Patent Grant
9371286
This patent application is a National Phase application under 35 U.S.C. §371 of International Application No. PCT/KR2011/003773, filed 23 May 2011, which claims priority to Korean Patent Application number 10-2011-0023211, filed 16 Mar. 2011, entire contents of which are incorporated herein by reference.
1. Technical Field
The present invention relates to a pharmaceutical composition for inhibiting angiogenesis, the composition containing, as an effective ingredient, a novel synthetic low-molecular compound targeting ubiquinol-cytochrome c reductase binding protein (UQCRB).
2. Description of the Related Art
Angiogenesis is a key process for progression of many solid tumors. Accordingly, the efficient inhibition of angiogenesis is considered to be a powerful way to suppress tumor growth and metastasis. Consequently, several specific target proteins of angiogenesis, including vascular endothelial growth factor receptors (VEGFs), matrix metalloproteinases, aminopeptidases, histone deacetylases, and calmodulin, have been identified and anti-angiogenic agents of various scaffolds have been developed based on their inhibitory activities toward the specific targets. We recently isolated terpestacin, a new angiogenesis inhibitor with a unique bicyclo sesterterpene structure, from fungal metabolites. To investigate the molecular mechanism of terpestacin regarding its anti-angiogenic activity, we identified a cellular binding protein of terpestacin using a reverse chemical proteomics approach. Terpestacin specifically bound to the 13.4-kDa subunit (UQCRB) of complex III in the mitochondrial respiratory chain. Recent reports have suggested that reactive oxygen species (ROS) generation at mitochondrial complex III triggers hypoxia-inducible factor-1a (HIF-1a) stabilization during hypoxia. Indeed, terpestacin binding to UQCRB inhibited hypoxia-induced ROS generation, leading to inhibition of HIF-1a and tumor angiogenesis in vivo, without disrupting mitochondrial respiration and complex III functional structure. In addition, the regulation of UQCRB expression demonstrated that the protein is a critical mediator of hypoxia-induced tumor angiogenesis via mitochondrial ROS-mediated signaling. This discovery suggested that small molecules targeting UQCRB in mitochondrial complex III can suppress tumor angiogenesis without acting as a respiratory poison. As such, we attempted to develop new small molecules that specifically regulate the function of UQCRB.
Throughout the specification, a number of publications and patent documents are referred to and cited. The disclosure of the cited publications and patent documents is incorporated herein by reference in its entirety to more clearly describe the state of the related art and the present disclosure.
The present inventors endeavored to develop an anti-angiogenesis agent for effectively inhibiting angiogenesis without cytotoxicity. As a result, the present inventors found a novel synthetic low-molecular compound targeting ubiquinol-cytochrome c reductase binding protein (UQCRB) of mitochondrial complex III, as a new molecular target for angiogenesis, and confirmed that this compound binds to UQCRB to effectively inhibit angiogenesis, based on which the present inventors completed the present invention.
Accordingly, an aspect of the present invention is to provide a pharmaceutical composition for inhibiting angiogenesis.
Another aspect of the present invention is to provide a novel sulfonyl amide derivative compound.
Still another aspect of the present invention is to provide a method for prevention or treatment of uncontrolled angiogenesis-related diseases or disorders.
Other purposes and advantages of the present invention will become clarified by the following detailed description of invention, claims, and drawings.
In accordance with an aspect of the present invention, there is provided a pharmaceutical composition for inhibiting angiogenesis, the pharmaceutical composition including, as an effective ingredient, a compound represented by Chemical Formula 1 below:
wherein, R1 is
(A1 is straight chain or branched chain C1-C6 alkyl, phenyl substituted with unsubstituted or straight chain or branched chain C1-C6 alkyl or halogen), or naphthalyl substituted with unsubstituted or straight chain or branched chain C1-C6 alkyl; and R2 is
(B1 to B5 each are independently hydrogen, halogen, hydroxy, nitro, or C1-C6 alkyl), hydroxy naphthalyl, 4-hydroxylbenzyl C1-C3 alkyl, 4-(2-hydroxyethyl)cyclohexyl, or quinoline substituted with unsubstituted or straight chain or branched chain C1-C6 alkyl, halogen, or hydroxy.
