CAN PT(IV)-AMINE COMPLEXES ACT AS PRODRUGS

Platinum antitumour drugs have been used for a number of years routine ly as Pt(II) amine compounds, the prototype being cis-PtCl2(NH3)(2). M ore recently, Pt(IV) compounds have been shown to be active, and one o f them is being introduced into clinical use. The present study deals with the question of whether such compounds are real drugs, or whether they act as prodrugs, being reduced to Pt(II) before reaching their D NA target. A few Pt(IV) amine complexes with the chelating Ligand tran s-R,R-diaminocyclohexane (R,R-dach), and a variety of coordinating ani ons, were reacted in the dark. with 9-methylxanthine, 9-methylhypoxant hine and guanosine-5'-monophosphate. It was found that the nature of t he coordinating anions, and also the DNA model base, determine the in vitro reactivity of these Pt(IV) compounds. The fastest reactions occu r with Pt(R,R-dach) (ox)Cl-2, and the slowest with Pt(R,R-dach) (ox) ( OC(O)C4H9)(2). Reactions with Pt(R,R-dach) (ox) (OC(O)C5H11)Cl occur w ith intermediate kinetics. In all cases a reaction was found, and Pt(I V)-DNA intermediates were determined unambiguously, allowing the hypot hesis that not all Pt(TV) compounds act necessarily as prodrugs. (C) 1 998 Elsevier Science S.A. All rights reserved.