Electron-transfer activated metal-based anticancer drugs

Platinum(II)-based anticancer drugs play an essential role in the clinic today, and a number of coordination compounds with other metals are in current development as promising antitumor drugs. Probably the most prominent non-platinum metal-based drugs are those of ruthenium. Various strategies have been applied for the design of novel drugs with an improved toxicological profile, and one of them involves the preparation of metal complexes in inert high oxidation states [e.g. Pt(IV), Ru(III)]. Three platinum(IV) and two ruthenium(III) drugs have already reached clinical trials. Ideally, hypoxia-selective drugs are delivered to the target environment without prior reduction or major transformation via substitution reactions at the metal center. A (selective) reduction has been proposed to activate the prodrugs by formation of active species, which react with the target more readily and lead ultimately to apoptosis. Investigations on the electrochemical behavior of platinum(IV) and ruthenium(III) cytotoxins and the establishment of preliminary structure–property relationships are therefore of current importance. Herein, we present recent results in the field of metal-centered electron-transfer activated Ru(III), Pt(IV) and Co(III) drugs with regard to design and targeting strategies, prediction of redox potentials in aqueous medium, labilization and enhanced reactivity with potential biological targets upon reduction, and correlations between electrochemical parameters and anticancer activity.

Three platinum(IV) and two ruthenium(III) anticancer drugs have entered clinical trials to date. The metallopharmaceuticals are believed to be activated (at least in part) by reduction to reactive M(II) species in vivo. Recent investigations on metal-centered electron-transfer activation of Ru(III), Pt(IV) and Co(III) prodrugs are described herein.Figure optionsDownload as PowerPoint slide