentanoyl, hexenoyl, heptanoyl, heptenoyl, octanoyl, octenoyl, nonanoyl, nonenoyl, decanoyl, decenoyl, propionyl, 2-propenoyl, 2-butenoyl, Isobutyryl, 2-methylpropanoyl, 2-ethylbutyryl, ethylbutanoyl, 2-ethylbutanoyl, butyryl, (E)-2,3-Dimethylacryloyl, (E)-2-Methylcrotonoyl, 3-cis-Methyl-methacryloyl, 3-Methyl-2-butenoyl, 3-Methylcrotonoyl, 4-Pentenoyl, (2E)-2-pentenoyl, Caproyl, 5-Hexenoyl, Capryloyl, Lauroyl, Dodecanoyl, Myristoyl, Tetradecanoyl, Oleoyl and C(2-18) Acyl.
NH-tigloyl, NH-angeloyl, NH-senecioyl, NH-acetyl, NH-Crotonoyl, NH-3,3-Dimethylartyloyl, NH-Cinnamoyl, NH-Pentenoyl, NH-Hexanoyl, NH-benzoyl, NH-Ethylbutyryl, NH-alkyl, NH-dibenzoyl, NH-benzoyl, NH-alkanoyl, NH-alkenoyl, NH-benzoyl alkyl substituted NH-alkanoyl, NH-alkanoyl substituted phenyl, NH-alkenoyl substituted phenyl, NH-aryl, NH-acyl, NH-heterocylic, NH-heteroraryl, NH-alkenylcarbonyl, NH-alkane, NH-alkene, NH-sugar moiety, NH-acid moiety, NH-ethanoyl, NH-propanoyl, NH-propenoyl, NH-butanoyl, NH-butenoyl, NH-pentanoyl, NH-hexenoyl, NH-heptanoyl, NH-heptenoyl, NH-octanoyl, NH-octenoyl, NH-nonanoyl, NH-nonenoyl, NH-decanoyl, NH-decenoyl, NH-propionyl, NH-2-propenoyl, NH-2-butenoyl, NH-Isobutyryl, NH-2-methylpropanoyl, NH-2-ethylbutyryl, NH-ethylbutanoyl, NH-2-ethylbutanoyl, NH-butyryl, NH-(E)-2,3-Dimethylacryloyl, NH-(E)-2-Methylcrotonoyl, NH-3-cis-Methyl-methacryloyl, NH-3-Methyl-2-butenoyl, NH-3-Methylcrotonoyl, NH-4-Pentenoyl, NH-(2E)-2-pentenoyl, NH-Caproyl, NH-5-Hexenoyl, NH-Capryloyl, NH-Lauroyl, NH-Dodecanoyl, NH-Myristoyl, NH-Tetradecanoyl, NH-Oleoyl, NH—C(2-18) Acyl,
CH2NH-tigloyl, CH2NH-angeloyl, CH2NH-senecioyl, CH2NH-acetyl, CH2NH-Crotonoyl, CH2NH-3,3-Dimethylartyloyl, CH2NH-Cinnamoyl, CH2NH-Pentenoyl, CH2NH-Hexanoyl, CH2NH-benzoyl, CH2NH-Ethylbutyryl, CH2NH-alkyl, CH2NH-dibenzoyl, CH2NH-benzoyl, CH2NH-alkanoyl, CH2NH-alkenoyl, CH2NH-benzoyl alkyl substituted CH2NH-alkanoyl, CH2NH-alkanoyl substituted phenyl, CH2NH-alkenoyl substituted phenyl, CH2NH-aryl, CH2NH-acyl, CH2NH-heterocylic, CH2NH-heteroraryl, CH2NH-alkenylcarbonyl, CH2NH-alkane, CH2NH-alkene, CH2NH-sugar moiety, CH2NH-acid moiety, CH2NH-ethanoyl, CH2NH-propanoyl, CH2NH-propenoyl, CH2NH-butanoyl, CH2NH-butenoyl, CH2NH-pentanoyl, CH2NH-hexenoyl, CH2NH-heptanoyl, CH2NH-heptenoyl, CH2NH-octanoyl, CH2NH-octenoyl, CH2NH-nonanoyl, CH2NH-nonenoyl, CH2NH-decanoyl, CH2NH-decenoyl, CH2NH-propionyl, CH2NH-2-propenoyl, CH2NH-2-butenoyl, CH2NH-Isobutyryl, CH2NH-2-methylpropanoyl, CH2NH-2-ethylbutyryl, CH2NH-ethylbutanoyl, CH2NH-2-ethylbutanoyl, CH2NH-butyryl, CH2NH-(E)-2,3-Dimethylacryloyl, CH2NH-(E)-2-Methylcrotonoyl, CH2NH-3-cis-Methyl-methacryloyl, CH2NH-3-Methyl-2-butenoyl, CH2NH-3-Methylcrotonoyl, CH2NH-4-Pentenoyl, CH2NH-(2E)-2-pentenoyl, CH2NH-Caproyl, CH2NH-5-Hexenoyl, CH2NH-Capryloyl, CH2NH-Lauroyl, CH2NH-Dodecanoyl, CH2NH-Myristoyl, CH2NH-Tetradecanoyl, CH2NH-Oleoyl, CH2NH—C(2-18) Acyl,
CH2NHCH2-tigloyl, CH2NHCH2-angeloyl, CH2NHCH2-senecioyl, CH2NHCH2-acetyl, CH2NHCH2-Crotonoyl, CH2NHCH2-3,3-Dimethylartyloyl, CH2NHCH2-Cinnamoyl, CH2NHCH2-Pentenoyl, CH2NHCH2-Hexanoyl, CH2NHCH2-benzoyl, CH2NHCH2-Ethylbutyryl, CH2NHCH2-alkyl, CH2NHCH2-dibenzoyl, CH2NHCH2-benzoyl, CH2NHCH2-alkanoyl, CH2NHCH2-alkenoyl, CH2NHCH2-benzoyl alkyl substituted CH2NHCH2-alkanoyl, CH2NHCH2-alkanoyl substituted phenyl, CH2NHCH2-alkenoyl substituted phenyl, CH2NHCH2-aryl, CH2NHCH2-acyl, CH2NHCH2-heterocylic, CH2NHCH2-heteroraryl, CH2NHCH2-alkenylcarbonyl, CH2NHCH2-alkane, CH2NHCH2-alkene, CH2NHCH2-sugar moiety, CH2NHCH2-acid moiety, CH2NHCH2-ethanoyl, CH2NHCH2-propanoyl, CH2NHCH2-propenoyl, CH2NHCH2-butanoyl, CH2NHCH2-butenoyl, CH2NHCH2-pentanoyl, CH2NHCH2-hexenoyl, CH2NHCH2-heptanoyl, CH2NHCH2-heptenoyl, CH2NHCH2-octanoyl, CH2NHCH2-octenoyl, CH2NHCH2-nonanoyl, CH2NHCH2-nonenoyl, CH2NHCH2-decanoyl, CH2NH-decenoyl, CH2NHCH2-propionyl, CH2NHCH2-2-propenoyl, CH2NHCH2-2-butenoyl, CH2NHCH2-Isobutyryl, CH2NHCH2-2-methylpropanoyl, CH2NHCH2-2-ethylbutyryl, CH2NHCH2-ethylbutanoyl, CH2NHCH2-2-ethylbutanoyl, CH2NHCH2-butyryl, CH2NHCH2-(E)-2,3-Dimethylacryloyl, CH2NHCH2-(E)-2-Methylcrotonoyl, CH2NHCH2-3-cis-Methyl-methacryloyl, CH2NHCH2-3-Methyl-2-butenoyl, CH2NHCH2-3-Methylcrotonoyl, CH2NHCH2-4-Pentenoyl, CH2NHCH2-(2E)-2-pentenoyl, CH2NHCH2-Caproyl, CH2NHCH2-5-Hexenoyl, CH2NHCH2-Capryloyl, CH2NHCH2-Lauroyl, CH2NHCH2-Dodecanoyl, CH2NHCH2-Myristoyl, CH2NHCH2-Tetradecanoyl, CH2NHCH2-Oleoyl, CH2NHCH2-C(2-18) Acyl,
CH2NHCO-tigloyl, CH2NHCO-angeloyl, CH2NHCO-senecioyl, CH2NHCO-acetyl, CH2NHCO-Crotonoyl, CH2NHCO-3,3-Dimethylartyloyl, CH2NHCO-Cinnamoyl, CH2NHCO-Pentenoyl, CH2NHCO-Hexanoyl, CH2NHCO-benzoyl, CH2NHCO-Ethylbutyryl, CH2NHCO-alkyl, CH2NHCO-dibenzoyl, CH2NHCO-benzoyl, CH2NHCO-alkanoyl, CH2NHCO-alkenoyl, CH2NHCO-benzoyl alkyl substituted CH2NHCO-alkanoyl, CH2NHCO-alkanoyl substituted phenyl, CH2NHCO-alkenoyl substituted phenyl, CH2NHCO-aryl, CH2NHCO-acyl, CH2NHCO-heterocylic, CH2NHCO-heteroraryl, CH2NHCO-alkenylcarbonyl, CH2NHCO-alkane, CH2NHCO-alkene, CH2NHCO-sugar moiety, CH2NHCO-acid moiety, CH2NHCO-ethanoyl, CH2NHCO-propanoyl, CH2NHCO-propenoyl, CH2NHCO-butanoyl, CH2NHCO-butenoyl, CH2NHCO-pentanoyl, CH2NHCO-hexenoyl, CH2NHCO-heptanoyl, CH2NHCO-heptenoyl, CH2NHCO-octanoyl, CH2NHCO-octenoyl, CH2NHCO-nonanoyl, CH2NHCO-nonenoyl, CH2NHCO-decanoyl, CH2NHCO-decenoyl, CH2NHCO-propionyl, CH2NHCO-2-propenoyl, CH2NHCO-2-butenoyl, CH2NHCO-Isobutyryl, CH2NHCO-2-methylpropanoyl, CH2NHCO-2-ethylbutyryl, CH2NHCO-ethylbutanoyl, CH2NHCO-2-ethylbutanoyl, CH2NHCO-butyryl, CH2NHCO-(E)-2,3-Dimethylacryloyl, CH2NHCO-(E)-2-Methylcrotonoyl, CH2NHCO-3-cis-Methyl-methacryloyl, CH2NHCO-3-Methyl-2-butenoyl, CH2NHCO-3-Methylcrotonoyl, CH2NHCO-4-Pentenoyl, CH2NHCO-(2E)-2-pentenoyl, CH2NHCO-Caproyl, CH2NHCO-5-Hexenoyl, CH2NHCO-Capryloyl, CH2NHCO-Lauroyl, CH2NHCO-Dodecanoyl, CH2NHCO-Myristoyl, CH2NHCO-Tetradecanoyl, CH2NHCO-Oleoyl, CH2NHCO—C(2-18) Acyl,
CH2NHCONH-tigloyl, CH2NHCONH-senecioyl, CH2NHCONH-acetyl, CH2NHCONH-Crotonoyl, CH2NHCONH-3,3-Dimethylartyloyl, CH2NHCONH-Cinnamoyl, CH2NHCONH-Pentenoyl, CH2NHCONH-Hexanoyl, CH2NHCONH-benzoyl, CH2NHCONH-Ethylbutyryl, CH2NHCONH-alkyl, CH2NHCONH-dibenzoyl, CH2NHCONH-benzoyl, CH2NHCONH-alkanoyl, CH2NHCONH-alkenoyl, CH2NHCONH-benzoyl alkyl substituted CH2NHCONH-alkanoyl, CH2NHCONH-alkanoyl substituted phenyl, CH2NHCONH-alkenoyl substituted phenyl, CH2NHCONH-aryl, CH2NHCONH-acyl, CH2NHCONH-heterocylic, CH2NHCONH-heteroraryl, CH2NHCONH-alkenylcarbonyl, CH2NHCONH-alkane, CH2NHCONH-alkene, CH2NHCONH-sugar moiety, CH2NHCONH-acid moiety, CH2NHCONH-ethanoyl, CH2NHCONH-propanoyl, CH2NHCONH-propenoyl, CH2NHCONH-butanoyl, CH2NHCONH-butenoyl, CH2NHCONH-pentanoyl, CH2NHCONH-hexenoyl, CH2NHCONH-heptanoyl, CH2NHCONH-heptenoyl, CH2NHCONH-octanoyl, CH2NHCONH-octenoyl, CH2NHCONH-nonanoyl, CH2NHCONH-nonenoyl, CH2NHCONH-decanoyl, CH2NHCONH-decenoyl, CH2NHCONH-propionyl, CH2NHCONH-2-propenoyl, CH2NHCONH-2-butenoyl, CH2NHCONH-Isobutyryl, CH2NHCONH-2-methylpropanoyl, CH2NHCONH-2-ethylbutyryl, CH2NHCONH-ethylbutanoyl, CH2NHCONH-2-ethylbutanoyl, CH2NHCONH-butyryl, CH2NHCONH-(E)-2,3-Dimethylacryloyl, CH2NHCONH-(E)-2-Methylcrotonoyl, CH2NHCONH-3-cis-Methyl-methacryloyl, CH2NHCONH-3-Methyl-2-butenoyl, CH2NHCONH-3-Methylcrotonoyl, CH2NHCONH-4-Pentenoyl, CH2NHCONH-(2E)-2-pentenoyl, CH2NHCONH-Caproyl, CH2NHCONH-5-Hexenoyl, CH2NHCONH-Capryloyl, CH2NHCONH-Lauroyl, CH2NHCONH-Dodecanoyl, CH2NHCONH-Myristoyl, CH2NHCONH-Tetradecanoyl, CH2NHCONH-Oleoyl, CH2NHCONH—C(2-18) Acyl,
NHSO2-tigloyl, NHSO2-senecioyl, NHSO2-acetyl, NHSO2-Crotonoyl, NHSO2-3,3-Dimethylartyloyl, NHSO2-Cinnamoyl, NHSO2-Pentenoyl, NHSO2-Hexanoyl, NHSO2-benzoyl, NHSO2-Ethylbutyryl, NHSO2-alkyl, NHSO2-dibenzoyl, NHSO2-benzoyl, NHSO2-alkanoyl, NHSO2-alkenoyl, NHSO2-benzoyl alkyl substituted NHSO2-alkanoyl, NHSO2-alkanoyl substituted phenyl, NHSO2-alkenoyl substituted phenyl, NHSO2-aryl, NHSO2-acyl, NHSO2-heterocylic, NHSO2-heteroraryl, NHSO2-alkenylcarbonyl, NHSO2-alkane, NHSO2-alkene, NHSO2-sugar moiety, NHSO2-acid moiety, NHSO2-ethanoyl, NHSO2-propanoyl, NHSO2-propenoyl, NHSO2-butanoyl, NHSO2-butenoyl, NHSO2-pentanoyl, NHSO2-hexenoyl, NHSO2-heptanoyl, NHSO2-heptenoyl, NHSO2-octanoyl, NHSO2-octenoyl, NHSO2-nonanoyl, NHSO2-nonenoyl, NHSO2-decanoyl, NHSO2-decenoyl, NHSO2-propionyl, NHSO2-2-propenoyl, NHSO2-2-butenoyl, NHSO2-Isobutyryl, NHSO2-2-methylpropanoyl, NHSO2-2-ethylbutyryl, NHSO2-ethylbutanoyl, NHSO2-2-ethylbutanoyl, NHSO2-butyryl, NHSO2-(E)-2,3-Dimethylacryloyl, NHSO2-(E)-2-Methylcrotonoyl, NHSO2-3-cis-Methyl-methacryloyl, NHSO2-3-Methyl-2-butenoyl, NHSO2-3-Methylcrotonoyl, NHSO2-4-Pentenoyl, NHSO2-(2E)-2-pentenoyl, NHSO2-Caproyl, NHSO2-5-Hexenoyl, NHSO2-Capryloyl, NHSO2-Lauroyl, NHSO2-Dodecanoyl, NHSO2-Myristoyl, NHSO2-Tetradecanoyl, NHSO2-Oleoyl, NHSO2-C(2-18) Acyl,
CH2NHSO2-tigloyl, CH2NHSO2-senecioyl, CH2NHSO2-acetyl, CH2NHSO2-Crotonoyl, CH2NHSO2-3,3-Dimethylartyloyl, CH2NHSO2-Cinnamoyl, CH2NHSO2-Pentenoyl, CH2NHSO2-Hexanoyl, CH2NHSO2-benzoyl, CH2NHSO2-Ethylbutyryl, CH2NHSO2-alkyl, CH2NHSO2-dibenzoyl, CH2NHSO2-benzoyl, CH2NHSO2-alkanoyl, CH2NHSO2-alkenoyl, CH2NHSO2-benzoyl alkyl substituted CH2NHSO2-alkanoyl, CH2NHSO2-alkanoyl substituted phenyl, CH2NHSO2-alkenoyl substituted phenyl, CH2NHSO2-aryl, CH2NHSO2-acyl, CH2NHSO2-heterocylic, CH2NHSO2-heteroraryl, CH2NHSO2-alkenylcarbonyl, CH2NHSO2-alkane, CH2NHSO2-alkene, CH2NHSO2-sugar moiety, CH2NHSO2-acid moiety, CH2NHSO2-ethanoyl, CH2NHSO2-propanoyl, CH2NHSO2-propenoyl, CH2NHSO2-butanoyl, CH2NHSO2-butenoyl, CH2NHSO2-pentanoyl, CH2NHSO2-hexenoyl, CH2NHSO2-heptanoyl, CH2NHSO2-heptenoyl, CH2NHSO2-octanoyl, CH2NHSO2-octenoyl, CH2NHSO2-nonanoyl, CH2NHSO2-nonenoyl, CH2NHSO2-decanoyl, CH2NHSO2-decenoyl, CH2NHSO2-propionyl, CH2NHSO2-2-propenoyl, CH2NHSO2-2-butenoyl, CH2NHSO2-Isobutyryl, CH2NHSO2-2-methylpropanoyl, CH2NHSO2-2-ethylbutyryl, CH2NHSO2-ethylbutanoyl, CH2NHSO2-2-ethylbutanoyl, CH2NHSO2-butyryl, CH2NHSO2-(E)-2,3-Dimethylacryloyl, CH2NHSO2-(E)-2-Methylcrotonoyl, CH2NHSO2-3-cis-Methyl-methacryloyl, CH2NHSO2-3-Methyl-2-butenoyl, CH2NHSO2-3-Methylcrotonoyl, CH2NHSO2-4-Pentenoyl, CH2NHSO2-(2E)-2-pentenoyl, CH2NHSO2-Caproyl, CH2NHSO2-5-Hexenoyl, CH2NHSO2-Capryloyl, CH2NHSO2-Lauroyl, CH2NHSO2-Dodecanoyl, CH2NHSO2-Myristoyl, CH2NHSO2-Tetradecanoyl, CH2NHSO2-Oleoyl, CH2NHSO2-C(2-18) Acyl In an embodiment, the compound(s) is(are) in form in form of powder, liquid or crystal. The active compounds of triterpenes in form of amine, sulfonamides, amide, and Urea Analogs, providing extremely stable activity in solution. They prolong the activities and duration of drug in a subject.