In accordance with another aspect of the present invention, there is provided a method for prevention or treatment of uncontrolled angiogenesis-related diseases or disorders, the method including administering the pharmaceutical composition to a subject in need thereof.
According to a preferable embodiment of the present invention, A1 of R1 in Chemical Formula 1 of the present invention is methyl, ethyl, phenyl, or tert-butyl.
According to a preferable embodiment of the present invention, B1 of R2 in Chemical Formula 1 of the present invention is hydrogen, chloride, fluoro, hydroxy, nitro, or methyl.
According to a preferable embodiment of the present invention, hydroxy naphthalyl of R2 in Chemical Formula 1 of the present invention is 7-hydroxy naphthalyl.
According to a preferable embodiment of the present invention, quinoline of R2 in Chemical Formula 1 of the present invention is 8-hydroxy quinoline.
According to a preferable embodiment of the present invention, the compound of the present invention is selected from the group consisting of compounds represented by Chemical Formulas 2 to 29 below.
More preferably, the compound of the present invention is selected from the group consisting of compounds represented by Chemical Formulas 5, 6, 12, 17, 21, 23, and 24 above.
Disease or disorders that can be prevented or treated by the pharmaceutical composition of the present invention include various diseases related to angiogenesis. Preferably, the pharmaceutical composition of the present invention is used for prevention or treatment of uncontrolled angiogenesis-related diseases or disorders including cancers, diabetic retinopathy, retinopathy of prematurity, corneal graft rejection, neovascular glaucoma, erythema, proliferative retinopathy, psoriasis, hemophiliac joints, capillary proliferation within atherosclerotic plaques, keloids, wound granulation, vascular adhesions, rheumatoid arthritis, osteoarthritis, autoimmune diseases, Crohn's disease, restenosis, atherosclerosis, intestinal adhesions, cat scratch disease, ulcers, liver cirrhosis, glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy, organ transplant rejection, glomerulopathy, diabetes, inflammation, and neurodegenerative diseases.
More preferably, the disease that can be prevented or treated by the pharmaceutical composition of the present invention may be cancers, diabetic retinopathy, or proliferative retinopathy. Most preferably, the proliferative retinopathy is age-related macular degeneration.
According to another aspect of the present invention, the present invention provides a sulfonyl amide derivative selected from the group consisting of compounds represented by Chemical Formulas 2 to 4, 8, 9, 11 to 13, 15, 16 to 20, 22 to 24, 26, 28, and 29 below:
Hereinafter, the present invention will be described in detail with reference to examples. These examples are only for illustrating the present invention more specifically, and it will be apparent to those skilled in the art that the scope of the present invention is not limited by these examples.
In accordance with an aspect of the present invention, there is provided a pharmaceutical composition for inhibiting angiogenesis, the pharmaceutical composition including, as an effective ingredient, a compound represented by Chemical Formula 1 below:
wherein, R1 is
(A1 is straight chain or branched chain C1-C6 alkyl, phenyl substituted with unsubstituted or straight chain or branched chain C1-C6 alkyl or halogen), or naphthalyl substituted with unsubstituted or straight chain or branched chain C1-C6 alkyl; and R2 is
(B1 to B5 each are independently hydrogen, halogen, hydroxy, nitro, or C1-C6 alkyl), hydroxy naphthalyl, 4-hydroxylbenzyl C1-C3 alkyl, 4-(2-hydroxyethyl)cyclohexyl, or quinoline substituted with unsubstituted or straight chain or branched chain C1-C6 alkyl, halogen, or hydroxy.
In accordance with another aspect of the present invention, there is provided a method for prevention or treatment of uncontrolled angiogenesis-related diseases or disorders, the method including administering the pharmaceutical composition to a subject in need thereof.
