Aqueous chemistry of mixed-amine cis- and transplatin analogues. Intramolecular preference for a kinetic six-membered ring over a thermodynamic five-membered ring ortho-platination product

Abstract

A series of mixed-amine cis- and trans-platin analogs, contg. benzylamine and 2-phenylethylamine functionalities, were synthesized and the aq. soln. chem. investigated. The cis- and trans-Pt(NH3)LCl2 (I; L = (1,2-bis(4-methoxyphenyl)ethylamine (MREA), 2-(4-methoxyphenyl)-1-phenylethylamine (MPPEA), bis(4-methoxyphenyl)methylamine (MPMA)) were synthesized in >98% isomeric purity. With the aim of investigating the pharmacoactivation of this class of compds., a reversed-phase HPLC assay was developed for detg. the rates of Pt-Cl hydrolysis of the cis-configured isomers. The precolumn addn. of KBr to the reaction solns. trapped the aquachloro- and diaquaplatinum hydrolysis products as their bromo adducts. The sepns. of dichloro-, bromochloro-, and dibromoplatinum complexes allowed the quantification of their time-dependent concns., and the hydrolysis rate consts. for cis-I could be detd. Following Pt-Cl hydrolysis, an intramol. ortho-platination occurred with I. Proton NMR studies showed that, for the trans-I (L = MPEA, MPPEA), the kinetically favored, 6-membered ring cycloplatinated products were formed specifically over the thermodn., 5-membered ring ones. For cis-I (L = MPEA), the kinetic product was formed selectively. The 6-membered cycloplatinated ring could be converted into the 5-membered, thermodn. favored one by heating in dil. KCl. The implications of these novel findings are discussed from both mechanistic chem. and pharmacol. points of view.