This invention provide the compound having structures of T1, T2, T3, T4, T5, T6, T7, T8, T9, T10, T11, T12, T13, T14, T15, T16, T17; T18, T19, T20, T21, T22, T23, T24, T25. T26 provided for treating cancers, inhibition of cancer growth, cancer invasion, cells invasion, cancer cell invasion; cell adhesion, cell attachment, cell circulating; for treating mad cow disease; treating prion diseases; for treating diabetes; for inhibiting viruses; for preventing cerebral aging; for improving memory; improving cerebral functions; for curing enuresis, frequent micturition, urinary incontinence; dementia, Alzheimer's disease, autism, brain trauma, Parkinson's disease or other diseases caused by cerebral dysfunctions or neurodegeneration; for treating arthritis, rheumatism, poor circulation, arteriosclerosis, Raynaud's syndrome, angina pectoris, cardiac disorder, coronary heart disease, headache, dizziness, kidney disorder; cerebrovascular diseasea; inhibiting NF-kappa B activation; for treating brain edema, severe acute respiratory syndrome, respiratory viral diseases, chronic venous insufficiency, hypertension, chronic venous disease, oedema, inflammation, hemorrhoids, peripheral edema formation, varicose vein disease, flu, post traumatic edema and postoperative swelling; for inhibiting blood clots, for inhibiting ethanol absorption; for lowering blood sugar; for regulating adrenocorticotropin and corticosterone levels. This invention provides a composition for Anti-MS, anti-aneurysm, anti-asthmatic, anti-oedematous, anti-inflammatory, anti-bradykinic, anti-capillarihemorrhagic, anti-cephalagic, anti-cervicobrachialgic, anti-eclamptic, anti-edemic, anti-encaphalitic, anti-epiglottitic, anti-exudative, anti-flu, anti-fracture, anti-gingivitic, anti-hematomic, anti-herpetic, anti-histaminic, anti-hydrathritic, anti-meningitic, antioxidant, anti-periodontic, anti-phlebitic, anti-pleuritic, anti-raucedo, anti-rhinitic, anti-tonsilitic, anti-ulcer, anti-varicose, anti-vertiginous, cancerostatic, corticosterogenic, diuretic, fungicide, hemolytic, hyaluronidase inhibitor, lymphagogue, natriuretic, pesticide, pituitary stimulant, thymolytic, vasoprotective, inhibiting leishmaniases, modulating adhesion or angiogenesis of cells, anti-parasitic; increase the expression of the genes: ANGPT2, DDIT3, LIF and NFKB1Z, and manufacturing an adjuvant composition and venotonic treatment. The compound blocks the DNA synthesis of cancer cell; wherein the cancers comprise breast cancer, leukocytic cancer, liver cancer, ovarian cancer, bladder cancer, prostatic cancer, skin cancer, bone cancer, brain cancer, leukemia cancer, lung cancer, colon cancer, CNS cancer, melanoma cancer, renal cancer, cervical cancer, esophageal cancer, testicular cancer, splenic cancer, kidney cancer, lymphatic cancer, pancreatic cancer, stomach cancer, eye cancer and thyroid cancer. This invention provides compounds to improve blood circulation; soothing stroke; Prevent plaque formation and promote their dissipated; improve blood viscosity; reduce cardiovascular; reduce cerebrovascular; reduce thrombosis, arteriosclerosis, coronary heart disease, hypertension, diabetes, thrombocytopenia purpura, hemoptysis, hematemesis; treating blood in the stool, uterine bleeding, traumatic bleeding, abdominal irritation, swelling, flutter, Blood circulation, swelling, pain; Treating bronchiectasis, tuberculosis and lung abscess caused by too hemoptysis; reducing bleeding, antitussive, expectorant and analgesic effect, dilate blood vessels; reducing blood pressure and the treatment of cerebral arteriosclerosis; elevated blood lipids and reduced cholesterol, Inducing or Increasing the number of Tumour Necrosis Factor (TNF) receptors (RELL1), DR1, DR4, or DR5.
Liposome is artificially prepared vesicles which made up of a lipid bilayer. Certain sizes of liposome can enter tumour sites from blood due to the enhanced permeability and retention effect. While human blood vessels are all surrounded by endothelial cells bound by tight junctions, those tight junctions binding tumour vessels are leakier than those binding other vessels and thus liposomes are able to enter these vessels to enhance the delivery, efficacy, bioavailability and absorption of liposome enclosed drug. This invention provides methods to use liposomes or nanoparticles capsules as a carrier delivering the compound as medicament, wherein the size of liposomes or nanoparticles capsules is less than 200 nm or 100-200 nm or 50-100 nm or 5-50 nm or less than 50 nm, wherein the medicament is included but not limited for treating cancer, inhibiting cancer growth, inhibiting cancer invasion, inhibiting cancer metastasis, modulating cell adhesion, modulating cell attachment, wherein the compound is selected from formula (2A) or formula (K) at the above. In an embodiment, the compound(s) is(are) in form in form of powder, liquid or crystal.
Substitution, deletion and/or addition of any group in the above-described compounds by other group(s) will be apparent to one of ordinary skill in the art based on the teachings of this application. In a further embodiment, the substitution, deletion and/or addition of the group(s) in the compound of the invention does not substantially affect the biological function of the compound is included in the invention.
In an embodiment, the compound is selected from the structures:
In embodiment, sugar moiety(ies) or acid moiety(ies) can be attached to the above compounds. In embodiment, the attachment of sugar moiety(ies) can be biosynthesized; In embodiment, the attachment of acid moiety can be biosynthesized; wherein the sugar moiety(ies) or acid moiety(ies) is/are included but not limited to a group of glucose, galactose, rhamnose, arabinose, xylose, fucose, allose, altrose, gulose, idose, lyxose, mannose, psicose, ribose, sorbose, tagatose, talose, fructose, alduronic acid, glucuronic acid, galacturonic acid, and derivatives or combinations thereof;
This invention provides compounds by esterification, amidation, amination, or sulfonamidation or methods of present invention of core compound (C), E4A, E4D1 or E4D in this application with acetyl chloride, angeloyl chloride, tigloyl chloride, senecioyl chloride, Crotonoyl chloride, O-3,3-Dimethylartyloyl chloride, Cinnamoyl chloride, Pentenoyl chloride, Hexanoyl chloride, benzoyl chloride, Ethylbutyryl chloride, and isolation of the compounds with HPLC, for treating cancer, inhibiting cancer growth, inhibiting cancer invasion, inhibiting cancer metastasis, modulating cell adhesion, modulating cell attachment, wherein the core compound selected from the following:
With experiments and methods in present application or esterification, amidation, amination, or sulfonamidation of compounds (C), E4A, E4D, or E4D1with acyl chloride, sulfonyl chloride, isocyanate, aldehyde, carboxylic acid, including Tigloyl chloride, angeloyl chloride, Acetyl chloride, Crotonoyl chloride, 3,3-Dimethylartyloyl chloride, senecioyl chloride, Cinnamoyl chloride, Pentenoyl chloride, Hexanoyl chloride, benzoyl chloride, Ethylbutyryl chloride, ethanoyl chloride, propanoyl chloride, propenoyl chloride, butanoyl chloride, butenoyl chloride, pentanoyl chloride, hexenoyl chloride, heptanoyl chloride, heptenoyl chloride, octanoyl chloride, octenoyl chloride, nonanoyl chloride, nonenoyl chloride, decanoyl chloride, decenoyl chloride, propionyl chloride, 2-propenoyl chloride, 2-butenoyl chloride, Isobutyryl chloride, 2-methylpropanoyl chloride, 2-ethylbutyryl chloride, ethylbutanoyl chloride, 2-ethylbutanoyl chloride, butyryl chloride, (E)-2,3-Dimethylacryloyl chloride, (E)-2-Methylcrotonoyl chloride, 3-cis-Methyl-methacryloyl chloride, 3-Methyl-2-butenoyl chloride, 3-Methylcrotonoyl chloride, 4-Pentenoyl chloride, (2E)-2-pentenoyl chloride, Caproyl chloride, 5-Hexenoyl chloride, Capryloyl chloride, Lauroyl chloride, Dodecanoyl chloride, Myristoyl chloride, Tetradecanoyl chloride, Oleoyl chloride, C(2-18) Acyl chloride. In an embodiment, the compound(s) is(are) in form in form of powder, liquid or crystal.
The compounds vary in composition when the time or temperature of the reaction is changed. The peaks, fractions and compounds are selected according to the activities of times studies and the changes of peaks. The compounds having strong to weak activities are selected and isolated. The anti cancer activities are the MTT studies of bone (U2OS), lung (H460), bladder (HTB-9), ovary (ES2), colon (HCT116), pancreas (Capan), ovary (OVCAR3), prostate (DU145), skin (SK-Mel-5), mouth (KB), kidney (A498), breast (MCF-7), liver (HepG2), brain (T98G), luekemia (K562), cervix (HeLa). The active esterification products are purified with HPLC. The reaction product of mixtures and individual compounds are tested with MTT Cytotoxic Assay. Details of method are in Experiment 3 of the present application. A second esterification of compound can be selected from the above experiment results to produce new active compounds. A partial esterification compound is selected from the above experiments to perform a second or repeated with a third esterification with different acyl chloride or methods in present application in order to produce new active compounds with the experiments in the present application, wherein the compound can be selected from K, (H1) or (H2):
R1, R2, R3, R4, R5, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18 are independently selected from the group of CH3, CH2OH, COOH, hydrogen, hydroxyl, methyl, O-angeloyl, O-tigloyl, O-senecioyl, O-acetyl, O-Crotonoyl, O-3,3-Dimethylartyloyl, O-Cinnamoyl, O-Pentenoyl, O-Hexanoyl, O-benzoyl, O-Ethylbutyryl, O-alkyl, O-dibenzoyl, O-benzoyl, O-alkanoyl, O-alkenoyl, O-benzoyl alkyl substituted O-alkanoyl, O-alkanoyl substituted phenyl, O-alkenoyl substituted phenyl, O-aryl, O-acyl, O-heterocylic, O-heteroraryl, O-alkenylcarbonyl, O-alkane, O-alkene, O-ethanoyl, O-propanoyl, O-propenoyl, O-butanoyl, O-butenoyl, O-pentanoyl, O-hexenoyl, O-heptanoyl, O-heptenoyl, O-octanoyl, O-octenoyl, O-nonanoyl, O-nonenoyl, O-decanoyl, O-decenoyl, O-propionyl, O-2-propenoyl, O-2-butenoyl, O-Isobutyryl, O-2-methylpropanoyl, O-2-ethylbutyryl, O-ethylbutanoyl, O-2-ethylbutanoyl, O-butyryl, O-(E)-2,3-Dimethylacryloyl, O-(E)-2-Methylcrotonoyl, O-3-cis-Methyl-methacryloyl, O-3-Methyl-2-butenoyl, O-3-Methylcrotonoyl, O-4-Pentenoyl, O-(2E)-2-pentenoyl, O-Caproyl, O-5-Hexenoyl, O-Capryloyl, O-Lauroyl, O-Dodecanoyl, O-Myristoyl, O-Tetradecanoyl, O-Oleoyl, O—C(2-18) Acyl; CH2O-angeloyl, CH2O-tigloyl, CH2O-senecioyl, CH2O-acetyl, CH2O-Crotonoyl, CH2O-3,3-Dimethylartyloyl, CH2O-Cinnamoyl, CH2O-Pentenoyl, CH2O-Hexanoyl, CH2O-benzoyl, CH2O-Ethylbutyryl, CH3, CH2OH, CH2O-alkyl, CH2O-dibenzoyl, CH2O-benzoyl, CH2O-alkanoyl, CH2O-alkenoyl, CH2O-benzoyl alkyl substituted O-alkanoyl, CH2O-alkanoyl substituted phenyl, CH2O-alkenoyl substituted phenyl, CH2O-aryl, CH2O-acyl, CH2O-heterocylic, CH2O-heteroraryl, CH2O-alkenylcarbonyl, CH2O-ethanoyl, CH2O-propanoyl, CH2O-propenoyl, CH2O-butanoyl, CH2O-butenoyl, CH2O-pentanoyl, CH2O-hexenoyl, CH2O-heptanoyl, CH2O-heptenoyl, CH2O-octanoyl, CH2O-octenoyl, CH2O-nonanoyl, CH2O-nonenoyl, CH2O-decanoyl, CH2O-decenoyl, CH2O-propionyl, CH2O-2-propenoyl, CH2O-2-butenoyl, CH2O-Isobutyryl, CH2O-2-methylpropanoyl, CH2O-2-ethylbutyryl, CH2O-ethylbutanoyl, CH2O-2-ethylbutanoyl, CH2O-butyryl, CH2O-(E)-2,3-Dimethylacryloyl, CH2O-(E)-2-Methylcrotonoyl, CH2O-3-cis-Methyl-methacryloyl, CH2O-3-Methyl-2-butenoyl, CH2O-3-Methylcrotonoyl, CH2O-4-Pentenoyl, CH2O-(2E)-2-pentenoyl, CH2O-Caproyl, CH2O-5-Hexenoyl, CH2O-Capryloyl, CH2O-Lauroyl, CH2O-Dodecanoyl, CH2O-Myristoyl, CH2O-Tetradecanoyl, CH2O-Oleoyl, CH2O—C(2-18) Acyl;