The present inventors endeavored to develop an anti-angiogenesis agent for effectively inhibiting angiogenesis without cytotoxicity. As a result, the present inventors found a novel synthetic low-molecular compound targeting ubiquinol-cytochrome c reductase binding protein (UQCRB) of mitochondrial complex III, and confirmed that this compound binds to UQCRB to effectively inhibit angiogenesis.
The composition of the present invention is expressed as “a pharmaceutical composition for inhibiting angiogenesis”, which may be expressed as “a pharmaceutical composition for prevention or treatment of angiogenesis-related diseases” or “a pharmaceutical composition for prevention or treatment of uncontrolled angiogenesis-related diseases”.
The compound used as an effective ingredient in the pharmaceutical composition of the present invention is represented by Chemical Formula 1. The compound of the present invention basically has a sulfonyl amide backbone.
As used herein, the term “alkyl” refers to an unsubstituted saturated hydrocarbon group, and includes for example methyl, ethyl, propyl, isobutyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, tridecyl, pentadecyl, and heptadecyl. The term straight chain or branched chain C1-C6 alkyl refers to a straight chain or branched chain alkyl group having an alkyl unit of 1 to 4 carbon atoms, and does not include carbon atoms of a substituent when C1-C6 alkyl is substituted.
As used herein, the term “hydroxybenzyl alkyl” refers to an alkyl group substituted with hydroxybenzyl (phenol). In Chemical Formula 1, the “4-hydroxybenzyl C1-C3 alkyl” at the R2 position refers to an alkyl unit of 1 to 3 carbon atoms, which is substituted with a phenyl group substituted with a hydroxy group on the para-position.
According to a preferable embodiment of the present invention, A1 of R1 in Chemical Formula 1 of the present invention is methyl, ethyl, phenyl, or tert-butyl.
According to a preferable embodiment of the present invention, B1 of R2 in Chemical Formula 1 of the present invention is hydrogen, chloride, fluoro, hydroxy, nitro, or methyl.
According to a preferable embodiment of the present invention, hydroxy naphthalyl of R2 in Chemical Formula 1 of the present invention is 7-hydroxy naphthalyl.
According to a preferable embodiment of the present invention, quinoline of R2 in Chemical Formula 1 of the present invention is 8-hydroxy quinoline.
According to a preferable embodiment of the present invention, the compound of the present invention is selected from the group consisting of compounds represented by Chemical Formulas 2 to 29 below.
More preferably, the compound of the present invention is selected from the group consisting of compounds represented by Chemical Formulas 5, 6, 12, 17, 21, 23, and 24 above.
According to the present invention, the seven compounds listed above have low IC50 values in the view of the HIF-1α protein level. Therefore, these may be used as effective compositions for treatment of various diseases related to angiogenesis.
Disease or disorders that can be prevented or treated by the pharmaceutical composition of the present invention include various diseases related to angiogenesis. Preferably, the pharmaceutical composition of the present invention is used for prevention or treatment of uncontrolled angiogenesis-related diseases or disorders including cancers, diabetic retinopathy, retinopathy of prematurity, corneal graft rejection, neovascular glaucoma, erythema, proliferative retinopathy, psoriasis, hemophiliac joints, capillary proliferation within atherosclerotic plaques, keloids, wound granulation, vascular adhesions, rheumatoid arthritis, osteoarthritis, autoimmune diseases, Crohn's disease, restenosis, atherosclerosis, intestinal adhesions, cat scratch disease, ulcers, liver cirrhosis, glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy, organ transplant rejection, glomerulopathy, diabetes, inflammation, and neurodegenerative diseases.
