Interest has increased in recent years in anticancer chemotherapy using metal chelates. Although a wide range of metal complexes have been studied, platinum compounds have been the most successful anticancer agents. Among the more notable successes is the platinum-based drug Cisplatin.
A central issue in cancer chemotherapy is the severe toxic side effects of the anticancer agents on healthy tissues, which invariably imposes dose limitations, treatment delay or even discontinuance of therapy. Notably, Cisplatin causes cytotoxicity to normal cells at a rate that is nearly equal to the cancerous cells, which leads to severe side effects such as extreme weight loss, vomiting, and/or even death. Thus, there is a need in the art for anticancer chemotherapeutic agents that preferentially attack cancer cells while leaving non-cancerous cells comparatively unharmed.
The present invention generally relates to the use of multidentate ligands for treating cancers. More specifically, the present invention relates to using families of macrocyclic ligands having sulfur and/or nitrogen hetero atoms for treating cancers, wherein the sulfur and nitrogen atoms are complexed to rhodium (Ill) and ruthenium (III). The present invention comprises two families of rhodium complexes that display anticancer activity, while leaving non-cancerous cells comparatively unharmed.
It is therefore an aspect of the present invention to provide a method of treating cancerous cells in a mammal comprising the step of administering to the cancerous cells an effective amount of a cyclic amine comprising the structure:
wherein each R is independently selected from the group consisting of a proton, an alkyl, an ether, an alcohol, a carboxylic acid, an aryl, an amino acid, or a peptide, wherein each n varies independently and is an integer equal to either 1 or 2, and wherein the structure further comprises an interchelated metal ion selected from the group consisting of iron, ruthenium, osmium, cobalt, rhodium, iridium, nickel, palladium, platinum, copper, chromium, gallium, molybdenum, manganese, and tungsten.
A preferred composition of the cyclic amine includes a cyclic amine rhodium(III)-trichloride complex wherein R is selected from the group consisting of a proton, an alkyl, an ether, an alcohol, a carboxylic acid, an aryl, an amino acid, and a peptide and wherein n is either 1 or 2.
Another aspect of the present invention is to provide a method of treating cancerous cells in a mammal comprising the step of administering to the cancerous cells an effective amount of a thiaether comprising the structure:
wherein each R is independently selected from the group consisting of a proton, an alkyl, an ether, an alcohol, a carboxylic acid, an aryl, an amino acid, a peptide, or null, wherein each X is independently either sulfur or nitrogen, when any X is sulfur the corresponding R is null, and wherein the structure further comprises an interchelated metal ion selected from the group consisting of iron, ruthenium, osmium, cobalt, rhodium, iridium, nickel, palladium, platinum, copper, chromium, gallium, molybdenum, manganese, and tungsten.
A preferred composition of the thiaether compound includes a rhodium(III)-trichloride complex wherein R is selected from the group consisting of a proton, an alkyl, an ether, an alcohol, a carboxylic acid, an aryl, an amino acid, a peptide, and null and wherein X is either sulfur or nitrogen; and if X is sulfur, R is null.
Another aspect of the present invention is to provide a method of treating cancerous cells in a mammal comprising the step of administering to cancerous cells a thiaether rhodium(III)-trichloride complex comprising the structure:
wherein R is selected from the group consisting of a proton, an alkyl, an ether, an alcohol, a carboxylic acid, an aryl, an amino acid, a peptide, and null, wherein X is either sulfur or nitrogen and when X is sulfur R is null.
Another aspect of the present invention is to provide a chemical composition comprising:
wherein each R is independently selected from the group consisting of a proton, an alkyl, an ether, an alcohol, a carboxylic acid, an aryl, an amino acid, or a peptide, wherein each n varies independently and is an integer equal to either 1 or 2, and wherein the structure further comprises an interchelated metal ion selected from the group consisting of iron, ruthenium, osmium, cobalt, rhodium, iridium, nickel, palladium, platinum, copper, chromium, gallium, molybdenum, manganese, and tungsten.
A preferred composition of the previous structure involves a structure comprising an interchelated Rh(III) metal bound to one or more nitrogen atoms present.
Another embodiment of the structure involves a composition comprising an interchelated Ru(III) metal bound to one or more nitrogen atoms present.
Another aspect of the present invention is to provide a chemical composition comprising:
wherein each R is independently selected from the group consisting of a proton, an alkyl, an ether, an alcohol, a carboxylic acid, an aryl, an amino acid, a peptide, or null, wherein each X is independently either sulfur or nitrogen, when any X is sulfur the corresponding R is null, and wherein the structure further comprises an interchelated metal ion selected from the group consisting of iron, ruthenium, osmium, cobalt, rhodium, iridium, nickel, palladium, platinum, copper, chromium, gallium, molybdenum, manganese, and tungsten.