CH2O-4-(dimethylamino)-2-methylbut-2-enoyl, CH2O-4-[(2-methoxyethyl)amino]-2-methyl-4oxobut-2-enoyl or wherein any 1 or 2 or 3 or 4 of R1, R2, R3, R4, R5, R8, R10, R16, R17, R18 is/are independently attached an 0-angeloyl, O-tigloyl, O-senecioyl, O-acetyl, O-Crotonoyl, O-3,3-Dimethylartyloyl, O-Cinnamoyl, O-Pentenoyl, O-Hexanoyl, O-benzoyl, O-Ethylbutyryl, O-alkyl, O-dibenzoyl, O-benzoyl, O-alkanoyl, O-alkenoyl, O-benzoyl alkyl substituted O-alkanoyl, O-alkanoyl substituted phenyl, O-alkenoyl substituted phenyl, O-aryl, O-acyl, O-heterocylic, O-heteroraryl, O-alkenylcarbonyl, O-ethanoyl, O-propanoyl, O-propenoyl, O-butanoyl, O-butenoyl, O-pentanoyl, O-hexenoyl, O-heptanoyl, O-heptenoyl, O-octanoyl, O-octenoyl, O-nonanoyl, O-nonenoyl, O-decanoyl, O-decenoyl, O-propionyl, O-2-propenoyl, O-2-butenoyl, O-Isobutyryl, O-2-methylpropanoyl, O-2-ethylbutyryl, O-ethylbutanoyl, O-2-ethylbutanoyl, O-butyryl, O-(E)-2,3-Dimethylacryloyl, O-(E)-2-Methylcrotonoyl, O-3-cis-Methyl-methacryloyl, O-3-Methyl-2-butenoyl, O-3-Methylcrotonoyl, O-4-Pentenoyl, O-(2E)-2-pentenoyl, O-Caproyl, O-5-Hexenoyl, O-Capryloyl, O-Lauroyl, O-Dodecanoyl, O-Myristoyl, O-Tetradecanoyl, O-Oleoyl, O—C(2-18) Acyl, CH2O-angeloyl, CH2O-tigloyl, CH2O-senecioyl, CH2O-acetyl, CH2O-Crotonoyl, CH2O-3,3-Dimethylartyloyl, CH2O-Cinnamoyl, CH2O-Pentenoyl, CH2O-Hexanoyl, CH2O-benzoyl, CH2O-Ethylbutyryl, CH3, CH2OH, CH2O-alkyl, CH2O-dibenzoyl, CH2O-benzoyl, CH2O-alkanoyl, CH2O-alkenoyl, CH2O-benzoyl alkyl substituted O-alkanoyl, CH2O-alkanoyl substituted phenyl, CH2O-alkenoyl substituted phenyl, CH2O-aryl, CH2O-acyl, CH2O-heterocylic, CH2O-heteroraryl, CH2O-alkenylcarbonyl, CH2O-ethanoyl, CH2O-propanoyl, CH2O-propenoyl, CH2O-butanoyl, CH2O-butenoyl, CH2O-pentanoyl, CH2O-hexenoyl, CH2O-heptanoyl, CH2O-heptenoyl, CH2O-octanoyl, CH2O-octenoyl, CH2O-nonanoyl, CH2O-nonenoyl, CH2O-decanoyl, CH2O-decenoyl, CH2O-propionyl, CH2O-2-propenoyl, CH2O-2-butenoyl, CH2O-Isobutyryl, CH2O-2-methylpropanoyl, CH2O-2-ethylbutyryl, CH2O-ethylbutanoyl, CH2O-2-ethylbutanoyl, CH2O-butyryl, CH2O-(E)-2,3-Dimethylacryloyl, CH2O-(E)-2-Methylcrotonoyl, CH2O-3-cis-Methyl-methacryloyl, CH2O-3-Methyl-2-butenoyl, CH2O-3-Methylcrotonoyl, CH2O-4-Pentenoyl, CH2O-(2E)-2-pentenoyl, CH2O-Caproyl, CH2O-5-Hexenoyl, CH2O-Capryloyl, CH2O-Lauroyl, CH2O-Dodecanoyl, CH2O-Myristoyl, CH2O-Tetradecanoyl, CH2O-Oleoyl, CH2O—C(2-18) Acyl, CH2O-4-(dimethylamino)-2-methylbut-2-enoyl, CH2O-4-[(2-methoxyethyl)amino]-2-methyl-4oxobut-2-enoyl; R9, R11, R12, R13, R14, R15 are independently attached a CH3; or wherein R10 is attached an O-angeloyl, O-tigloyl, O-senecioyl, O-acetyl, O-Crotonoyl, O-3,3-Dimethylartyloyl, O-Cinnamoyl, O-Pentenoyl, O-Hexanoyl, O-benzoyl, O-Ethylbutyryl, O-alkyl, O-dibenzoyl, O-benzoyl, O-alkanoyl, O-alkenoyl, O-benzoyl alkyl substituted O-alkanoyl, O-alkanoyl substituted phenyl, O-alkenoyl substituted phenyl, O-aryl, O-acyl, O-heterocylic, O-heteroraryl, O-alkenylcarbonyl, O-ethanoyl, O-propanoyl, O-propenoyl, O-butanoyl, O-butenoyl, O-pentanoyl, O-hexenoyl, O-heptanoyl, O-heptenoyl, O-octanoyl, O-octenoyl, O-nonanoyl, O-nonenoyl, O-decanoyl, O-decenoyl, O-propionyl, O-2-propenoyl, O-2-butenoyl, O-Isobutyryl, O-2-methylpropanoyl, O-2-ethylbutyryl, O-ethylbutanoyl, O-2-ethylbutanoyl, O-butyryl, O-(E)-2,3-Dimethylacryloyl, O-(E)-2-Methylcrotonoyl, O-3-cis-Methyl-methacryloyl, O-3-Methyl-2-butenoyl, O-3-Methylcrotonoyl, O-4-Pentenoyl, O-(2E)-2-pentenoyl, O-Caproyl, O-5-Hexenoyl, O-Capryloyl, O-Lauroyl, O-Dodecanoyl, O-Myristoyl, O-Tetradecanoyl, O-Oleoyl, O—C(2-18) Acyl, O-4-(dimethylamino)-2-methylbut-2-enoyl, and O-4-[(2-methoxyethyl)amino]-2-methyl-4oxobut-2-enoyl, CH2O-angeloyl, CH2O-tigloyl, CH2O-senecioyl, CH2O-acetyl, CH2O-Crotonoyl, CH2O-3,3-Dimethylartyloyl, CH2O-Cinnamoyl, CH2O-Pentenoyl, CH2O-Hexanoyl, CH2O-benzoyl, CH2O-Ethylbutyryl, CH3, CH2OH, CH2O-alkyl, CH2O-dibenzoyl, CH2O-benzoyl, CH2O-alkanoyl, CH2O-alkenoyl, CH2O-benzoyl alkyl substituted O-alkanoyl, CH2O-alkanoyl substituted phenyl, CH2O-alkenoyl substituted phenyl, CH2O-aryl, CH2O-acyl, CH2O-heterocylic, CH2O-heteroraryl, CH2O-alkenylcarbonyl, CH2O-ethanoyl, CH2O-propanoyl, CH2O-propenoyl, CH2O-butanoyl, CH2O-butenoyl, CH2O-pentanoyl, CH2O-hexenoyl, CH2O-heptanoyl, CH2O-heptenoyl, CH2O-octanoyl, CH2O-octenoyl, CH2O-nonanoyl, CH2O-nonenoyl, CH2O-decanoyl, CH2O-decenoyl, CH2O-propionyl, CH2O-2-propenoyl, CH2O-2-butenoyl, CH2O-Isobutyryl, CH2O-2-methylpropanoyl, CH2O-2-ethylbutyryl, CH2O-ethylbutanoyl, CH2O-2-ethylbutanoyl, CH2O-butyryl, CH2O-(E)-2,3-Dimethylacryloyl, CH2O-(E)-2-Methylcrotonoyl, CH2O-3-cis-Methyl-methacryloyl, CH2O-3-Methyl-2-butenoyl, CH2O-3-Methylcrotonoyl, CH2O-4-Pentenoyl, CH2O-(2E)-2-pentenoyl, CH2O-Caproyl, CH2O-5-Hexenoyl, CH2O-Capryloyl, CH2O-Lauroyl, CH2O-Dodecanoyl, CH2O-Myristoyl, CH2O-Tetradecanoyl, CH2O-Oleoyl, CH2O—C(2-18) Acyl; CH2O-4-(dimethylamino)-2-methylbut-2-enoyl, CH2O-4-[(2-methoxyethyl)amino]-2-methyl-4oxobut-2-enoyl or wherein R4 and R10 are independently attached an CH2O-angeloyl, CH2O-tigloyl, CH2O-senecioyl, CH2O-acetyl, CH2O-Crotonoyl, CH2O-3,3-Dimethylartyloyl, CH2O-Cinnamoyl, CH2O-Pentenoyl, CH2O-Hexanoyl, CH2O-benzoyl, CH2O-Ethylbutyryl, CH2OH, CH2O-alkyl, CH2O-dibenzoyl, CH2O-benzoyl, CH2O-alkanoyl, CH2O-alkenoyl, CH2O-benzoyl alkyl substituted O-alkanoyl, CH2O-alkanoyl substituted phenyl, CH2O-alkenoyl substituted phenyl, CH2O-aryl, CH2O-acyl, CH2O-heterocylic, CH2O-heteroraryl, CH2O-alkenylcarbonyl, CH2O-ethanoyl, CH2O-propanoyl, CH2O-propenoyl, CH2O-butanoyl, CH2O-butenoyl, CH2O-pentanoyl, CH2O-hexenoyl, CH2O-heptanoyl, CH2O-heptenoyl, CH2O-octanoyl, CH2O-octenoyl, CH2O-nonanoyl, CH2O-nonenoyl, CH2O-decanoyl, CH2O-decenoyl, CH2O-propionyl, CH2O-2-propenoyl, CH2O-2-butenoyl, CH2O-Isobutyryl, CH2O-2-methylpropanoyl, CH2O-2-ethylbutyryl, CH2O-ethylbutanoyl, CH2O-2-ethylbutanoyl, CH2O-butyryl, CH2O-(E)-2,3-Dimethylacryloyl, CH2O-(E)-2-Methylcrotonoyl, CH2O-3-cis-Methyl-methacryloyl, CH2O-3-Methyl-2-butenoyl, CH2O-3-Methylcrotonoyl, CH2O-4-Pentenoyl, CH2O-(2E)-2-pentenoyl, CH2O-Caproyl, CH2O-5-Hexenoyl, CH2O-Capryloyl, CH2O-Lauroyl, CH2O-Dodecanoyl, CH2O-Myristoyl, CH2O-Tetradecanoyl, CH2O-Oleoyl, CH2O—C(2-18) Acyl; CH2O-4-(dimethylamino)-2-methylbut-2-enoyl, CH2O-4-[(2-methoxyethyl)amino]-2-methyl-4oxobut-2-enoyl or wherein R17 and R18 are independently attached an O-angeloyl, O-tigloyl, O-senecioyl, O-acetyl, O-Crotonoyl, O-3,3-Dimethylartyloyl, O-Cinnamoyl, O-Pentenoyl, O-Hexanoyl, O-benzoyl, O-Ethylbutyryl, O-alkyl, O-dibenzoyl, O-benzoyl, O-alkanoyl, O-alkenoyl, O-benzoyl alkyl substituted O-alkanoyl, O-alkanoyl substituted phenyl, O-alkenoyl substituted phenyl, O-aryl, O-acyl, O-heterocylic, O-heteroraryl, O-alkenylcarbonyl, O-ethanoyl, O-propanoyl, O-propenoyl, O-butanoyl, O-butenoyl, O-pentanoyl, O-hexenoyl, O-heptanoyl, O-heptenoyl, O-octanoyl, O-octenoyl, O-nonanoyl, O-nonenoyl, O-decanoyl, O-decenoyl, O-propionyl, O-2-propenoyl, O-2-butenoyl, O-Isobutyryl, O-2-methyl propanoyl, O-2-ethylbutyryl, O-ethylbutanoyl, O-2-ethylbutanoyl, O-butyryl, O-(E)-2,3-Dimethylacryloyl, O-(E)-2-Methylcrotonoyl, O-3-cis-Methyl-methacryloyl, O-3-Methyl-2-butenoyl, O-3-Methylcrotonoyl, O-4-Pentenoyl, O-(2E)-2-pentenoyl, O-Caproyl, O-5-Hexenoyl, O-Capryloyl, O-Lauroyl, O-Dodecanoyl, O-Myristoyl, O-Tetradecanoyl, O-Oleoyl, O—C(2-18) Acyl; wherein R3 is OH or H or absent; wherein R1, R2, R3, R5, R8 are OH or H or absent; wherein R9, R11, R12, R13, R14, and R15 are CH3; or wherein R1, R2, R5, R8 represent OH; R3 represents OH, H or absent; R4, R10 represent CH2Oangeloyl; R9, R11, R12, R13, R14, R15 represent CH3; or wherein R1, R2, R5, R8 represent OH or 0-tigloyl; R3 represents OH, H, or absent; R4, R10 represent CH2O tigloyl; R9, R11, R12, R13, R14, R15 represent CH3;
R1, R2, R3, R4, R5, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18 are independently selected from the group of OH, CH3, H, O, NH2, CH3, CH2OH, COOH NH-tigloyl, NH-angeloyl, NH-senecioyl, NH-acetyl, NH-Crotonoyl, NH-3,3-Dimethylartyloyl, NH-Cinnamoyl, NH-Pentenoyl, NH-Hexanoyl, NH-benzoyl, NH-Ethylbutyryl, NH-alkyl, NH-dibenzoyl, NH-benzoyl, NH-alkanoyl, NH-alkenoyl, NH-benzoyl alkyl substituted NH-alkanoyl, NH-alkanoyl substituted phenyl, NH-alkenoyl substituted phenyl, NH-aryl, NH-acyl, NH-heterocylic, NH-heteroraryl, NH-alkenylcarbonyl, NH-alkane, NH-alkene, NH-sugar moiety, NH-acid moiety, NH-ethanoyl, NH-propanoyl, NH-propenoyl, NH-butanoyl, NH-butenoyl, NH-pentanoyl, NH-hexenoyl, NH-heptanoyl, NH-heptenoyl, NH-octanoyl, NH-octenoyl, NH-nonanoyl, NH-nonenoyl, NH-decanoyl, NH-decenoyl, NH-propionyl, NH-2-propenoyl, NH-2-butenoyl, NH-Isobutyryl, NH-2-methylpropanoyl, NH-2-ethylbutyryl, NH-ethylbutanoyl, NH-2-ethylbutanoyl, NH-butyryl, NH-(E)-2,3-Dimethylacryloyl, NH-(E)-2-Methylcrotonoyl, NH-3-cis-Methyl-methacryloyl, NH-3-Methyl-2-butenoyl, NH-3-Methylcrotonoyl, NH-4-Pentenoyl, NH-(2E)-2-pentenoyl, NH-Caproyl, NH-5-Hexenoyl, NH-Capryloyl, NH-Lauroyl, NH-Dodecanoyl, NH-Myristoyl, NH-Tetradecanoyl, NH-Oleoyl, NH—C(2-18) Acyl, NH-ethanyl, NH-propanyl, NH-propenyl, NH-butanyl, NH-butenyl, NH-pentanyl, NH-hexenyl, NH-heptanyl, NH-heptenyl, NH-octanyl, NH-octenyl, NH-nonanyl, NH-nonenyl, NH-decanyl, NH-decenyl, NH-alkyl, NH-haloalkyl, NH-alkenyl, NH-alkynyl, NH-hydroxyalkyl, NH-alkylene-O-alkyl, NH-aryl, NH-alkylene-aryl, NH-heteroaryl, NH-alkylene-heteroaryl, NH-cycloalkyl, NH-heterocyclyl, and NH-alkylene-heterocyclyl, CH2NH-tigloyl, CH2NH-angeloyl, CH2NH-senecioyl, CH2NH-acetyl, CH2NH-Crotonoyl, CH2NH-3,3-Dimethylartyloyl, CH2NH-Cinnamoyl, CH2NH-Pentenoyl, CH2NH-Hexanoyl, CH2NH-benzoyl, CH2NH-Ethylbutyryl, CH2NH-alkyl, CH2NH-dibenzoyl, CH2NH-benzoyl, CH2NH-alkanoyl, CH2NH-alkenoyl, CH2NH-benzoyl alkyl substituted CH2NH-alkanoyl, CH2NH-alkanoyl substituted phenyl, CH2NH-alkenoyl substituted phenyl, CH2NH-aryl, CH2NH-acyl, CH2NH-heterocylic, CH2NH-heteroraryl, CH2NH-alkenylcarbonyl, CH2NH-alkane, CH2NH-alkene, CH2NH-sugar moiety, CH2NH-acid moiety, CH2NH-ethanoyl, CH2NH-propanoyl, CH2NH-propenoyl, CH2NH-butanoyl, CH2NH-butenoyl, CH2NH-pentanoyl, CH2NH-hexenoyl, CH2NH-heptanoyl, CH2NH-heptenoyl, CH2NH-octanoyl, CH2NH-octenoyl, CH2NH-nonanoyl, CH2NH-nonenoyl, CH2NH-decanoyl, CH2NH-decenoyl, CH2NH-propionyl, CH2NH-2-propenoyl, CH2NH-2-butenoyl, CH2NH-Isobutyryl, CH2NH-2-methylpropanoyl, CH2NH-2-ethylbutyryl, CH2NH-ethylbutanoyl, CH2NH-2-ethylbutanoyl, CH2NH-butyryl, CH2NH-(E)-2,3-Dimethylacryloyl, CH2NH-(E)-2-Methylcrotonoyl, CH2NH-3-cis-Methyl-methacryloyl, CH2NH-3-Methyl-2-butenoyl, CH2NH-3-Methylcrotonoyl, CH2NH-4-Pentenoyl, CH2NH-(2E)-2-pentenoyl, CH2NH-Caproyl, CH2NH-5-Hexenoyl, CH2NH-Capryloyl, CH2NH-Lauroyl, CH2NH-Dodecanoyl, CH2NH-Myristoyl, CH2NH-Tetradecanoyl, CH2NH-Oleoyl, CH2NH—C(2-18) Acyl, CH2NH-ethanyl, CH2NH-propanyl, CH2NH-propenyl, CH2NH-butanyl, CH2NH-butenyl, CH2NH-pentanyl, CH2NH-hexenyl, CH2NH-heptanyl, CH2NH-heptenyl, CH2NH-octanyl, CH2NH-octenyl, CH2NH-nonanyl, CH2NH-nonenyl, CH2NH-decanyl, CH2NH-decenyl, CH2NH-alkyl, CH2NH-haloalkyl, CH2NH-alkenyl, CH2NH-alkynyl, CH2NH-hydroxyalkyl, CH2NH-alkylene-O-alkyl, CH2NH-aryl, CH2NH-alkylene-aryl, CH2NH-heteroaryl, CH2NH-alkylene-heteroaryl, CH2NH-cycloalkyl, CH2NH-heterocyclyl, and CH2NH-alkylene-heterocyclyl,