Examples of the autoimmune diseases that can be prevented or treated by the composition of the present invention may include, but are not limited to, alopecia greata, ankylosing spondylitis, antiphospholipid syndrome, autoimmune Addison's disease, autoimmune adrenal disease, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune ovaritis and testitis, autoimmune thrombocytopenia, Behcet's disease, bullous pemphigoid, cardiomyopathy, celiac sprue-dermatitis, chronic fatigue immune dysfunction syndrome, chronic inflammatory demyelinating polyradiculoneuropathy, Churg-Strauss syndrome, cicatricial pemphigoid, CREST syndrome, cold agglutinin disease, Crohn's disease, discoid lupus, essential mixed cryoglobulinemia, fibromyalgia-fibromyositis, glomerulonephritis, Grave's disease, Guillain-Barre syndrome, Hashimoto's thyroiditis, idiopathic pulmonary fibrosis, idiopathic thrombocytopenic purpuras, IgA nephropathy, juvenile arthritis, lichen planus, lupus erythematosus, Meniere's disease, mixed connective tissue disease, multiple sclerosis, type I or immune-mediated diabetes, myasthenia gravis, pemphigus vulgaris, pernicious anemia, polyarteritis nodosa, polychondritis, autoimmune polyglandular syndrome, polymyalgia rheumatica, polymyositis and dermatomyositis, primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, psoriatic arthritis, Raynaud's phenomenon, Reiter's syndrome, rheumatoid arthritis, Sarcoidosis, scleroderma, stiff-person syndrome, systemic lupus erythematosus, lupus erythematosus, Takayasu's arteritis, temporal arteritis, giant cell arteritis, ulcerative colitis, uveitis, vitiligo and Wegener's granulomatosis.
Examples of the inflammatory diseases that can be prevented or treated by the composition of the present invention may include, but are not limited to, asthma, encephilitis, inflammatory enteritis, chronic obstructive pulmonary disease, allergy, septic shock, pulmonary fibrosis, undifferentiated spondyloarthropathy, undifferentiated arthropathy, arthritis, inflammatory osteolysis, and chronic inflammation by chronic viral or bacterial infections.
More preferably, the disease that can be prevented or treated by the pharmaceutical composition of the present invention may be cancers, diabetic retinopathy, or proliferative retinopathy. Most preferably, the proliferative retinopathy is age-related macular degeneration.
Preferably, the pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier. The pharmaceutically acceptable carriers included in the pharmaceutical composition of the present invention are conventionally used in formulations, and examples thereof include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, and mineral oil. The pharmaceutical composition of the present invention may further include, besides the above components, a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifier, a suspending agent, a preservative, and the like. Appropriate pharmaceutically acceptable carriers and agents are described in detail in Remington's Pharmaceutical Sciences (19th ed., 1995).
The pharmaceutical composition of the present invention may be administered orally or parenterally. Examples of parenteral administration may include intravenous, subcutaneous, intramuscular, intraperitoneal, and transdermal injections.
The appropriate dose of the pharmaceutical composition of the present invention may be varied depending on factors, such as formulating method, manner of administration, age, body weight, sex, and morbidity of patient, food, time of administration, route of administration, excretion rate, and response sensitivity. The dose per day of the pharmaceutical composition of the present invention may be, for example, 0.001 to 100 mg/kg.
The pharmaceutical composition of the present invention may be formulated into a unit dosage form or injected in a multidose container by using a pharmaceutically acceptable carrier and/or excipient, according to the method easily conducted by a person having ordinary skills in the art to which the present invention pertains. Here, the dosage form may be a solution in an oily or aqueous medium, a suspension, a syrup, or an emulsion, an extract, a powder, a granule, a tablet, or a capsule, and may further include a dispersant or a stabilizer.
According to another aspect of the present invention, the present invention provides a sulfonyl amide derivative selected from the group consisting of compounds represented by Chemical Formulas 2 to 4, 8, 9, 11 to 13, 15, 16 to 20, 22 to 24, 26, 28, and 29 below:
Features and advantages of the present invention are summarized as follows:
(a) The present invention provides a pharmaceutical composition for inhibiting angiogenesis and a novel sulfonyl amide derivative compound, which can be effectively used for prevention or treatment of angiogenesis-related diseases or disorders.
