SBIR-STTR Award

The objective of this study is to prepare antineoplastic platinum complexes with stabilities in solution greater than that of 4-carboxyphthalato (1,2-diaminocyclohexane platinum (NSC 271674; DACHPT). NSC 271674 is a cisplatin analog invented by the Andrulis Research Corporation and is now in Phase II clinical trials at Memorial SloanKettering Cancer Center, New York. It is active against cisplatin-resistant tumors with substantially reduced toxicity. Its development has been hampered because of difficulties in analyzing the compound caused by hydrolysis reactions in basic solution which result in complex HPLC chromatograms which are difficult to interpret precisely. New chemically related complexes which would hydrolyze at significantly reduced rates would be likely to retain the excellent biological properties of NSC 271674, but would be more readily analyzed and therefore could be more readily developed as pharmaceutical products.During Phase I of this project, complexes will be synthesized in which the phthalic acid ligand will be replaced by more weakly acidic ligands resulting in more stable platinum complexes. Such ligands will include substituted salicylic acids and catechols in which the substituent group will aid in solubilization of the complex. The diaminocyclohexane chelating ligand will be retained as it has been shown that this type of chelate is necessary to achieve a lack of cisplatin cross resistance. The ligand will be separated though into its cis and trans isomers to determine differential effect on activity and/or toxicity among h@e isomers. In addition, the isolation of isomerically pure complexes will further simplify the analytical procedure and thereby facilitate commercial development.Dissociation rates will be determined using uv and hpic techniques. Those complexes having greater stability than NSC 271674 will be submitted to the National Cancer Institute for antitumor evaluation. The successful development of stable, soluble platinum complexes with improved therapeutic properties (more active, less toxic) compared to cisplatin would be highly beneficial to the oncologist and to cancer patients.National Cancer Institute

The overall objective of ongoing research is to develop as a new marketable pharmaceutical product, a platinum based antitumor agent which would have significant advantages over the commercially very successful drug, cisplatin. Advantages sought include but are not limited to overcoming the dose limiting nephro- and gastrointestinal toxicities of cisplatin. Of especial importance is the need to develop a drug which would have therapeutic value to patients whose tumors have developed resistance to cisplatin therapy. During the Phase I research, a series of new platinum complexes related to the clinically tested complex 4-carboxyphthalato(1,2-diaminocyclohexane)platinum (NSC 271674) were synthesized and screened against L1210 leukemia. Modifications incorporated included using substituted catechols and salicylic acids in place of the phthalic acid ligand. One such compound, 5-carboxysalicylato(1,2-diaminocyclohexane)platinum (NSC 377217D), was screened by NCI and shown in repeated testing to have T/C percent values in excess of 300, including as high as 4/6 cures. Phase II research will focus on further development of this and other compounds including alternate synthetic approaches, scale up, and additional screening and toxicity testing. At the end of the Phase II period much of the data required to file an IND with the FDA will be available.

Thesaurus Terms:
chemistry, analytical, drugs synthesis, design and production, metals, heavy metals, platinum (compounds), cis platinum compounds, neoplastic therapy, antineoplastic agents, chemical stability chemical reactions (dynamics), chemical structure--biological activity, drugs adverse effects, drugs screening and evaluation, metal complexes, ligands, chelating agents, neoplasms of blood and re system, leukemia mouse, l-1210, phenols, catechols, phenylcarboxylates, salicylates, toxicology, cytotoxicity chemistry, analytical methods, spectrometry, infrared, chemistry, analytical methods, spectrometry, ultraviolet, physical properties, densitometry, physical separation, chromatography, high pressure liquid, physical separation, chromatography, thin layer