CH2NHCH2-tigloyl, CH2NHCH2-angeloyl, CH2NHCH2-senecioyl, CH2NHCH2-acetyl, CH2NHCH2-Crotonoyl, CH2NHCH2-3,3-Dimethylartyloyl, CH2NHCH2-Cinnamoyl, CH2NHCH2-Pentenoyl, CH2NHCH2-Hexanoyl, CH2NHCH2-benzoyl, CH2NHCH2-Ethylbutyryl, CH2NHCH2-alkyl, CH2NHCH2-dibenzoyl, CH2NHCH2-benzoyl, CH2NHCH2-alkanoyl, CH2NHCH2-alkenoyl, CH2NHCH2-benzoyl alkyl substituted CH2NHCH2-alkanoyl, CH2NHCH2-alkanoyl substituted phenyl, CH2NHCH2-alkenoyl substituted phenyl, CH2NHCH2-aryl, CH2NHCH2-acyl, CH2NHCH2-heterocylic, CH2NHCH2-heteroraryl, CH2NHCH2-alkenylcarbonyl, CH2NHCH2-alkane, CH2NHCH2-alkene, CH2NHCH2-sugar moiety, CH2NHCH2-acid moiety, CH2NHCH2-ethanoyl, CH2NHCH2-propanoyl, CH2NHCH2-propenoyl, CH2NHCH2-butanoyl, CH2NHCH2-butenoyl, CH2NHCH2-pentanoyl, CH2NHCH2-hexenoyl, CH2NHCH2-heptanoyl, CH2NHCH2-heptenoyl, CH2NHCH2-octanoyl, CH2NHCH2-octenoyl, CH2NHCH2-nonanoyl, CH2NHCH2-nonenoyl, CH2NHCH2-decanoyl, CH2NH-decenoyl, CH2NHCH2-propionyl, CH2NHCH2-2-propenoyl, CH2NHCH2-2-butenoyl, CH2NHCH2-Isobutyryl, CH2NHCH2-2-methylpropanoyl, CH2NHCH2-2-ethylbutyryl, CH2NHCH2-ethylbutanoyl, CH2NHCH2-2-ethylbutanoyl, CH2NHCH2-butyryl, CH2NHCH2-(E)-2,3-Dimethylacryloyl, CH2NHCH2-(E)-2-Methylcrotonoyl, CH2NHCH2-3-cis-Methyl-methacryloyl, CH2NHCH2-3-Methyl-2-butenoyl, CH2NHCH2-3-Methylcrotonoyl, CH2NHCH2-4-Pentenoyl, CH2NHCH2-(2E)-2-pentenoyl, CH2NHCH2-Caproyl, CH2NHCH2-5-Hexenoyl, CH2NHCH2-Capryloyl, CH2NHCH2-Lauroyl, CH2NHCH2-Dodecanoyl, CH2NHCH2-Myristoyl, CH2NHCH2-Tetradecanoyl, CH2NHCH2-Oleoyl, CH2NHCH2-C(2-18) Acyl, CH2NHCH2-ethanyl, CH2NHCH2-propanyl, CH2NHCH2-propenyl, CH2NHCH2-butanyl, CH2NHCH2-butenyl, CH2NHCH2-pentanyl, CH2NHCH2-hexenyl, CH2NHCH2-heptanyl, CH2NHCH2-heptenyl, CH2NHCH2-octanyl, CH2NHCH2-octenyl, CH2NHCH2-nonanyl, CH2NHCH2-nonenyl, CH2NHCH2-decanyl, CH2NHCH2-decenyl, CH2NHCH2-alkyl, haloalkyl, CH2NHCH2-alkenyl, CH2NHCH2-alkynyl, CH2NHCH2-hydroxyalkyl, CH2NHCH2-alkylene-O-alkyl, CH2NHCH2-aryl, CH2NHCH2-alkylene-aryl, CH2NHCH2-heteroaryl, CH2NHCH2-alkylene-heteroaryl, CH2NHCH2-cycloalkyl, CH2NHCH2-heterocyclyl, and CH2NHCH2-alkylene-heterocyclyl,
CH2NHCO-tigloyl, CH2NHCO-angeloyl, CH2NHCO-senecioyl, CH2NHCO-acetyl, CH2NHCO-Crotonoyl, CH2NHCO-3,3-Dimethylartyloyl, CH2NHCO-Cinnamoyl, CH2NHCO-Pentenoyl, CH2NHCO-Hexanoyl, CH2NHCO-benzoyl, CH2NHCO-Ethylbutyryl, CH2NHCO-alkyl, CH2NHCO-dibenzoyl, CH2NHCO-benzoyl, CH2NHCO-alkanoyl, CH2NHCO-alkenoyl, CH2NHCO-benzoyl alkyl substituted CH2NHCO-alkanoyl, CH2NHCO-alkanoyl substituted phenyl, CH2NHCO-alkenoyl substituted phenyl, CH2NHCO-aryl, CH2NHCO-acyl, CH2NHCO-heterocylic, CH2NHCO-heteroraryl, CH2NHCO-alkenylcarbonyl, CH2NHCO-alkane, CH2NHCO-alkene, CH2NHCO-sugar moiety, CH2NHCO-acid moiety, CH2NHCO-ethanoyl, CH2NHCO-propanoyl, CH2NHCO-propenoyl, CH2NHCO-butanoyl, CH2NHCO-butenoyl, CH2NHCO-pentanoyl, CH2NHCO-hexenoyl, CH2NHCO-heptanoyl, CH2NHCO-heptenoyl, CH2NHCO-octanoyl, CH2NHCO-octenoyl, CH2NHCO-nonanoyl, CH2NHCO-nonenoyl, CH2NHCO-decanoyl, CH2NHCO-decenoyl, CH2NHCO-propionyl, CH2NHCO-2-propenoyl, CH2NHCO-2-butenoyl, CH2NHCO-Isobutyryl, CH2NHCO-2-methylpropanoyl, CH2NHCO-2-ethylbutyryl, CH2NHCO-ethylbutanoyl, CH2NHCO-2-ethylbutanoyl, CH2NHCO-butyryl, CH2NHCO-(E)-2,3-Dimethylacryloyl, CH2NHCO-(E)-2-Methylcrotonoyl, CH2NHCO-3-cis-Methyl-methacryloyl, CH2NHCO-3-Methyl-2-butenoyl, CH2NHCO-3-Methylcrotonoyl, CH2NHCO-4-Pentenoyl, CH2NHCO-(2E)-2-pentenoyl, CH2NHCO-Caproyl, CH2NHCO-5-Hexenoyl, CH2NHCO-Capryloyl, CH2NHCO-Lauroyl, CH2NHCO-Dodecanoyl, CH2NHCO-Myristoyl, CH2NHCO-Tetradecanoyl, CH2NHCO-Oleoyl, CH2NHCO—C(2-18) Acyl, CH2NHCO-ethanyl, CH2NHCO-propanyl, CH2NHCO-propenyl, CH2NHCO-butanyl, CH2NHCO-butenyl, CH2NHCO-pentanyl, CH2NHCO-hexenyl, CH2NHCO-heptanyl, CH2NHCO-heptenyl, CH2NHCO-octanyl, CH2NHCO-octenyl, CH2NHCO-nonanyl, CH2NHCO-nonenyl, CH2NHCO-decanyl, CH2NHCO-decenyl, CH2NHCO-alkyl, CH2NHCO-haloalkyl, alkenyl, CH2NHCO-alkynyl, CH2NHCO-hydroxyalkyl, CH2NHCO-alkylene-O-alkyl, CH2NHCO-aryl, CH2NHCO-alkylene-aryl, CH2NHCO-heteroaryl, CH2NHCO-alkylene-heteroaryl, CH2NHCO-cycloalkyl, CH2NHCO-heterocyclyl, and CH2NHCO-alkylene-heterocyclyl,
CH2NHCONH-tigloyl, CH2NHCONH-senecioyl, CH2NHCONH-acetyl, CH2NHCONH-Crotonoyl, CH2NHCONH-3,3-Dimethylartyloyl, CH2NHCONH-Cinnamoyl, CH2NHCONH-Pentenoyl, CH2NHCONH-Hexanoyl, CH2NHCONH-benzoyl, CH2NHCONH-Ethylbutyryl, CH2NHCONH-alkyl, CH2NHCONH-dibenzoyl, CH2NHCONH-benzoyl, CH2NHCONH-alkanoyl, CH2NHCONH-alkenoyl, CH2NHCONH-benzoyl alkyl substituted CH2NHCONH-alkanoyl, CH2NHCONH-alkanoyl substituted phenyl, CH2NHCONH-alkenoyl substituted phenyl, CH2NHCONH-aryl, CH2NHCONH-acyl, CH2NHCONH-heterocylic, CH2NHCONH-heteroraryl, CH2NHCONH-alkenylcarbonyl, CH2NHCONH-alkane, CH2NHCONH-alkene, CH2NHCONH-sugar moiety, CH2NHCONH-acid moiety, CH2NHCONH-ethanoyl, CH2NHCONH-propanoyl, CH2NHCONH-propenoyl, CH2NHCONH-butanoyl, CH2NHCONH-butenoyl, CH2NHCONH-pentanoyl, CH2NHCONH-hexenoyl, CH2NHCONH-heptanoyl, CH2NHCONH-heptenoyl, CH2NHCONH-octanoyl, CH2NHCONH-octenoyl, CH2NHCONH-nonanoyl, CH2NHCONH-nonenoyl, CH2NHCONH-decanoyl, CH2NHCONH-decenoyl, CH2NHCONH-propionyl, CH2NHCONH-2-propenoyl, CH2NHCONH-2-butenoyl, CH2NHCONH-Isobutyryl, CH2NHCONH-2-methylpropanoyl, CH2NHCONH-2-ethylbutyryl, CH2NHCONH-ethylbutanoyl, CH2NHCONH-2-ethylbutanoyl, CH2NHCONH-butyryl, CH2NHCONH-(E)-2,3-Dimethylacryloyl, CH2NHCONH-(E)-2-Methylcrotonoyl, CH2NHCONH-3-cis-Methyl-methacryloyl, CH2NHCONH-3-Methyl-2-butenoyl, CH2NHCONH-3-Methylcrotonoyl, CH2NHCONH-4-Pentenoyl, CH2NHCONH-(2E)-2-pentenoyl, CH2NHCONH-Caproyl, CH2NHCONH-5-Hexenoyl, CH2NHCONH-Capryloyl, CH2NHCONH-Lauroyl, CH2NHCONH-Dodecanoyl, CH2NHCONH-Myristoyl, CH2NHCONH-Tetradecanoyl, CH2NHCONH-Oleoyl, CH2NHCONH—C(2-18) Acyl, CH2NHCONH-ethanyl, CH2NHCONH-propanyl, CH2NHCONH-propenyl, CH2NHCONH-butanyl, CH2NHCONH-butenyl, CH2NHCONH-pentanyl, CH2NHCONH-hexenyl, CH2NHCONH-heptanyl, CH2NHCONH-heptenyl, CH2NHCONH-octanyl, CH2NHCONH-octenyl, CH2NHCONH-nonanyl, CH2NHCONH-nonenyl, CH2NHCONH-decanyl, CH2NHCONH-decenyl, NH—CO—NH-ethyl, NH—CO—NH—(Z)-1-(2-methylbut-2-en-1-yl), NH—CO—NH-(E)-1-(2-methylbut-2-en-1-yl), NH—CO—NH-1-(3-methylbut-2-en-1-yl), NH—CO—NH-(E)-1-(but-2-en-1-yl), NH—CO—NH-1-cinnamyl, NH—CO—NH-1-(but-3-en-1-yl), NH—CO—NH-(E)-1-(4-(dimethylamino)but-3-en-1-yl),
NHSO2-tigloyl, NHSO2-senecioyl, NHSO2-acetyl, NHSO2-Crotonoyl, NHSO2-3,3-Dimethylartyloyl, NHSO2-Cinnamoyl, NHSO2-Pentenoyl, NHSO2-Hexanoyl, NHSO2-benzoyl, NHSO2-Ethylbutyryl, NHSO2-alkyl, NHSO2-dibenzoyl, NHSO2-benzoyl, NHSO2-alkanoyl, NHSO2-alkenoyl, NHSO2-benzoyl alkyl substituted NHSO2-alkanoyl, NHSO2-alkanoyl substituted phenyl, NHSO2-alkenoyl substituted phenyl, NHSO2-aryl, NHSO2-acyl, NHSO2-heterocylic, NHSO2-heteroraryl, NHSO2-alkenylcarbonyl, NHSO2-alkane, NHSO2-alkene, NHSO2-sugar moiety, NHSO2-acid moiety, NHSO2-ethanoyl, NHSO2-propanoyl, NHSO2-propenoyl, NHSO2-butanoyl, NHSO2-butenoyl, NHSO2-pentanoyl, NHSO2-hexenoyl, NHSO2-heptanoyl, NHSO2-heptenoyl, NHSO2-octanoyl, NHSO2-octenoyl, NHSO2-nonanoyl, NHSO2-nonenoyl, NHSO2-decanoyl, NHSO2-decenoyl, NHSO2-propionyl, NHSO2-2-propenoyl, NHSO2-2-butenoyl, NHSO2-Isobutyryl, NHSO2-2-methylpropanoyl, NHSO2-2-ethylbutyryl, NHSO2-ethylbutanoyl, NHSO2-2-ethylbutanoyl, NHSO2-butyryl, NHSO2-(E)-2,3-Dimethylacryloyl, NHSO2-(E)-2-Methylcrotonoyl, NHSO2-3-cis-Methyl-methacryloyl, NHSO2-3-Methyl-2-butenoyl, NHSO2-3-Methylcrotonoyl, NHSO2-4-Pentenoyl, NHSO2-(2E)-2-pentenoyl, NHSO2-Caproyl, NHSO2-5-Hexenoyl, NHSO2-Capryloyl, NHSO2-Lauroyl, NHSO2-Dodecanoyl, NHSO2-Myristoyl, NHSO2-Tetradecanoyl, NHSO2-Oleoyl, NHSO2-C(2-18) Acyl, NHSO2-ethanyl, NHSO2-propanyl, NHSO2-propenyl, NHSO2-butanyl, NHSO2-butenyl, NHSO2-pentanyl, NHSO2-hexenyl, NHSO2-heptanyl, NHSO2-heptenyl, NHSO2-octanyl, NHSO2-octenyl, NHSO2-nonanyl, NHSO2-nonenyl, NHSO2-decanyl, NHSO2-decenyl, NHSO2-alkyl, NHSO2-haloalkyl, NHSO2-alkenyl, NHSO2-alkynyl, NHSO2-hydroxyalkyl, NHSO2-alkylene-O-alkyl, NHSO2-aryl, NHSO2-alkylene-aryl, NHSO2-heteroaryl, NHSO2-alkylene-heteroaryl, NHSO2-cycloalkyl, NHSO2-heterocyclyl, NHSO2-alkylene-heterocyclyl, NHSO2-ethyl, NHSO2-(Z)-(2-methylbut-2-en-1-yl), NHSO2-(E)-prop-1-enyl, NHSO2-(E)-2-phenylethenyl, NHSO2-but-3-enyl,
CH2NHSO2-tigloyl, CH2NHSO2-senecioyl, CH2NHSO2-acetyl, CH2NHSO2-Crotonoyl, CH2NHSO2-3,3-Dimethylartyloyl, CH2NHSO2-Cinnamoyl, CH2NHSO2-Pentenoyl, CH2NHSO2-Hexanoyl, CH2NHSO2-benzoyl, CH2NHSO2-Ethylbutyryl, CH2NHSO2-alkyl, CH2NHSO2-dibenzoyl, CH2NHSO2-benzoyl, CH2NHSO2-alkanoyl, CH2NHSO2-alkenoyl, CH2NHSO2-benzoyl alkyl substituted CH2NHSO2-alkanoyl, CH2NHSO2-alkanoyl substituted phenyl, CH2NHSO2-alkenoyl substituted phenyl, CH2NHSO2-aryl, CH2NHSO2-acyl, CH2NHSO2-heterocylic, CH2NHSO2-heteroraryl, CH2NHSO2-alkenylcarbonyl, CH2NHSO2-alkane, CH2NHSO2-alkene, CH2NHSO2-sugar moiety, CH2NHSO2-acid moiety, CH2NHSO2-ethanoyl, CH2NHSO2-propanoyl, CH2NHSO2-propenoyl, CH2NHSO2-butanoyl, CH2NHSO2-butenoyl, CH2NHSO2-pentanoyl, CH2NHSO2-hexenoyl, CH2NHSO2-heptanoyl, CH2NHSO2-heptenoyl, CH2NHSO2-octanoyl, CH2NHSO2-octenoyl, CH2NHSO2-nonanoyl, CH2NHSO2-nonenoyl, CH2NHSO2-decanoyl, CH2NHSO2-decenoyl, CH2NHSO2-propionyl, CH2NHSO2-2-propenoyl, CH2NHSO2-2-butenoyl, CH2NHSO2-Isobutyryl, CH2NHSO2-2-methylpropanoyl, CH2NHSO2-2-ethylbutyryl, CH2NHSO2-ethylbutanoyl, CH2NHSO2-2-ethylbutanoyl, CH2NHSO2-butyryl, CH2NHSO2-(E)-2,3-Dimethylacryloyl, CH2NHSO2-(E)-2-Methylcrotonoyl, CH2NHSO2-3-cis-Methyl-methacryloyl, CH2NHSO2-3-Methyl-2-butenoyl, CH2NHSO2-3-Methylcrotonoyl, CH2N HSO2-4-Pentenoyl, CH2NHSO2-(2E)-2-pentenoyl, CH2NHSO2-Caproyl, CH2NHSO2-5-Hexenoyl, CH2NHSO2-Capryloyl, CH2NHSO2-Lauroyl, CH2NHSO2-Dodecanoyl, CH2NHSO2-Myristoyl, CH2NHSO2-Tetradecanoyl, CH2NHSO2-Oleoyl, CH2NHSO2-C(2-18) Acyl, CH2NHSO2-ethanyl, CH2NHSO2-propanyl, CH2NHSO2-propenyl, CH2NHSO2-butanyl, CH2NHSO2-butenyl, CH2NHSO2-pentanyl, CH2NHSO2-hexenyl, CH2NHSO2-heptanyl, CH2NHSO2-heptenyl, CH2NHSO2-octanyl, CH2NHSO2-octenyl, CH2NHSO2-nonanyl, CH2NHSO2-nonenyl, CH2NHSO2-decanyl, CH2NHSO2-decenoyl, CH2NHSO2-alkyl, CH2NHSO2-haloalkyl, CH2NHSO2-alkenyl, CH2NHSO2-alkynyl, CH2NHSO2-hydroxyalkyl, CH2NHSO2-alkylene-O-alkyl, CH2NHSO2-aryl, CH2NHSO2-alkylene-aryl, CH2NHSO2-heteroaryl, CH2NHSO2-alkylene-heteroaryl, CH2NHSO2-cycloalkyl, CH2NHSO2-heterocyclyl, and CH2NHSO2-alkylene-heterocyclyl, CH2NHSO2-ethyl, CH2NHSO2-(Z)-(2-methylbut-2-en-1-yl), CH2NHSO2-(E)-prop-1-enyl, CH2NHSO2-(E)-2-phenylethenyl, CH2NHSO2-but-3-enyl,
In an embodiment, the compound(s) is(are) in form of powder, liquid, or crystal. In an embodiment, the compound(s) is(are) in form of salt, ester, amine, diamine, amide, sulfonamide, urea thereof, or metabolite thereof'
The compounds of present application on cells is arresting cells in the S-phase and blocking their entering into the G2/M phase of cell cycle. The compounds block the DNA synthesis of cancer cell This invention provides compounds and method for improving blood circulation; soothing stroke; Prevent plaque formation and promote their dissipated; improve blood viscosity; reducing cardiovascular; reducing cerebrovascular; reducing thrombosis, arteriosclerosis, coronary heart disease, hypertension, diabetes, thrombocytopenia purpura, hemoptysis, hematemesis; treating blood in the stool, uterine bleeding, traumatic bleeding, abdominal irritation, swelling, flutter, Blood circulation, swelling, pain; Treating bronchiectasis, tuberculosis and lung abscess caused by too hemoptysis; reducing bleeding, antitussive, expectorant and analgesic effect, dilate blood vessels; reducing blood pressure and the treatment of cerebral arteriosclerosis; elevated blood lipids and reduced cholesterol.