(b) The compound used as an effective ingredient in the pharmaceutical composition of the present invention specifically binds to UQCRB to inhibit biological functions thereof, thereby inhibiting angiogenic responses without inducing apoptosis, leading to a great improvement in the safety of drugs.
In the synthesis mechanism below, Reactant 2 (an amine derivative) was added to Reactant 1 (a sulfonyl chloride derivative) in a 0.1 M solution of tetrahydrofuran, followed by stirring at room temperature, and then triethyl amine was added thereto, followed by stirring at room temperature for 12 hours. After that, the mixture was filtered with ethyl acetate, and then concentrated under reduced pressure. The thus obtained compound was subjected to silica gel column chromatography or recrystallization, thereby obtaining Product 3.
Synthesis Mechanism
Preparation of the compounds of the present invention based on the synthesis mechanism above will be described by taking A2060 (preparation of biphenyl-4-sulfonic acid [2-(4-hydroxy-phenyl)-ethyl]-amide) as an example, as follows.
While biphenyl-4-sulfonyl chloride (1, 300 mg, 1.19 mmol) and 0.1 M tertrahydrofuran were stirred, 4-(2-aminoethyl)phenol (2, 217 mg, 1.25 mmol) and triethyl amine (497 ml, 3.57 mmol) were introduced thereinto, followed by stirring at room temperature for 12 hours. The resultant mixture was filtered with ethyl acetate, and then concentrated under reduced pressure. The thus obtained mixture was subjected to purification through a silica gel column chromatography (eluent-hexane:ethylacetate=1:5) or recrystallization with ethyl alcohol. The target compound was obtained at a yield of 250 (104 mg, 0.29 mmol).
500 MHz, DMSO-d6, δ 9.18 (s, 1H), 7.86 (q, 4H, J=9.0 Hz), 7.74 (d, 3H, J=8.5 Hz), 7.51 (t, 2H, J=7.5 Hz), 7.44 (t, 1H, J=7.5 Hz), 6.94 (d, 2H, J=8.5 Hz), 6.64 (d, 2H, J=8.5 Hz), 2.92 (t, 2H, J=9.3 Hz), 2.58 (t, 2H, J=7.5 Hz) ESI (m/z) 354.10 (M+), 376.10 (MNa+)
The other compounds of the present invention were prepared by the same method as in the foregoing synthesis mechanism and the representative preparative example, and their spectroscopic data were tabulated in Table 1.
HIF-1α Stability Analysis
HepG2 cells were pretreated with indicated concentrations of the synthetic derivatives for 30 minutes and then exposed to 1% O2 for 4 hours. HIF-1α and tubulin protein levels were analyzed using western blot analysis. When HepG2 cells were treated with A1893 and A1938, hypoxia-induced HIF-1α protein accumulation was greatly reduced (Table 2 and
Hereinafter, additional experiments were conducted using two compounds having the lowest IC50 value, A1893 and A1938.
