STABLE ANTITUMOR PLATINUM COMPLEXES

THE OBJECTIVE OF THIS STUDY IS TO PREPARE ANTINEOPLASTIC PLATINUM COMPLEXES WITH STABILITIES IN SOLUTION GREATER THANTHAT OF 4-CARBOXYPHTHALATO(1,2-DIAMINOCYCLOHEXANE) PLATINUM (NSC 271674;DACHPT). NSC 271674 IS A CISPLATIN ANALOG INVENTED BY THE APPLICANT AND NOW IN PHASE II CLINICAL TRIALS AT MEMORIAL SLOAN-KETTERING CANCER CENTER IN 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, DIFFICULT TO INTERPRETPRECISELY. NEW CHEMICALLY RELATED COMPLEXES WHICH WOULD HYDROLYZE AT SIGNIFICANTLY REDUCED RATES WOULD LIKELY RETAINTHE EXCELLENT BIOLOGICAL PROPERTIES OF NSC 271674, BUT WOULDBE 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 THE ISOMERS. IN ADDITION, THE ISOLATION OF ISOMERICALLY PURE COMPLEXES WILL FURTHER SIMPLIFY THE ANALYTICAL PROCEDURE AND THEREBY FACILITATE COMMERCIAL DEVELOPMENT. DISSOCIATIONRATES WILL BE DETERMINED USING UV AND HPLC TECHNIQUES. THOSE COMPLEXES HAVING GREATER STABILITY THAN NSC 271674 WILL BE SUBMITTED TO NCI FOR ANTITUMOR EVALUATION. THE SUCCESSFUL DEVELOPMENT OF STABLE, SOLUBLE PLATINUM COMPLEXESWITH IMPROVED THERAPEUTIC PROPERTIES (MORE ACTIVE, LESS TOXIC) COMPARED TO CISPLATIN WOULD BE HIGHLY BENEFICIAL TO THE ONCOLOGIST AND TO CANCER PATIENTS.