A composition comprising an effective amount of compound selected from the above formula or a salt, ester, amine, diamine, amide, sulfonamide, urea, metabolite or derivative thereof can be used as a medicament for blocking the invasion, migration, metastasis of cancer cells, inhibiting tumor or cancer cell growth and for treating cancer, wherein the cancers comprise breast cancer, leukocytic cancer, liver cancer, ovarian cancer, bladder cancer, prostatic cancer, skin cancer, bone cancer, brain cancer, leukemia cancer, lung cancer, colon cancer, CNS cancer, melanoma cancer, renal cancer, cervical cancer, esophageal cancer, testicular cancer, splenic cancer, kidney cancer, lymphatic cancer, pancreatic cancer, stomach cancer, eye cancer and thyroid cancer.
This invention provides a composition comprising the compounds provided in the invention for treating cancers; for inhibiting viruses; for preventing cerebral aging; for improving memory; improving cerebral functions; for curing enuresis, frequent micturition, urinary incontinence; dementia, Alzheimer's disease, autism, brain trauma, Parkinson's disease or other diseases caused by cerebral dysfunctions; for treating arthritis, rheumatism, poor circulation, arteriosclerosis, Raynaud's syndrome, angina pectoris, cardiac disorder, coronary heart disease, headache, dizziness, kidney disorder; diabetes; cerebrovascular diseasea; inhibiting NF-kappa B activation; for treating brain edema, severe acute respiratory syndrome, respiratory viral diseases, chronic venous insufficiency, hypertension, chronic venous disease, oedema, inflammation, hemonhoids, peripheral edema formation, varicose vein disease, flu, post traumatic edema and postoperative swelling; for inhibiting blood clots, for inhibiting ethanol absorption; for lowering blood sugar; for regulating adrenocorticotropin and corticosterone levels. This invention provides a composition for Anti-MS, anti-aneurysm, anti-asthmatic, anti-oedematous, anti-inflammatory, anti-bradykinic, anti-capillarihemorrhagic, anti-cephalagic, anti-cervicobrachialgic, anti-eclamptic, anti-edemic, anti-encaphalitic, anti-epiglottitic, anti-exudative, anti-flu, anti-fracture, anti-gingivitic, anti-hematomic, anti-herpetic, anti-histaminic, anti-hydrathritic, anti-meningitic, antioxidant, anti-periodontic, anti-phlebitic, anti-pleuritic, anti-raucedo, anti-rhinitic, anti-tonsilitic, anti-ulcer, anti-varicose, anti-vertiginous, cancerostatic, corticosterogenic, diuretic, fungicide, hemolytic, hyaluronidase inhibitor, lymphagogue, natriuretic, pesticide, pituitary stimulant, thymolytic, vasoprotective, inhibiting leishmaniases, modulating adhesion or angiogenesis of cells, anti-parasitic; increase the expression of the genes: ANGPT2, DDIT3, LIF and NFKB1Z, and manufacturing an adjuvant composition and venotonic treatment. The composition block the DNA synthesis of cancer cell.
This invention provides a method of synthesis compound, wherein the compound is selected from formula
or salt, ester, diamine, amine, amide, sulfonamide or urea thereof, wherein R4 and R10 are selected from CH2O-tigloyl, NH-tigloyl, CH2NH-tigloyl, CH2NHCO-tigloyl, CH2NHCONH-tigloyl, CH2NHSO2-tigloyl; R1, R2, R3, R5, R8, R9, R11, R12, R13, R14, R15, R16 are independently selected from the group of H, O, OH, NH2, CH3, CH2OH, and COOH.
In an embodiment, the structure of above wherein R4 and R10 are selected from CH2O-tigloyl, NH-tigloyl, CH2NH-tigloyl, CH2NHCO-tigloyl, CH2NHCONH-tigloyl, CH2NHSO2-tigloyl; CH2O-angeloyl, CH2O-tigloyl, CH2O-senecioyl, CH2O-acetyl, CH2O-Crotonoyl, CH2O-3,3-Dimethylartyloyl, CH2O-Cinnamoyl, CH2O-Pentenoyl, CH2O-Hexanoyl, CH2O-benzoyl, CH2O-Ethylbutyryl; NH-angeloyl, NH-tigloyl, NH-senecioyl, NH-acetyl, NH-Crotonoyl, NH-3,3-Dimethylartyloyl, NH-Cinnamoyl, NH-Pentenoyl, NH-Hexanoyl, NH-benzoyl, NH-Ethylbutyryl; CH2NH-angeloyl, CH2NH-tigloyl, CH2NH-senecioyl, CH2NH-acetyl, CH2NH-Crotonoyl, CH2NH-3,3-Dimethylartyloyl, CH2NH-Cinnamoyl, CH2NH-Pentenoyl, CH2NH-Hexanoyl, CH2NH-benzoyl, CH2NH-Ethylbutyryl; CH2NHCO-angeloyl, CH2NHCO-tigloyl, CH2NHCO-senecioyl, CH2NHCO-acetyl, CH2NHCO-Crotonoyl, CH2NHCO-3,3-Dimethylartyloyl, CH2NHCO-Cinnamoyl, CH2NHCO-Pentenoyl, CH2NHCO-Hexanoyl, CH2NHCO-benzoyl, CH2NHCO-Ethylbutyryl; CH2NHCONH-angeloyl, CH2NHCONH-tigloyl, CH2NHCONH-senecioyl, CH2NHCONH-acetyl, CH2NHCONH-Crotonoyl, CH2NHCONH-3,3-Dimethylartyloyl, CH2NHCONH-Cinnamoyl, CH2NHCONH-Pentenoyl, CH2NHCONH-Hexanoyl, CH2NHCONH-benzoyl, CH2NHCONH-Ethylbutyryl; CH2NHSO2-angeloyl, CH2NHSO2-tigloyl, CH2NHSO2-senecioyl, CH2NHSO2-acetyl, CH2NHSO2-Crotonoyl, CH2NHSO2-3,3-Dimethylartyloyl, CH2NHSO2-Cinnamoyl, CH2NHSO2-Pentenoyl, CH2NHSO2-Hexanoyl, CH2NHSO2-benzoyl, CH2NHSO2-Ethylbutyryl; wherein R1, R2, R3, R5, R8, R9, R11, R12, R13, R14, R15, R16 are independently selected from the group of H, O, OH, NH2, CH3, CH2OH, and COOH; wherein the compound is in form in form of powder, liquid or crystal.
To a solution of 24,28-diamine(E4D) (0.1 mmol.) and aldehyde (RCHO, 0.3 mmol) in dimethylformamide (DMF, 1 mL) in a fritted plastic reaction tube was added SiliaBondCyanoborohydride (Si-CBH, 0.3 mmol). The reaction mixture was shaken at room temperature overnight. The reaction mixture was filtered into a fritted plastic reaction tube. Tosic acid functionalized silica (Si-SCX, 0.3 mmol) was added. The reaction mixture was shaken at room temperature overnight. The liquid was filtered off. A solution of 5% ammonia-methanol (1 mL) was added to the product captured silica. The mixture was shaken at room temperature overnight. The methanolic solution was filtered off and concentrated under reduced pressure to yield the desired amine analog.
To a solution of 24,28-diamine(E4D) (0.1 mmol.) and carboxylic acid (RCO2H, 0.3 mmol) in dimethylformamide (DMF, 1 mL) in a fritted plastic reaction tube was added EDC functionalized silica (Si-EDC, 0.3 mmol). The reaction mixture was shaken at room temperature overnight. Carbonate functionalized silica (Si—CO3, 0.3 mmol) was added. The reaction mixture was shaken at room temperature overnight. The reaction mixture was filtered and concentrated under reduced pressure to yield the desired amide analog
To a solution of 24,28-diamine(E4D) (0.1 mmol.) and sulfonyl chloride (RSO2Cl, 0.3 mmol) in dimethylformamide (DMF, 1 mL) in a fritted plastic reaction tube was added triethylamine functionalized silica (Si-WAX-2, 0.3 mmol). The reaction mixture was shaken at room temperature overnight. Amine functionalized silica (Si-WAX, 0.3 mmol) was added. The reaction mixture was shaken at room temperature overnight. The reaction mixture was filtered and concentrated under reduced pressure to yield the desired sulfonamide analog.
A solution of 24,28-diamine(E4D) (0.1 mmol.) and isocyanate (RNCO, 0.3 mmol) in dimethylformamide (DMF, 1 mL) in a fritted plastic reaction tube was shaken at room temperature overnight. Piperazine functionalized silica (Si-PPZ, 0.3 mmol) was added. The reaction mixture was shaken at room temperature overnight. The reaction mixture was filtered and concentrated under reduced pressure to yield the desired urea analog.
R group for amine, sulfonamides, amide analog, Urea Analogs, wherein sulfonyl chloride (RSO2Cl), carboxylic acid (RCO2H), isocyanate (RNCO), where is selected from the group consisting of alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, -alkylene-O-alkyl, aryl, -alkylene-aryl, heteroaryl, -alkylene-heteroaryl, cycloalkyl, heterocyclyl, and -alkylene-heterocyclyl, wherein said aryl, heteroaryl, the aryl portion of said -alkylene-aryl, or the heteroaryl portion of said -alkylene-heteroaryl are unsubstituted or substituted with one or more groups Y which are selected; said heterocyclyl or the heterocyclyl portion of said -alkylene-hterocyclyl are unsubstituted or substituted with one or more groups of Z.
Y is one or more substituents independently selected from the group consisting of halogen, alkyl, haloalkyl, aryl, -alkylene-aryl, —OH, —CN, —N(R′)2, —N(R′)—C(O)—R′, —N(R′)—C(O)—(N′)2, —C(O)N(R′)2, —C(O)OH, —C(O)O-alkyl, N(R′)—S(O)2—(R′) and —S(O)2N(R′)2; Each R′ is independently selected from the group consisting of H, alkyl, cyloalkyl, haloalkyl, heterocyclyl, -alkelene-hterocyclyl, aryl, -alkylene-aryl, heteroaryl, -alkylene-heteroaryl;
Z is one or more substituents independently selected from the group consisting of alkyl, one or more hydroxy substituted alkyl, aryl, -alkylene-aryl, -alkylene-O-alkyl, -alkylene-O-alkylene-aryl, -alkylene-O-aryl, -alkylene-O-alkyl, -alkylene-O-alkylene-aryl, -alkylene-O-aryl, —CN, haloalkyl, -alkylene-C(O)—N(R″)2, —C(O)—N(R″)2, —C(O)OH, —C(O)O-alkyl, —N(R″)2, and -alkylene-N(R″)2, —S(O)2—N(R″)2, -alkylene-S(O)2—N(R″)2, —N(R″)—C(O)—R″, —N(R″)—C(O)—R″, —N(R″)—C(O)—N(R″)2, -alkylene-N(R″)—C(O)—N(R″)2, -alkylene-N(R″)—C(O)—R″, -alkylene-S(O)2-R″, —N(R″)—S(O)2—R″, and -alkylene-N(R″)—S(O)2—R″, cycloalkyl, heterocyclyl, -alkylene-heterocyclyl, heteroaryl and -alkylene-heteroaryl, or wherein two Z substituents on adjacent carbon atoms, on a carbon atom and an adjacent heteroatom, or on a single carbon atom, together with carbon atom(s) and/or the combination of the carbon atom and the adjacent heteroatom to which said Z substituents are attached form a four to seven-membered cycloalkyl, cyloalkeny, heterocyclyl, aryl or heteroaryl ring, wherein said aryl, heteroaryl, the aryl portion of said -alkylene-aryl, -alkylene-O-alkylene-aryl, -alkylene-O-alkylene-aryl, -alkylene-O-aryl, and the heteroaryl portion of said -alkylene-heteroaryl are unsubstituted or substituted with one or more R* substituents which are independently selected; and R* is one or more substituents independently selected from the group consisting of halogen, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, nitro, —NH2, —NH(alkyl), —N(alkyl)2, —NH-alkylene-aryl, —N(alkyl)-alkylene-aryl, -alkylene-aryl, —C(O)NH2, —C(O)NH(alkyl), —C(O)N(alkyl)2, —S(O)2NH2, —S(O)2NH(akyl), —S(O)2N(alkyl)2, —NHC(O)-alkyl, —N(alkyl)C(O)-alkyl, —NHC(O)-aryl, —N(alkyl)C(O)-aryl, —NH—S(O)2-alkyl, —N(alkyl)-S(O)2-alkyl, —NH—S(O)2-aryl, and —N(alkyl)-S(O)2-aryl.
Alkenyl means unsaturated linear or branched structures and combinations thereof, having formula R2C═CR2, one or more double bonds therein. Examples of alkenyl groups include vinyl, propenyl, isopropenyl, butenyl, s- and t-butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, and hexadienyl. An aryl is a functional group of organic molecule derived from an aromatic compound such as benzene, a 6-14 membered carbocyclic aromatic ring system comprising 1-3 benzene rings. If two or more aromatic rings are present, then the rings are fused together, so that adjacent rings share a common bond. Examples include phenyl and naphthyl. The aryl group may be substituted with one or more substitutes independently selected from halogen, alkyl or alkoxy. Acyl is a functional group which can be obtained from an organic acid by the removal of the carboxyl. Acyl groups can be written using the general formula —COR, where there is a double bond between the carbon and oxygen. The names of acyl groups typically end in -yl, such as formyl, acetyl, propionyl, butyryl and benzoyl. Benzoyl is one of the acyls, C6H5COR, obtained from benzoic acid by the removal of the carboxyl. A heterocyclic compound is a compound containing a heterocyclic ring which refers to a non-aromatic ring having 1-4 heteroatoms, said ring being isolated or fused to a second ring selected from 3- to 7-membered alicyclic ring containing 0-4 heteroatoms, aryl and heteroaryl, wherein heterocyclic compounds include pyrrolidinyl, pipyrazinyl, morpholinyl, trahydrofuranyl, imidazolinyl, thiomorpholinyl, and the like. Heterocyclyl groups are derived from heteroarenes by removal of a hydrogen atom from any ring atom. Alkanoyl is the general name for an organic functional group RCO—, where R represents hydrogen or an alkyl group. Examples of alkanoyls are acetyl, propionoyl, butyryl, isobutyryl, pentanoyl and hexanoyl. Alkenoyl is an alkenylcarbonyl in which the alkenyl is defined above. Examples are pentenoyl (tigloyl) and pentenoyl (angeloyl). Alkyl is a radical containing only carbon and hydrogen atoms arranged in a chain, branched, cyclic or bicyclic structure or their combinations, having 1-18 carbon atoms. Examples include but are not limited to methyl, ethyl, propyl isopropyl, butyl, s- and t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Benzoyl alkyl substituted alkanoyl refers to straight or branched alkanoyl substituted with at least one benzoyl and at least one alkyl, wherein the benzoyl is attached to a straight or branched alkyl. An example of a benzoyl alkyl substituted alkanoyl is benzoyl methyl isobutanoyl. A sugar moiety is a segment of molecule comprising one or more sugars or derivatives thereof or alduronic acid thereof.