A preferred composition of the previous structure involves a structure further comprising an interchelated Rh(III) metal bound to one or more nitrogen atoms present.
Another aspect of the present invention is to provide a chemical composition comprising:
wherein the structure further comprises an interchelated Rh(III) metal bound to the nitrogen atom and one or both of the sulfur atoms.
Another aspect of the present invention to provide a chemical composition comprising:
Another aspect of the present invention to provide a composition comprising:
wherein M comprises a metal ion selected from the group consisting of iron, ruthenium, osmium, cobalt, rhodium, iridium, nickel, palladium, platinum, copper, chromium, gallium, molybdenum, manganese, and tungsten.
The present invention generally relates to the use of multidentate ligands as anticancer agents. More specifically, the present invention includes without limitation the use of a family of cyclic amine ligands, as well as, the use of a family of thiaether ligands, all of which are bound to rhodium (III), ruthenium (III) or other multivalent metal ions.
The term interchelated metal ion is used as a description of how the metal ion reacts with the cyclic ring. Interchelated being defined as a chemical compound in the form of a heterocyclic ring, containing a metal ion attached by coordinate bonds to at least two nonmetal ions. A broader term that can also be substituted is that of an intercalated metal ion.
The cyclic amine ligands used to complex rhodium (III), rhodium (III) trichloride, ruthenium(III) and other metals are generally represented by formula 1:
wherein each n is an integer and can vary independently from one to two. Each R group (1 through 3) can vary independently and can be a hydrogen atom, an alkyl such as but not limited to a methyl, an ether such as but not limited to methyl ethyl ether, an alcohol such as but limited to ethanol, methanol or propanol, a carboxylic acid such as but not limited to acetic acid, an aryl such as but not limited to benzene, an amino acid such as but not limited to serine or threonine, or a peptide such as but not limited to luetinizing hormone. The foregoing R groups can be modified or derivatized for increased lipophilicity, increased hydrophilicity, and/or in vivo targeting enhancement for tumor specificity.
In addition to rhodium, other metal-based compounds may be used in the form of alkoxides, bromides, chlorides, or iodides. For example, metals yielding ions within the scope of the present invention include without limitation iron, ruthenium, osmium, cobalt, rhodium, iridium, nickel, palladium, platinum, copper, chromium, gallium, molybdenum, manganese, and tungsten. In general, the characteristics of a suitable metal ion include without limitation stability under physiological conditions. Additionally, suitable metal ions are further characterized by sufficient lipophilicity to be delivered to a locus within the body for which dosing is indicated.
Examples of ligand formula within the scope of the present invention include without limitation formula 2 through 5:
In one embodiment a cyclic amine ligand of formula 2, namely Me3TacnRhCl3, tests positive for anticancer activity against the cervical cancer cell line Hela S3. Various concentrations of Me3TacnRhCl3 where shown to have anticancer properties, including 1.5×10−2, 1.5×10−3, 1.5×10−4, and 1.5×10−6 M. The 10−2 molar preparation's Hela cell death rate was approximately 93.1% and the death rate of the 10−3 molar preparation was approximately 90%.
In another embodiment cyclic amines of the present invention are effective in killing the ovarian cancer cell line NUTU-19 while leaving non-cancerous ovarian cells known as OVEPI cells comparatively unharmed.
The circular bodies indicate detached, non-viable, or lysed cells. The cells in the middle of
Toxicity studies in rat models of the compound detailed in
The thiaether ligands of the present invention are represented by the following formula 9:
wherein each n is an integer and can vary independently from 1 to 2. Each R group (1-4) can vary independently and can be a hydrogen atom, an alkyl such as but not limited to a methyl, an ether such as but not limited to methyl ethyl ether, an alcohol such as but not limited to ethanol, methanol or propanol, a carboxylic acid such as but not limited to acetic acid, an aryl such as but not limited to benzene, an amino acid such as but not limited to serine or threonine, a peptide such as but not limited to luetinizing hormone, or nothing at all, i.e. null. Each X group (1-4) varies independently and can be either sulfur or nitrogen. Note that when X is sulfur there is no R group attached to X, i.e. the R group becomes null.
In addition to rhodium, other metal-based compounds may be used in the form of alkoxides, bromides, chlorides, or iodides. For example, metals yielding ions within the scope of the present invention include without limitation iron, ruthenium, osmium, cobalt, rhodium, iridium, nickel, palladium, platinum, copper, chromium, gallium, molybdenum, manganese, and tungsten. In general, the characteristics of a suitable metal ion include without limitation stability under physiological conditions. Additionally, suitable metal ions are further characterized by sufficient lipophilicity to be delivered to locus within the body for which dosing is indicated.
Examples of ligand formula within the scope of the present invention include without limitation:
Thiaether-RhCl3 complexes according to formula 13 were tested against the Hela S3 cell line and showed anticancer activity. The resulting death rate of the 1.5×10−3 molar preparation was approximately 93%, showing a killing efficacy similar to that of Me3TacnRhCl3.
