DDP has become one of the most widely used drugs in the treatment of human tumors. Unfortunately, the usefulness of DDP is limited by such untoward effects as nephrotoxicity, nausea and vomiting, ototoxicity, neurotoxicity and the potential development of resistance to DDP by the tumor cell. During the past two years our group has synthesized in excess of 130 Pt complexes in an attempt to develop Pt analogs possessing increased efficacy, decreased toxicity, lack of cross resistance with DDP, or ideally, some combination of all three attributes. This effort has led to the development of at least 30 compounds with significant activity. The purpose of the present research proposal is two-fold. First, we intend to continue our drug synthesis program, preparing Pt complexes altered at both the stable amine and leaving group function alike. We intend to investigate the effect of diaminocyclohexane (DACH) isomers on the activity of DACH-Pt complexes, the enhanced solubility of Pt complexes using hydrophilic amines, the effect of mixed monodenate amines on Pt complexes activity and, finally, the effect of leaving group substitution on water solubility and activity of the Pt complexes. Second, we intend to perform chemical, biochemical and pharmacological investigations on 3 or 4 of the most interesting Pt complexes synthesized by our group. We have concentrated our efforts on the development of new complexes and testing them for efficacy and toxicity. We now intend to study the mechanism of action, DNA cross-linking effects, pharmacokinetics, tissue distribution, and the sites of DNA-Pt interactions of our most exciting complexes. In addition, we will perform NMR, conductivity, HPLC, I.R. and, if possible, X-crystallographic analyses of these complexes. This approach will enable us to better understand the chemical and biological effects of our previously synthesized complexes while further extending our new drug synthesis program.