(Y)Y3, Y and Y3 represent the same compound. YM and (ACH-Y) represent the same compound. Connecting moiety is a substructure or a group of atoms which connect the functional group to a core compound. Example: angeloyl group is connected by a sugar moiety to a triterpene core.
Acetyl=ethanoyl; Propionyl=methylpropanoyl; Crotonoyl=2-butenoyl; Isobutyryl=2-methylpropanoyl; 2-Ethylbutyryl=2-Ethylbutanoyl; Butyryl=n-Butyryl=butanoyl=C-4 Acyl; trans-2-Methyl-2-butenoyl=(E)-2,3-Dimethylacryloyl chloride=(E)-2-Methylcrotonoyl=3-cis-Methyl-methacryloyl=Tigloyl; 3,3-Dimethylacryloyl=3-Methyl-2-butenoyl=3-Methylcrotonoyl=Senecioyl; Propionyl chloride=methylpropanoyl; Hexanoyl=Caproyl; Heptanoyl=Enanthic=Oenanthic; Octanoyl=Capryloyl; Dodecanoyl=Lauroyl; Tetradecanoyl=Myristoyl; C(2-18)Acyl is an acyl group having 2 to 18 carbons.
ethanoyl is a C-2 Acyl, propanoyl is a C-3 Acyl, propenoyl is a C-3 Acyl, propionyl is a C-3 Acyl, butanoyl is a C-4 Acyl, butenoyl is a C-4 Acyl, crotonoyl is a C-4 Acyl, pentanoyl is a C-5 Acyl, pentenoyl is a C-5 Acyl, angeloyl is C-5 Acyl, tigloyl is C-5 Acyl, senecioyl is C-5 Acyl, hexanoyl is a C-6 Acyl, hexenoyl is a C-6 Acyl, heptanoyl is a C-7 Acyl, heptenoyl is a C-7 Acyl, octanoyl is a C-8 Acyl, octenoyl is a C-8 Acyl, nonanoyl is a C-9 Acyl, nonenoyl is a C-9 Acyl, decanoyl is a C-10 Acyl, decenoyl is a C-10 Acyl, lauroyl is a C-12 Acyl, dodecanoyl is a C-12 Acyl, myristoyl is a C-14 Acyl, oleoyl is a C-18 Acyl.
The building blocks used in the invention including triterpenes, hydroxylated triterpenes, acetyl, angeloyl, tigloyl, senecioyl, Crotonoyl, 3,3-Dimethylartyloyl, Cinnamoyl, Pentenoyl, Hexanoyl, benzoyl, Ethylbutyryl, alkyl, dibenzoyl, benzoyl, methylbutanoyl, methylpropanoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, alkanoyl substituted phenyl, alkenoyl substituted phenyl, aryl, acyl, heterocylic, heteroraryl, alkenylcarbonyl, ethanoyl, propanoyl, propenoyl, butanoyl, butenoyl, pentanoyl, hexenoyl, heptanoyl, heptenoyl, octanoyl, octenoyl, nonanoyl, nonenoyl, decanoyl, decenoyl, propionyl, 2-propenoyl, 2-butenoyl, Isobutyryl, 2-methylpropanoyl, 2-ethylbutyryl, ethylbutanoyl, 2-ethylbutanoyl, butyryl, (E)-2,3-Dimethylacryloyl, (E)-2-Methylcrotonoyl, 3-cis-Methyl-methacryloyl, 3-Methyl-2-butenoyl, 3-Methylcrotonoyl, 4-Pentenoyl, (2E)-2-pentenoyl, Caproyl, 5-Hexenoyl, Capryloyl, Lauroyl, Dodecanoyl, Myristoyl, Tetradecanoyl and Oleoyl, 4-(dimethylamino)-2-methylbut-2-enoyl, 4-[(2-methoxyethyl)amino]-2-methyl-4oxobut-2-enoyl or halides thereof, or chloride.thereof.
Acryloyl chloride [Synonym: 2-propenoly chloride]; Propionyl chloride [Synonym: methylpropanoyl chloride]; Crotonoyl chloride [Synonym: 2-butenoyl chloride]; Isobutyryl chloride [Synonym: 2-methylpropanoyl chloride]; 2-Ethylbutyryl chloride [Synonym: 2-Ethylbutanoyl chloride]; Butyryl chloride (Synonym: n-Butyryl chloride, butanoyl chloride, or C-4 Acyl halide); trans-2-Methyl-2-butenoyl chloride [Synonym: (E)-2,3-Dimethylacryloyl chloride, (E)-2-Methylcrotonoyl chloride, 3-cis-Methyl-methacryloyl chloride, Tigloyl chloride]; 3,3-Dimethylacryloyl chloride [Synonym: 3-Methyl-2-butenoyl chloride, 3-Methylcrotonoyl chloride, Senecioyl chloride ]; Hexanoyl chloride [Synonym: Caproyl chloride]; Heptanoyl chloride [Synonym: Enanthic chloride, Oenanthic chloride] Octanoyl chloride [Synonym: Capryloyl chloride].
In the presented experiments, concentrations of drug that inhibit 15% cell-growth or less (i.e. 85% of control or above) as compared to the no-drug control (DMSO) are considered non-cytotoxic concentrations. In an embodiment, the concentrations of drug that inhibit 10% cell-growth or less (i.e. 90% of control or above) as compared to the no-drug control (DMSO) are considered non-cytotoxic concentrations. In an embodiment, the concentrations of drug that inhibit 5% cell-growth or less (i.e. 95% of control or above) as compared to the no-drug control (DMSO) are considered non-cytotoxic concentrations. In an embodiment, the concentrations of drug that inhibit 20% cell-growth or less (i.e. 80% of control or above) as compared to the no-drug control (DMSO) are considered non-cytotoxic concentrations. In an embodiment, the concentrations of drug that inhibit 25% cell-growth or less (i.e. 75% of control or above) as compared to the no-drug control (DMSO) are considered non-cytotoxic concentrations. In an embodiment, the concentrations of drug that inhibit 30% cell-growth or less as compared to the no-drug control (DMSO) are considered non-cytotoxic concentrations. In an embodiment, the concentrations of drug that inhibit 45% cell-growth or less as compared to the no-drug control (DMSO) are considered non-cytotoxic concentrations.
The triterpene compound or compounds selected from this invention can be administered to a subject in need thereof, treating the subject, wherein including preventing cancer, or providing an adjuvant effect to the subject, or inhibiting the initation or promotion of cancer, or killing the cancer/tumor cells, or inhibiting cancer cell invasion. In an embodiment the compounds inhibit the activation of Nuclear Factor-kB, wherein inhibiting the localization or wherein binding the DNA. In an embodiment the compounds block the DNA synthesis. In an embodiment the compounds induce apoptosis in cancer cells.
The saponins are partially hydrolyzed into a mixture of products which can be separated by HPLC. Specific partial hydrolysis of saponins can also be achieved with enzymes. The glycosidases catalyze the hydrolysis of the glycosidic linkage. Galactosidase is an enzyme which catalyzes the hydrolysis of galactosides. Glucosidase is an enzyme which breaks glucose from saponin. Other enzyme examples are xylanases, lactase, amylase, chitinase, sucrase, maltase, and neuraminidase.
The sugar moiety of the triterpenoid saponin (example Xanifolia Y) can be removed by acid hydrolysis. The synthetic compound of ACH-Y is obtained. ACH-Y is a triterpene with acyl groups but no sugar moiety. The acyl group of the saponin (example Xanifolia Y) can be removed by alkaline hydrolysis. The synthetic compound AKOH-Y can be obtained. AKOH-Y is a pentacyclic triterpene with sugar moieties. A pentacyclic triterpene can be obtained by acid and alkaline hydroysis of saponins from natural sources. A pentacyclic triterpene can be obtained by synthetic methods (Reference: Surendra et al., Rapid and Enantioselective Synthetic Approaches to Germanicol and Other Pentacyclic Triterpenes, Journal of the American Chemical Society, 2008, 130(27), 8865-8869). Pentacyclic triterpenes with sugar moieties can also be obtained by synthesis (Reference: Ple et al., Synthesis of L-arabinopyranose containing hederagenin saponins, Tetrahedron 61 (2005) 4347-4362). Acylation is the process of adding an acyl group to a compound. The Friedel-Crafts reaction is an example of this process. An active compound can be obtained by acylating a pentacyclic triterpenes, or hydroxylated triterpenes. In an embodiment, acylating C24, C28, C21 and C22 of a pentacyclic triterpenes, or hydroxylated triterpenes produce compounds for inhibiting cancer growth, cancer invasion, cell invasion, cancer cell invasion, molecular cell invasion, cell attachment adhesion, or cell circulation. In an embodiment, the acyl group(s) may be at C3. In an embodiment, a sugar moiety is at C21, 22, or 28, wherein the sugar moiety is attached with 2 acyl groups. In an embodiment, acylating the compounds of (A), (B), (C), (D1), (D2), (F), (G), (H), produce the compounds for inhibiting cancer invasion, cells invasion or cancer cell invasion; cancer metastasis; or cancer growth. The building blocks in the present application are used to synthesise active saponins. In embodiment, the sugar moiety(ies) is/are included but not limited to a group of glucose, galactose, rhamnose, arabinose, xylose, fucose, allose, altrose, gulose, idose, lyxose, mannose, psicose, ribose, sorbose, tagatose, talose, fructose, alduronic acid, glucuronic acid, galacturonic acid, and derivatives or combinations thereof;
Acylating the compound (G) with angeloyl or tigloyl group gives the following compounds
wherein R1, R2, R5, R8 represent OH or O-angeloyl; R3 represents OH, H or O-angeloyl; R4, R10 represent CH3, CH2OH or CH2Oangeloyl; R3 represents OH, H or O-angeloyl; R9, R11, R12, R13, R14, R15 represent CH3; or wherein R1, R2, R5, R8 represent OH or O-tigloyl; R3 represents OH, H or O-tigloyl; R4, R10 represent CH3, CH2OH or CH2O tigloyl; R9, R11, R12, R13, R14, R15 represent CH3; wherein the compounds inhibit cancer growth, cancer invasion, cells invasion or cancer cell invasion.
Acylating the compound (G) with angeloyl, tigloyl, senecioyl, acetyl, Crotonoyl, 3,3-Dimethylartyloyl, Cinnamoyl, Pentenoyl, Hexanoyl, benzoyl, Ethylbutyryl, alkyl, dibenzoyl, benzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted O-alkanoyl, alkanoyl substituted phenyl, alkenoyl substituted phenyl, aryl, acyl, heterocylic, heteroraryl, CH2O-alkenylcarbonyl, alkane, alkene give the compound (K) wherein R1, R2, R5, R8 represent OH, O-angeloyl, O-tigloyl, O-senecioyl, O-acetyl, O-Crotonoyl, O-3,3-Dimethylartyloyl, O-Cinnamoyl, O-Pentenoyl, O-Hexanoyl, O-benzoyl, O-Ethylbutyryl, O-alkyl, O-dibenzoyl, O-benzoyl, O-alkanoyl, O-alkenoyl, O-benzoyl alkyl substituted O-alkanoyl, O-alkanoyl substituted phenyl, O-alkenoyl substituted phenyl, O-aryl, O-acyl, O-heterocylic, O-heteroraryl, O-alkenylcarbonyl; R4, R10 represent CH3, CH2OH, CH2O-angeloyl, CH2O-tigloyl, CH2O-senecioyl, CH2O-acetyl, CH2O-Crotonoyl, CH2O-3,3-Dimethylartyloyl, CH2O-Cinnamoyl, CH2O-Pentenoyl, CH2O-Hexanoyl, CH2O-benzoyl, CH2O-Ethylbutyryl, CH2O-alkyl, CH2O-dibenzoyl, CH2O-benzoyl, CH2O-alkanoyl, CH2O-alkenoyl, CH2O-benzoyl alkyl substituted O-alkanoyl, CH2O-alkanoyl substituted phenyl, CH2O-alkenoyl substituted phenyl, CH2O-aryl, CH2O-acyl, CH2O-heterocylic, CH2O-heteroraryl, CH2O-alkenylcarbonyl, alkane, alkene; R3 is absent of represents OH, H, O-angeloyl, O-tigloyl, O-senecioyl, O-acetyl, O-Crotonoyl, O-3,3-Dimethylartyloyl, O-Cinnamoyl, O-Pentenoyl, O-Hexanoyl, O-benzoyl, O-Ethylbutyryl, O-alkyl, O-dibenzoyl, O-benzoyl, O-alkanoyl, O-alkenoyl, O-benzoyl alkyl substituted O-alkanoyl, O-alkanoyl substituted phenyl, O-alkenoyl substituted phenyl, O-aryl, O-acyl, O-heterocylic, O-heteroraryl, O-alkenylcarbonyl; wherein R9, R11, R12, R13, R14, R15 represent CH3; wherein the compounds inhibit cancer growth, cancer invasion, cells invasion or cancer cell invasion; wherein the compound for use as mediator or inhibitor of adhesion protein or angiopoietin; wherein the compounds use as mediator modulating the secretion, expression, or synthesis of adhesion protein comprises reducing the fibronectin for inhibiting cell attachment, cell adhesion or cell circulation; wherein the adhesion proteins comprise fibronectin, integrins family, myosin, vitronectin, collagen, laminin, polyglycans, cadherin, heparin, tenascin, CD54, and CAM; the compounds use for anti adhesion therapy and targeting adhesion molecules for therapy.
Applicant further states that anti-adhesion therapy and targeting adhesion molecules for therapy is a new direction for development of drugs. Some examples of anti-adhesion drugs in clinical trials are Efalizumab, Odulimomab, Alicaforsen, Aselizumab etc, which target varies adhesion proteins. Please see TEXT BOOK, Adhesion Molecules: Function and Inhibition, (Reference 2), edited by Klaus Ley page 289-291, 297.
Adhesion molecules in inflammatory disease, (Reference 4), Abstract, line 7-8 “Blockade of the function of expression of CAM has emerged as a new therapeutic target in inflammatory diseases”. Applicants' invention is an anti-adhesion therapy which is a new use of the compound as a mediator or inhibitor of adhesion proteins and angiopoietins. It inhibits excess adhesion and inhibits cell attachment.
In the present application, Applicants have used compounds selected from structure (2A) for anti adhesion therapy, as a mediator or inhibitor of adhesion proteins and angiopoietins, and modulation of the cell attachment, and cell adhesion.
This invention provide a synthetic method to obtain semi-natural compounds by chemically removing functional groups of complex natural products to the basic core structure before de-novo chemically adding on active groups directly or sequentially by reaction with the active group donating chemical under different reaction temperature and time to produce series of different active group modified core structure compounds that can be fractionated and easily structurally determined as well as screening for different bio-active efficacies and toxicities as potential new drug candidates.
The activities of compounds are tested with cancer of leukemia (CCRF-CEM, HL60(TB), K-562, MOLT-4, RPM18226, SR), lung(A549/ATCC, HOP-62, HOP92, NCI-H226, NCI-H322M, NCI-H460, colon (COLO205, HCC-2998, HCT-116, HCT-15, HT29, KM12, SW-620), CNS (SF-268, SF295, SF539, SNB-19, SNB-75, US51), melanoma (LOX IMVI, MALME-3M, M14, MDA-MB-3M, M14, MDA-MB-435, SK-MEL-2, SK-MEL-28, SK-MEL-5, UACC-257, UACC-62), ovary (ICTOV1, OVCAR-3, OVCAR-4, OVCAR-5, OVCAR-8, NCIADR-RES, SKOV3), renal (786-0, A498, ACHN, CAKI-1, SN12C, TK-10, UO-31), prostate (PC-3, DU-145), breast (MCF7, MDA-MB-231, HS578T, T47D, MDA-MB-468). The room temperature is 25 C in the present application.
Experimental Details
Experiment 1: Removal of the Sugar Moiety from Saponin by Acid Hydrolysis
15 mg saponin was dissolved in 1 ml of Methanol. 1 ml of 2N HCl was then added. The mixture was refluxed in 80 C water bath for 5 hours. The solution was then neutralized by adding 2 ml of 1N NaOH (to final pH 4-6). The aglycone was then extracted with ethylacetate 3 ml×2. The extracts were collected and pooled. Further isolation of aglycone (sugar-removed saponin) was achieved by HPLC with isocratic elution of 80-100% acetonitrile.
Experiment 2: Removal of the Acyl Group by Alkaline Hydrolysis
Methods: 20 mg of saponin was dissolved in 0.5 ml of 1N NaOH. The solution was incubated in 80C water bath for 4 hours. It was cooled to room temperature before neutralized with 0.5 ml 1N HCl (adjust pH to about 3). The mixture was extracted with 2 ml 1-butanol 3 times. The butanol fractions were collected and lyophilized. The hydrolyzed saponin with further purified with HPLC in a C-18 column eluted with 25% acetonitrile.