The foregoing thiaether rhodium complexes have also been tested against the ovarian cancer cell line NUTU-19 for anticancer activity. Preliminary results showed that thiaether Rh(III) complexes had killing efficacy's of approximately 83%. The photos shown in
The thiaether ligands of the present invention are also represented by formula 14:
Wherein each R group (1-3) can vary independently and can be a hydrogen atom, an alkyl such as but not limited to a methyl, an ether such as but not limited to methyl ethyl ether, an alcohol such as but not limited to ethanol, methanol or propanol, a carboxylic acid such as but not limited to acetic acid, an aryl such as but not limited to benzene, an amino acid such as but not limited to serine or threonine, a peptide such as but not limited to luetinizing hormone, or null. Each X group (1-3) varies independently and can be either a sulfur or nitrogen. Note when X is sulfur there is no R group attached to X, i.e. the R group becomes null. In addition to rhodium, other metal-based compounds may be used in the form of alkoxides, bromides, chlorides, or iodides. Examples of ligand formula within the scope of the present invention include without limitation:
Thiaether-RhCl3 complexes according to formula 15 and 16 have been tested against the normal ovarian cell line OVepi and the ovarian cancer cell line NUTU-19 and have shown anticancer activity. Formula 16 is further represented in
The graphs shown in
The synthesis of the rhodium (III) complexes of the present invention can be readily accomplished in relatively high yield in a one-pot synthesis by refluxing the respective ligands with rhodium (III) trichloride in ethanol for 2 hours in accordance with Weiss, B. et al., J. Chem. Ber. 1979, 112, 2220; and Flood, T. et al., Organometallics. 1996, 15, 491-498. The previously synthesized complexes used in this invention are also water soluble and have been found stable in aqueous solutions including physiological saline. This high stability of the rhodium (III) complexes under physiological conditions is crucial to their use in vivo as anticancer agents.
In one embodiment, the cyclic amine ligand from formula 7 (as previously described) was synthesized as outlined using established procedures previously detailed. The reaction of 7 with RhCl3 in ethanol at reflux for two hours yields 8 at 80% yield. Complex 8, which was crystallographically characterized in
The first thiaether ligand 18 synthesized is a derivative of 13 where both R groups are protons. The synthesis of 18 is outlined below. Compound 18 was then reacted with RhCl3 in ethanol to give the rhodium complex 19. Compound 19 has been crystallographically characterized as well, and a thermal ellipsoid plot (TEP) structure is shown in
The metal complex in Formula 19 and/or
Death rates are reported in percentage of total cells killed after 24 hour incubation with
As shown in
The term effective amount defines the dosage needed to effectuate proper treatment. This dosage will vary based on the chemical and physiological make-up of the person/animal treated, the nature and exact location of the cancerous cells and the exact type of cancerous cells being treated. A preferred dosage range for the effective amount is 1-1000 mg/kg, also preferred is the range 10-100 mg/kg, and also preferred is the range 35-65 mg/kg.
The method of application can be but is not limited to intravenous injection, intraperitoneal (i.e. abdominal cavity) injection or oral ingestion. Using the injection method, the drug is dissolved into a suitable solution. One such solution is a physiological sodium chloride solution. Such a solution can be but is not limited to 0.5% to 1.0% sodium chloride in water, a concentration that is of biological significance as it is isotonic with blood plasma. Also significant is the fact that the metal complexes are water and sodium chloride solution soluble. Another suitable solution into which the drug dissolves includes dimethyl sufloxide (DMSO). In addition, other solvents which will solubilize the drug and are compatible with the human/mammal body are acceptable. The oral ingestion method includes a pill, capsule, caplet or tablet. Such an ingestion could be the pure form of the drug or of a lower concentration that has been mixed with a carrier and/or binder known in the art.
The foregoing examples are considered only illustrative of the principles of the invention rather than an exclusive list of embodiments. Further, since numerous modifications and changes will readily occur to those skilled in the art, the invention is not intended to be limited to the exact construction and operation shown and described, and accordingly, all suitable modifications and equivalents are within the scope of the present invention.
This application claims priority to previously filed U.S. Provisional Application No. 60/690,536, filed on Jun. 14, 2005 entitled “Macrocyclic Metal Complexes for their Use as Anticancer Agents” and to previously filed U.S. Provisional Application No. 60/785,311, filed on Mar. 23, 2006 entitled “Macrocyclic Metal Complexes for their Use as Anticancer Agents”. Both are herby incorporated by reference in their entirety.
Filing Document | Filing Date | Country | Kind | 371c Date |
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PCT/US06/23137 | 6/14/2006 | WO | 00 | 11/5/2010 |
Number | Date | Country | |
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60690536 | Jun 2005 | US | |
60785311 | Mar 2006 | US |