Surface Plasmon Resonance (SPR) Analysis
In order to further investigate the binding of A1893 and A1938 to UQCRB, the present inventors performed SPR (BIAcore) analysis. Control biotin and biotinylated terpestacin were sequentially immobilized onto the surface of a streptavidin-coated sensor chip. Competitive binding molecules (A1893 and A1938, 25 μM) were incubated with the purified UQCRB protein (25 μM) in the buffer (10 mM HEPES, 150 mM NaCl, 3 mM EDTA (pH 7.4)), and then UQCRB-competitive binding molecule complexes were injected onto the sensor chip at a flow rate of 30 μl/min. The surface of the sensor chip was regenerated by the injection of 5 μl of the regeneration buffer (50 mM NaOH). Molecular interaction analysis was performed using the BIAcore 2000 system (BIAcore AB), and the apparent binding affinities were calculated by the subtraction of resonance values of UQCRB binding to control biotin from those of UQCRB binding to biotinylated terpestacin. For competitive binding analysis, terpestacin and the compounds of the present invention were each incubated with the UQCRB protein, and then the complexes were injected into flow cells of the sensor chip. Consequently, when terpestacin and the compounds of the present invention were each incubated with the UQCRB protein, the binding efficiency of UQCRB to BT was significantly decreased, which confirmed that A1893 and A1938 directly bind to UQCRB (
Angiogenesis-Inhibitory Activity Analysis
1. Invasiveness Analysis
Serum-starved human umbilical vein endothelial cells (HUVECs) were treated with VEGF with or without A1893 or A1938, and then the in vitro angiogenesis analysis was performed. The invasiveness of HUVECs was investigated using the Transwell chamber system with 8.0-μm pore-sized polycarbonate filter (Corning Costar). First, a lower portion of the filter was coated with 10 μl gelatin (10 mg/ml) for 1 hour, and an upper portion of the filter was coated with 10 μl Matrigel (3 mg/ml) for 2 hours. Then, 600 μl of the EBM-2 medium was put into the Transwell, and then, VEGF (30 ng/ml) and the compound of the present invention DPCN (2.5 μM and 5 μM) were added thereto. The coated filter was placed on the Transwell, and HUVECs (1×105 cells/well) were inoculated on the upper portion of the filter, following by incubation for 18 hours. After that, the cells were fixed with 70% methanol, and then stained with hematoxylin/eosin. Then, the total number of invaded cells was measured using an optical microscope at 100× magnification. As a result of the measurement, it was confirmed that A1893 and A1938 inhibited VEGF-induced invasion without affecting viability of endothelial cells (
2. Tube Formation Analysis
Tube formation analysis was performed using HUVECs growing on Matrigel (Collaborative Biomedical Products). The 48-well plate was coated with 150 μl Matrigel, followed by polymerization at 37 for 2 hours. Then, human umbilical vein endothelial cells (HUVECs, 1×105 cells/well) were inoculated on Matrigel, and then VEGF (30 ng/ml) and the compound of the present invention DPCN (2.5 μM and 5 μM) were added thereto. The morphological change of cells was observed while the cells were incubated at room temperature for 8 hours. Tube formation was quantified by measuring the number of connected cells in randomly selected fields and dividing the measured number by the total number of cells in the same field. As a result of the measurement, it was confirmed that A1893 and A1938 inhibited the tube formation of HUVECs without affecting viability of endothelial cells (
Mitochondrial ROS Generation Analysis
The increase in ROS generation due to complex III during hypoxia triggers HIF-1α stabilization, and consequently mediates the expression of its target genes such as VEGF. UQCRB, which is an important component in mitochondrial complex III, acts as an O2 sensor and mediates hypoxia-induced tumor angiogenesis. In order to determine whether anti-angiogenic activity of A1893 and A1938 is associated with the modulation of the O2 sensing function of UQCRB, the present inventors investigated the mitochondrial ROS-mediated hypoxic signal transmission procedure of A1893 and A1938. HepG2 liver cancer cells were pretreated with A1893 and A1938 for 30 minutes, and then exposed to 1% O2 for 10 minutes. Intracellular ROS levels were determined by the DCF fluorescence. A1893 and A1938 suppressed the hypoxia-induced mitochondrial ROS generation in HepG2 cells in a dose-dependent manner (
Although the present invention has been described in detail with reference to the specific features, it will be apparent to those skilled in the art that this description is only for a preferred embodiment and does not limit the scope of the present invention. Thus, the substantial scope of the present invention will be defined by the appended claims and equivalents thereof.
| Number | Date | Country | Kind |
|---|---|---|---|
| 10-2011-0023211 | Mar 2011 | KR | national |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/KR2011/003773 | 5/23/2011 | WO | 00 | 7/6/2014 |
| Publishing Document | Publishing Date | Country | Kind |
|---|---|---|---|
| WO2012/124858 | 9/20/2012 | WO | A |
| Number | Name | Date | Kind |
|---|---|---|---|
| 20080064714 | Vennemann et al. | Mar 2008 | A1 |
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| Number | Date | Country | |
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| 20140315947 A1 | Oct 2014 | US |