Experiment 3: Adding the Acyl Group to Triterpene by Esterification
Method: 40 mg of triterpene core (fraction IV) was dissolved in 1 ml pyridine in a 50 ml tube. Reaction is started by adding 0.2 ml of acyl chloride (Tigloyl chloride, angeloyl chloride, Acetyl chloride, Crotonoyl chloride, 3,3-Dimethylartyloyl chloride(senecioyl chloride), Cinnamoyl chloride, Pentenoyl chloride, Hexanoyl chloride, benzoyl chloride or Ethylbutyryl chloride). The mixture is stirred for 5 sec, 1 min, 2 min, 5 min, 10 min, 30 min, 1 hr, 2 hr, 18 hr, 2 days or 3 days at 0 C, 25 C or 75 C temperature. At the end of reaction, 5 ml of 2N HCl or 1M NaHCO3 is added to the reaction mixture. The solution is then extracted 3 times with 10 ml of ethyl acetate which is then evaporated under vacuum and at 45 C and lyophilization. The reaction product is dissolved in 80% acetonitrile-0.005% Trifluoroacetic acid or DMSO; and was separated with HPLC. Selecting the HPLC fractions for isolation is according to the cytotoxic activity of the reaction product obtained at a specific reaction time. The active esterification products are purified with HPLC. The reaction product of mixtures and individual compounds are tested with MTT cytotoxic assay. Structures are determined with NMR. See examples
Experiment 4: Preparation of E4A
Experiment 5: Esterification of E4A with Tigloyl Chloride
Experiment 6: Isolation of E4A-Tig Active Compounds with HPLC
Experiment 7: MTT Experiment
Cells. HTB-9 (bladder), HeLa-S3 (cervix), DU145 (prostate), H460 (lung), MCF-7 (breast), K562 (leukemia), HCT116 (colon), HepG2 (liver), U2OS (bone), T98G (brain), SK-MEL-5 (Skin) and OVCAR 3, ES2 (ovary), Pancreas (Capan), Mouth (KB), Kidney (A498).
MTT Assay. The procedure for MTT assay followed the method described by Carmichael et al. (1987) with modifications. The cells were seeded into a 96-well plate at for 24 hours before drug-treatment. The cells were then exposed to the drugs for 48, 72, or 96 hours. After the drug-treatment, MTT (0.5 mg/mL) was added to cultures and incubated for an hour. The formazan (product of the reduction of tetrazolium by viable cells) formed and was dissolved with DMSO and the O.D. at 490 nm, and was measured by an ELISA reader. The MTT level of the cells before drug-treatment was also measured (T0). The % cell-growth (% G) is calculated as: % G=(TD−T0/TC−T0)×100(1), where TC or TD represents O.D. readings of control or drug-treated cells.
When T0>TD, then the cytotoxicity (LC) expressed as % of the control is calculated as: % LC=(TD−T0/T0)×100(2).
MTT Assay is performed to intermediate and final products from experiments.
Experiment 8: Chemical Synthesis, Isolation and Characterization of E4A-Tig-R
Chemical synthesis of E4A-Tig-R: 1. Preparation of E4A; 2. Esterification of E4A with Tigloyl Chloride; 3. Isolation of E4A-Tig-R with HPLC
Cytotoxic activity determination: 1. MTT assay
Chemical structure determination: 1. NMR analysis; 2. Mass Spectrum analysis
Compound E4A-Tig-R: 24,28-O-Tigloyl-3β,16α,21β,22α,24β,28-hexahydroxyolean-12-ene
Experiment 9: Chemical Synthesis, Isolation and Characterization of E4A-Tig-N
Chemical synthesis of E4A-Tig-N: 1. Preparation of E4A; 2. Esterification of E4A with Tigloyl Chloride; 3. Isolation of E4A-Tig-N with HPLC
Cytotoxic activity determination: 1. MTT assay
Chemical structure determination: 1. NMR analysis; 2. Mass Spectrum analysis
Experiment 10: Chemical Synthesis, Isolation and Characterization of E4A-Tig-Q
Chemical synthesis of E4A-Tig-Q: 1. Preparation of E4A; 2. Esterification of E4A with Tigloyl Chloride; 3. Isolation of E4A-Tig-Q with HPLC
Cytotoxic activity determination: 1. MTT assay
Chemical structure determination: 1. NMR analysis; 2. Mass Spectrum analysis
Experiment 11: Chemical Synthesis, Isolation and Characterization of E4A-Tig-V
Chemical synthesis of E4A-Tig-V: 1. Preparation of E4A; 2. Esterification of E4A with Tigloyl Chloride; 3. Isolation of E4A-Tig-V with HPLC
Cytotoxic activity determination: 1. MTT assay
Chemical structure determination: 1. NMR analysis; 2. Mass Spectrum analysis
Experiment 12: Chemical Synthesis, Isolation and Characterization of E4A-Tig-T
Chemical synthesis of E4A-Tig-T: 1. Preparation of E4A; 2. Esterification of E4A with Tigloyl Chloride; 3. Isolation of E4A-Tig-T with HPLC
Cytotoxic activity determination: 1. MTT assay
Chemical structure determination: 1. NMR analysis; 2. Mass Spectrum analysis
Experiment 13: Chemical Synthesis, Isolation and Characterization of E4A-Tig-U
Chemical synthesis of E4A-Tig-U: 1. Preparation of E4A; 2. Esterification of E4A with Tigloyl Chloride; 3. Isolation of E4A-Tig-U with HPLC
Cytotoxic activity determination: 1. MTT assay
Chemical structure determination: 1. NMR analysis; 2. Mass Spectrum analysis
Experiment 14: Chemical Synthesis, Isolation and Characterization of E4A-Tig-S
Chemical synthesis of E4A-Tig-S: 1. Preparation of E4A; 2. Esterification of E4A with Tigloyl Chloride; 3. Isolation of E4A-Tig-S with HPLC
Cytotoxic activity determination: 1. MTT assay
Chemical structure determination: 1. NMR analysis; 2. Mass Spectrum analysis
Experiment 15: Using method in Experiment 3, esterification of E4A with acetyl, angeloyl, tigloyl, senecioyl, Crotonoyl, Cinnamoyl, Pentenoyl gave the following compounds:
Experiment 16: Esterification of E4A-Tig-N with Senecioyl Chloride
Chemical synthesis of E4A-Tig-Sen-1: 1. Esterification of E4A-Tig-N with Senecioyl Chloride; 3. Isolation of E4A-Tig-Sen-1 with HPLC
Cytotoxic activity determination: 1. MTT assay
Chemical structure determination: 1. NMR analysis; 2. Mass Spectrum analysis
Experiment 17: Esterification of E4A-Tig-N with angeloyl chloride, Acetyl chloride, Crotonoyl chloride, 3,3-Dimethylartyloyl chloride, senecioyl chloride, Cinnamoyl chloride, Pentenoyl chloride, Hexanoyl chloride, Benzoyl chloride or Ethylbutyryl chloride; Isolation with HPLC; Cytotoxic activity determination; Chemical structure determination with the method of Experiment 8, gave the Following Compounds:
Experiment 20: Esterification of E4A with Propionyl Chloride
Methods: 50 mg of E4A in 1 ml pyridine, stir gently in a 50 ml tube. Esterification was carried out at 25 C by adding 200 ul Propionyl chloride, and immediately withdrawn 200 ul from the mixture and added to 1 ml of 2N HCl. (ASAP sample). At 1, 2, 5, 10 and 60 minutes afterward; 200 ul of reaction mixture was similarly withdrawn and add to 1 ml of 2N HCl. Mixtures were sit at room-Temp over night. Extract the esterification products with 2 ml ethylacetate. Evaporate the ethylacetate. Dissolve the sample with DMSO (final concentration of 40 mg/ml). Fractionate the reaction products with HPLC (C18 column, 1 ml/min).
HPLC condition: Column: C18 (9.4×250 mm, 5 um); Solvents: 80% Acetonitrile-0.005% TFA; Gradient: isocratic; Flow-rate: 1 ml/min; O.D.: 207 nm, AT=1024; Chart speed: 0.1 cm/min; Run time: 120 min; MTT assay (Cytotoxicity determination) condition: Cells: ES2 (ovarian cancer). Cell density: plate 10K cells per well over night before addition of drug. Drug incubation time: 2 days.
Experiment 21: Esterification of E4A with Isobutyryl Chloride
Methods: 52 mg of E4A in 1 ml pyridine, stir gently in a 50 ml tube. Esterification was carried out at 25° C. by adding 200 ul of isobutyryl chloride. 2 minute later, 4 ml 2N HCl was added to the reaction mixture. Mixtures were kept at room-Temp over night. Extract the esterification products with 5 ml ethyl acetate. Evaporate the ethyl acetate. Dissolve the sample with DMSO (final concentration of 40 mg/ml). Fractionate the reaction products with HPLC (C18 column).
HPLC condition: Column: C18 (9.4×250 mm, 5 um); Solvents: 80% Acetonitrile-0.005% TFA; Gradient: isocratic; Flow-rate: 1 ml/min; O.D.: 207 nm, AT=1024; Chart speed: 0.1 cm/min; Run time: 200 min.
MTT assay (Cytotoxicity determination) condition: Cells: ES2 (ovarian cancer); Cell density: plate 10K cells per well over night before addition of drug; Drug incubation time: 2 days.
Experiment 22: Esterification of E4A with 3,3-dimethylacryloly chloride from different times of esterification reaction. Reaction products obtained from each time of reaction (5 sec, 1 min, 2 min, 5 min, and 10 min) were fractionated by HPLC. The profile is plotted according to HPLC elution time and optical density of fractions. Reaction was performed at Room temperature and 0 C. Fractionate the reaction products with HPLC (C18 column). Cytotoxic activity is determined with MTT. Chemical structure determined with NMR.
Experiment 23: Esterification of E4A with Pentenoyl chloride-from different times of esterification reaction. Reaction products obtained from each time of reaction (5 sec, 1 min, 2 min, 5 min, and 10 min) were fractionated by HPLC. The profile is plotted according to HPLC elution time and optical density of fractions. Reaction was performed at Room temperature. Fractionate the reaction products with HPLC (C18 column). Cytotoxic activity is determined with MTT. Chemical structure determined with NMR.
Experiment 24: Esterification of E4A with Hexanoly chloride from different times of esterification reaction. Reaction products obtained from each time of reaction (5 sec, 1 min, 2 min, 5 min, and 10 min) were fractionated by HPLC. The profile is plotted according to HPLC elution time and optical density of fractions. Reaction was performed at 0 C. Fractionate the reaction products with HPLC (C18 column). Cytotoxic activity is determined with MTT. Chemical structure determined with NMR.
Experiment 25: Esterification of E4A with Acetyl chloride (H) from different times of esterification reaction. Reaction products obtained from each time of reaction (1 min, 2 min, 5 min and 10 min) were fractionated by HPLC. The profile is plotted according to HPLC elution time and optical density of fractions. Reaction was performed at Room temperature. Fractionate the reaction products with HPLC (C18 column). Cytotoxic activity is determined with MTT. Chemical structure determined with NMR.
Experiment 26: Esterification products of E4A with Crotonoyl chloride (I) from different times of esterification reaction. Reaction products obtained from each time of reaction (5 sec, 1 min, 2 min, 5 min and 10 min) were fractionated by HPLC. The profile is plotted according to HPLC elution time and optical density of fractions. Reaction was performed at Room temperature. Fractionate the reaction products with HPLC (C18 column). Cytotoxic activity is determined with MTT. Chemical structure determined with NMR.
Experiment 27: Esterification products of E4A with Cinnamoyl chloride (J) from different times of esterification reaction. Reaction products obtained from each time of reaction (1 min, 1hour, 2 hours, 18 hours, 18 hours(heat)) were fractionated by HPLC. The profile is plotted according to HPLC elution time and optical density of fractions. Reaction was performed at Room temperature and 75 C. Fractionate the reaction products with HPLC (C18 column). Cytotoxic activity is determined with MTT. Chemical structure determined with NMR.
Experiment 28: Esterification products of E4A with pentenoyl, hexanoyl, benzoyl, ethylbutyryl, propionyl, 2-propenoyl, isobutyryl, butyryl, (2E)-2-pentenoyl, 4-Pentenoyl, 5-hexenoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, Lauroyl, myristoyl, from different times of esterification reaction. Reaction products obtained from each time of reaction were fractionated by HPLC. The profile is plotted according to HPLC elution time and optical density of fractions. Fractionate the reaction products with HPLC (C18 column). Cytotoxic activity is determined with MTT. Chemical structure determined with NMR.
Experiment 29: Esterification products of E4A with propanoyl, propenoyl, butanoyl, butenoyl, pentanoyl, hexenoyl, heptanoyl, heptenoyl, octanoyl, octenoyl, nonanoyl, nonenoyl, decanoyl, decenoyl, propionyl, 2-propenoyl, 2-butenoyl, Isobutyryl, 2-methylpropanoyl, 2-ethylbutyryl, ethylbutanoyl, 2-ethylbutanoyl, butyryl, (E)-2,3-Dimethylacryloyl, (E)-2-Methylcrotonoyl, 3-cis-Methyl-methacryloyl, 3-Methyl-2-butenoyl, 3-Methylcrotonoyl, 4-Pentenoyl, (2E)-2-pentenoyl, Caproyl, 5-Hexenoyl, Capryloyl, Lauroyl, Dodecanoyl, Myristoyl, Tetradecanoyl, Oleoyl from different times of esterification reaction. Reaction products obtained from each time of reaction were fractionated by HPLC. The profile is plotted according to HPLC elution time and optical density of fractions. Fractionate the reaction products with HPLC (C18 column). Cytotoxic activity is determined with MTT. Chemical structure determined with NMR.
Experiment 30: A Comparison of Non-Cancerous with Cancer Cells:
B. Drug Treatment:
C. At the End of the Drug-Treatment, Cytotoxic Test was Performed with MTT Assay.
Conclusion:
Experiment 31: Inhibition of Cell Cycling
Results: Cells with no drug, or with 0.15 ug/ml and 0.3 ug/ml of Tig-S, have a similar (same) cell distribution in the G0/G1, S and G2/M phases of cell-cycle. With higher Tig-S concentrations, starting from 0.6 ug/ml, the cells in G2/M phase decrease. The decrease of G2/M cells correlated with higher drug concentrations (up to 20 ug/ml). These results indicate that drug-treated cells were arrested in the S-phase and unable to enter into the G2/M phase of the cell cycle.
Conclusion: The drug-effect of Tig-S on human leukemia K562 cells is arresting cells in the S-phase and blocking their entering into the G2/M phase of cell cycle. The Compound Tig-S block the DNA synthesis of cancer cell.
Experiment 32: Inhibition of H460 Cells Growth with Tig-S
Methods:
A. Cells
B. Drug Treatment:
C. At the end of the drug-treatment, cytotoxic test was performed with MTT assay.
Results:
The results indicate that Tig-S inhibits the H460 cell's growth, but is not killing cells at high concentrations. Therefore, Tig-S is an effective drug for inhibition of cancer growth but has low toxicity.
Experiment 33: Inhibition of Human Leukemia K562 Cells by Tig-S
Method:
Conclusion:
Tig-S inhibits Leukemia K562 cells growth with IC50 about 0.6 ug/ml.
No grow (IC100) was observed beginning on day 2 at 2.5 ug/ml or higher.
Experiment 34: Apoptosis in K562 Cells Induced by Tig-S
Results:
The background apoptosis level of K562 cells (no-drug control) is about 10-15%. After drug-treatment with Tig-S, the apoptotic cells population increased (from 15% to 27%) with increased drug concentration (from 2.5 ug/ml to 20 ug/ml).
Similarly, the dead cell population was also increase with the drug concentration.
Conclusion:
Tig-S induces cell-death by the apoptosis mechanism (not necrosis mechanism).
Experiment 35: The Haemolytic Assay
Erythrocytes (RBC) were isolated from human blood (EDTA whole blood, collected randomly). 50 ul of the 10% RBC suspension (in PBS) was added to 2 ml of sample solutions (concentration range from 0.1 ug/ml to 400 ug/ml) in PBS. The mixture was vortexed briefly and sat for 60 min at room temperature. The mixture was spun at 3K for 10 min and the relative amounts of lysed hemoglobin in the supernatant were measured at 540 nm. The synthetic compounds of present application were tested with this method.
Experiment 36: Animals Experiments
Methods
Result in
Experiment 37: Animals Experiments
Methods
Result in
Experiment 38: Animals Experiments
Methods
Result in
Experiment 39: Inhibition of Capan Cells Growth by Tig-S
A. Cells: Capan cells are derived from Human pancreas carcinoma (pancreas). Cells were grew in RPMI 1640 medium supplemented with 10% FCS, antibiotics and glutamine. 10000 cells were seeded in a well (96-welled plate) for one day before drug-treatment
B. Drug Treatment:
C. At the end of the drug-treatment, cytotoxic test was performed with MTT assay. The percentage of drug-treated cells' growth as compared to those of the no drug control is determined.
Experiment 40: Using method in Experiment 3, esterification of E4A2Y with acetyl, angeloyl, tigloyl, senecioyl, Crotonoyl, Cinnamoyl, Pentenoyl, 4-(dimethylamino)-2-methylbut-2-enoyl, and 4-[(2-methoxyethyl)amino]-2-methyl-4oxobut-2-enoyl gave the following compounds:
wherein:
1) R1, R2, R3, R5, R8 are OH; R17, R18 are O-acetyl;
2) R1, R2, R3, R5, R8 are OH; R17, R18 are O-angeloyl
3) R1, R2, R3, R5, R8 are OH; R17, R18 are O-tigloyl
4) R1, R2, R3, R5, R8 are OH; R17, R18 are O-senecioyl
5) R1, R2, R3, R5, R8 are OH; R17, R18 are O-Crotonoyl
6) R18, R2, R3, R5, R8 are OH; R17, R18 are O-Cinnamoyl
7) R18, R2, R3, R5, R8 are OH; R17, R18 are O-Pentenoyl
8) R18, R2, R3, R5, R8 are OH; R17, R18 are O-4-(dimethylamino)-2-methylbut-2-enoyl
9) R18, R2, R3, R5, R8 are OH; R17, R18 are O-4-[(2-methoxyethyl)amino]-2-methyl-4oxobut-2-enoyl
10) R18, R2, R3, R5, R8 are OH; R17, R1 are O-acetyl;
11) R18, R2, R3, R5, R8 are OH; R17, R1 are O-angeloyl
12) R18, R2, R3, R5, R8 are OH; R17, R1 are O-tigloyl
13) R18, R2, R3, R5, R8 are OH; R17, R1 are O-senecioyl
14) R18, R2, R3, R5, R8 are OH; R17, R1 are O-Crotonoyl
15) R18, R2, R3, R5, R8 are OH; R17, R1 are O-Cinnamoyl
16) R18, R2, R3, R5, R8 are OH; R17, R1 are O-Pentenoyl
17) R18, R2, R3, R5, R8 are OH; R17, R1 are O-4-(dimethylamino)-2-methylbut-2-enoyl
18) R18, R2, R3, R5, R8 are OH; R17, R1 are O-4-[(2-methoxyethyl)amino]-2-methyl-4oxobut-2-enoyl
19) R2, R3, R5, R8 are OH; R1, R17, R18 are O-acetyl;
20) R2, R3, R5, R8 are OH; R1, R17, R18 are O-angeloyl
21) R2, R3, R5, R8 are OH; R1, R17, R18 are O-tigloyl
22) R2, R3, R5, R8 are OH; R1, R17, R18 are O-senecioyl
23) R2, R3, R5, R8 are OH; R1, R17, R18 are O-Crotonoyl
24) R2, R3, R5, R8 are OH; R1, R17, R18 are O-Cinnamoyl
25) R2, R3, R5, R8 are OH; R1, R17, R18 are O-Pentenoyl
26) R2, R3, R5, R8 are OH; R1, R17, R18 are O-4-(dimethylamino)-2-methylbut-2-enoyl
27) R2, R3, R5, R8 are OH; R1, R17, R18 are O-4-[(2-methoxyethyl)amino]-2-methyl-4oxobut-2-enoyl
Experiment 41: Preparation of E4A(E4)
The product Structure E4A(E4)
Experiment 42:
Method for the Preparation of 24,28-diamine
To a solution of compound (E4A)E4 (2 mmol) in tetrahydrofuran (THF, 10 mL) were added methanesulfonyl chloride (Ms-Cl, 2.2 mmol) and triethylamine (TEA, 3 mmol) at 0° C. and the resulting mixture was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (EtOAc) and washed with water. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in 10 mL of dimethylformamide (DMF), and then sodium azide (NaN3, 6 mmol) was added. After overnight stirring at 60° C., the reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Then, the obtained compound was dissolved in methanol (MeOH), and 10% palladium on carbon (Pd—C, 0.2 mmol) was added. After overnight stirring under hydrogen atmosphere, the reaction mixture was filtered, washed with methanol and concentrated under reduced pressure to provide the desired 24,28-diamine(E4D).
Experiment 43:
To a solution of 24,28-diamine(E4D) (0.1 mmol.) and aldehyde (RCHO, 0.3 mmol) in dimethylformamide (DMF, 1 mL) in a fritted plastic reaction tube was added SiliaBondCyanoborohydride (Si-CBH, 0.3 mmol). The reaction mixture was shaken at room temperature overnight. The reaction mixture was filtered into a fritted plastic reaction tube. Tosic acid functionalized silica (Si-SCX, 0.3 mmol) was added. The reaction mixture was shaken at room temperature overnight. The liquid was filtered off. A solution of 5% ammonia-methanol (1 mL) was added to the product captured silica. The mixture was shaken at room temperature overnight. The methanolic solution was filtered off and concentrated under reduced pressure to yield the desired amine analog.
Experiment 44:
To a solution of 24,28-diamine(E4D) (0.1 mmol.) and carboxylic acid (RCO2H, 0.3 mmol) in dimethylformamide (DMF, 1 mL) in a fritted plastic reaction tube was added EDC functionalized silica (Si-EDC, 0.3 mmol). The reaction mixture was shaken at room temperature overnight. Carbonate functionalized silica (Si—CO3, 0.3 mmol) was added. The reaction mixture was shaken at room temperature overnight. The reaction mixture was filtered and concentrated under reduced pressure to yield the desired amide analog.
Experiment 45:
Method for the Preparation of Sulfonamide Analogs
To a solution of 24,28-diamine(E4D) (0.1 mmol.) and sulfonyl chloride (RSO2Cl, 0.3 mmol) in dimethylformamide (DMF, 1 mL) in a fritted plastic reaction tube was added triethylamine functionalized silica (Si-WAX-2, 0.3 mmol). The reaction mixture was shaken at room temperature overnight. Amine functionalized silica (Si-WAX, 0.3 mmol) was added. The reaction mixture was shaken at room temperature overnight. The reaction mixture was filtered and concentrated under reduced pressure to yield the desired sulfonamide analog.
Experiment 46:
Method for the Preparation of Urea Analogs
A solution of 24,28-diamine(E4D) (0.1 mmol.) and isocyanate (RNCO, 0.3 mmol) in dimethylformamide (DMF, 1 mL) in a fritted plastic reaction tube was shaken at room temperature overnight. Piperazine functionalized silica (Si-PPZ, 0.3 mmol) was added. The reaction mixture was shaken at room temperature overnight. The reaction mixture was filtered and concentrated under reduced pressure to yield the desired urea analog.
Experiment 47: Using method in Experiment 43, (E4D) with acetaldehyde, (Z)-2-methylbut-2-enal, (E)-2-methylbut-2-enal, 3-methylbut-2-enal, (E)-but-2-enal, cinnamaldehyde, pent-4-enal, (E)-4-(dimethylamino)but-2-enal gave the following compounds:
wherein:
1) R1, R2, R3, R5, R8 are OH; R17, R18 are NH-ethyl;
2) R1, R2, R3, R5, R8 are OH; R17, R18 are NH—(Z)-(2-methylbut-2-en-1-yl);
3) R1, R2, R3, R5, R8 are OH; R17, R18 are NH-(E)-(2-methylbut-2-en-1-yl);
4) R1, R2, R3, R5, R8 are OH; R17, R18 are NH-(3-methylbut-2-en-1-yl;
5) R1, R2, R3, R5, R8 are OH; R17, R18 are NH-(E)-(but-2-en-1-yl;
6) R18, R2, R3, R5, R8 are OH; R17, R18 are NH-cinnamyl;
7) R18, R2, R3, R5, R8 are OH; R17, R18 are NH-pent-4-en-1-yl;
8) R18, R2, R3, R5, R8 are OH; R17, R18 are NH-(E)-3-((4-(dimethylamino)but-2-en yl.
Experiment 48: Using Method in Experiment 46, (E4D) with isocyanatomethane, (Z) isocyanato-2-methylbut-2-ene, (E)-1-isocyanato-2-methylbut-2-ene, 1-isocyanato-3-methylbut-2-ene, (E)-1-isocyanatobut-2-ene, (E)-(3-isocyanatoprop-1-en-1-yl)benzene, 4-isocyanatobut-1-ene, (E)-4-isocyanato-N,N-dimethylbut-1-en-1-amine gave the following compounds:
wherein:
1) R1, R2, R5, R8 are OH; R17, R18 are NH—CO—NH-ethyl;
2) R1, R2, R5, R8 are OH; R17, R18 are NH—CO—NH—(Z)-1-(2-methylbut-2-en-1-yl)
3) R1, R2, R5, R8 are OH; R17, R18 are NH—CO—NH-(E)-1-(2-methylbut-2-en-1-yl)
4) R1, R2, R5, R8 are OH; R17, R18 are NH—CO—NH-1-(3-methylbut-2-en-1-yl)
5) R1, R2, R5, R8 are OH; R17, R18 are NH—CO—NH-(E)-1-(but-2-en-1-yl)
6) R18, R2, R5, R8 are OH; R17, R18 are NH—CO—NH-1-cinnamyl
7) R18, R2, R5, R8 are OH; R17, R18 are NH—CO—NH-1-(but-3-en-1-yl)
8) R18, R2, R5, R8 are OH; R17, R18 are NH—CO—NH-(E)-1-(4-(dimethylamino)but-3-en-1-yl)
Experiment 49: Using method in Experiment 44, (E4D) with ethanoyl, angeloyl, tigloyl, senecioyl, Crotonoyl, Cinnamoyl, Pentenoyl, (E)-3-(dimethylamino)acryloyl, 4-[(2-methoxyethyl)amino]-2-methyl-4oxobut-2-enoyl gave the following compounds:
wherein:
1) R1, R2, R5, R8 are OH; R17, R18 are NH-acetyl;
2) R1, R2, R5, R8 are OH; R17, R18 are NH-angeloyl
3) R1, R2, R5, R8 are OH; R17, R18 are NH-tigloyl
4) R1, R2, R5, R8 are OH; R17, R18 are NH-senecioyl
5) R1, R2, R5, R8 are OH; R17, R18 are NH-Crotonoyl
6) R18, R2, R5, R8 are OH; R17, R18 are NH-Cinnamoyl
7) R18, R2, R5, R8 are OH; R17, R18 are NH-Pentenoyl
8) R18, R2, R5, R8 are OH; R17, R18 are NH-4-(dimethylamino)-2-methylbut-2-enoyl
9) R18, R2, R3, R5, R8 are OH; R17, R18 are NH-4-[(2-methoxyethyl)amino]-2-methyl-4oxobut-2-enoyl
Experiment 50:
Using method in Experiment 45, (E4D) with ethanesulfonyl, (Z)-but-2-ene-2-sulfonyl, (E)-prop-1-ene-1-sulfonyl, (E)-2-phenylethene-1-sulfonyl, but-3-ene-1-sulfonyl gave the following compounds:
wherein:
1) R1, R2, R5, R8 are OH; R17, R18 are NHSO2-ethyl;
2) R1, R2, R5, R8 are OH; R17, R18 are NHSO2-(Z)-(2-methylbut-2-en-1-yl)
3) R1, R2, R5, R8 are OH; R17, R18 are NHSO2-(E)-prop-1-enyl
4) R18, R2, R5, R8 are OH; R17, R18 are NHSO2-(E)-2-phenylethenyl
5) R18, R2, R5, R8 are OH; R17, R18 are NHSO2-but-3-enyl
Experiment 51:
Acid Cl+Amine
The reaction of acid chlorides and amines to form amides. The reaction takes place at RT with a suitable base (ex. TEA or DIEA) in an aprotic solvent (ex. DCM, THF, or DMF).
Experiment 52: Using method in Experiment 51, (E4D) with ethanoyl chlorides, angeloyl chlorides, tigloyl chlorides, senecioyl chlorides, Crotonoyl chlorides, Cinnamoyl chlorides, Pentenoyl chlorides, (E)-3-(dimethylamino)acryloyl chlorides, 4-[(2-methoxyethyl)amino]-2-methyl-4oxobut-2-enoyl chlorides gave the following compounds:
wherein:
1) R1, R2, R5, R8 are OH; R17, R18 are NH-acetyl;
2) R1, R2, R5, R8 are OH; R17, R18 are NH-angeloyl
3) R1, R2, R5, R8 are OH; R17, R18 are NH-tigloyl
4) R1, R2, R5, R8 are OH; R17, R18 are NH-senecioyl
5) R1, R2, R5, R8 are OH; R17, R18 are NH-Crotonoyl
6) R18, R2, R5, R8 are OH; R17, R18 are NH-Cinnamoyl
7) R18, R2, R5, R8 are OH; R17, R18 are NH-Pentenoyl
8) R18, R2, R5, R8 are OH; R17, R18 are NH-4-(dimethylamino)-2-methylbut-2-enoyl
9) R18, R2, R5, R8 are OH; R17, R18 are NH-4-[(2-methoxyethyl)amino]-2-methyl-4oxobut-2-enoyl
Experiment 53
Pharmacokinetic (PK) Study: Blood from Cutting Tail
Results and conclusion: over 80% of Test Drug (E4A-TigR) in blood is cleared during the first 4 hours. The half-life is estimated to be about one hour; over 80% of Test Drug (E4D-Tig-R) in blood is cleared during the first 8 hours.
Experiment 54
Pharmacokinetic (PK) Study: Blood from Cardiac Puncture
Results and conclusion: over 80% of Test Drug (E4A-Tig-R) in blood is cleared during the first 4 hours. The half-life is estimated to be about one hour; over 80% of Test Drug (E4D-Tig-R) in blood is cleared during the first 8 hours.
Definations in Experiments 43, 44, 45 and 46
R group for amine, sulfonamides, amide analog, Urea Analogs, wherein sulfonyl chloride (RSO2Cl), carboxylic acid (RCO2H), isocyanate (RNCO), where is selected from the group consisting of alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, -alkylene-O-alkyl, aryl, -alkylene-aryl, heteroaryl, -alkylene-heteroaryl, cycloalkyl, heterocyclyl, and -alkylene-heterocyclyl, wherein said aryl, heteroaryl, the aryl portion of said -alkylene-aryl, or the heteroaryl portion of said -alkylene-heteroaryl are unsubstituted or substituted with one or more groups Y which are selected; said heterocyclyl or the heterocyclyl portion of said -alkylene-hterocyclyl are unsubstituted or substituted with one or more groups of Z.
Y is one or more substituents independently selected from the group consisting of halogen, alkyl, haloalkyl, aryl, -alkylene-aryl, —OH, —CN, —N(R′)2, —N(R′)—C(O)—R′, —N(R′)—C(O)—(N′)2, —C(O)N(R′)2, —C(O)OH, —C(O)O-alkyl, N(R′)—S(O)2—(R′) and —S(O)2N(R′)2;
Each R′ is independently selected from the group consisting of H, alkyl, cyloalkyl, haloalkyl, heterocyclyl, -alkelene-hterocyclyl, aryl, -alkylene-aryl, heteroaryl, -alkylene-heteroaryl;
Z is one or more substituents independently selected from the group consisting of alkyl, one or more hydroxy substituted alkyl, aryl, -alkylene-aryl, -alkylene-O-alkyl, -alkylene-O-alkylene-aryl, -alkylene-O-aryl, -alkylene-O-alkyl, -alkylene-O-alkylene-aryl, -alkylene-O-aryl, —CN, haloalkyl, -alkylene-C(O)—N(R″)2, —C(O)—N(R″)2, —C(O)OH, —C(O)O-alkyl, —N(R″)2, and -alkylene-N(R″)2, —S(O)2—N(R″)2, -alkylene-S(O)2—N(R″)2, —N(R″)—C(O)—R″, —N(R″)—C(O)—R″, —N(R″)—C(O)—N(R″)2, -alkylene-N(R″)—C(O)—N(R″)2, -alkylene-N(R″)—C(O)—R″, -alkylene-S(O)2—R″, —N(R″)—S(O)2—R″, and -alkylene-N(R″)—S(O)2—R″, cycloalkyl, heterocyclyl, -alkylene-heterocyclyl, heteroaryl and -alkylene-heteroaryl, or wherein two Z substituents on adjacent carbon atoms, on a carbon atom and an adjacent heteroatom, or on a single carbon atom, together with carbon atom(s) and/or the combination of the carbon atom and the adjacent heteroatom to which said Z substituents are attached form a four to seven-membered cycloalkyl, cyloalkeny, heterocyclyl, aryl or heteroaryl ring, wherein said aryl, heteroaryl, the aryl portion of said -alkylene-aryl, -alkylene-O-alkylene-aryl, -alkylene-O-alkylene-aryl, -alkylene-O-aryl, and the heteroaryl portion of said -alkylene-heteroaryl are unsubstituted or substituted with one or more R* substituents which are independently selected; and R* is one or more substituents independently selected from the group consisting of halogen, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, nitro, —(NH2, —NH(alkyl), —N(alkyl)2, —NH-alkylene-aryl, —N(alkyl)-alkylene-aryl, -alkylene-aryl, —C(O)NH2, —C(O)NH(alkyl), —C(O)N(alkyl)2, —S(O)2NH2, —S(O)2NH(akyl), —S(O)2N(alkyl)2, —NHC(O)-alkyl, —N(alkyl)C(O)-alkyl, —NHC(O)-aryl, —N(alkyl)C(O)-aryl, —NH—S(O)2-alkyl, —N(alkyl)-S(O)2-alkyl, —NH—S(O)2-aryl, and —N(alkyl)-S(O)2-aryl.
| Number | Date | Country | Kind |
|---|---|---|---|
| 2021903740 | Nov 2021 | AU | national |
| 2022901291 | May 2022 | AU | national |
