Cyclometallated platinum(IV) compounds as promising antitumour agents

Abstract

Since the discovery of the anticancer activity of cisplatin by Rosenberg, extensive research has been carried out in order to develop new and more efficient platinum-containing drugs. In recent years, platinum(IV) compounds are appealing due to their inertness and high lipophilicity. On the other hand, interest in organometallic platinum compounds such as cyclometallated platinum(II) compounds is based on their stability and on the fact that the presence of a σ(Pt-C) bond increases the lability of the ligand in trans. In contrast, cyclometallated platinum(IV) compounds which combine the properties imparted by the presence of a platinum(IV) centre and a cyclometallated ligand have received little attention. The aim of this review is to present the results obtained so far for cyclometallated platinum(IV) compounds tested as antitumour agents. These compounds are prepared either by intramolecular oxidative addition from electron-rich platinum precursors and adequate ligands or by intermolecular oxidative addition to previously obtained cyclometallated platinum(II) compounds. Tridentate [C,N,N'] cyclometallated platinum(IV) compounds containing one, two or three carbon donor ligands exhibit a remarkable cytotoxicity, in most cases greater than that of cisplatin, against a panel of human cancer cell lines. In contrast, compounds containing a [C,N] platinacycle are less active. For the most active tridentate [C,N,N'] platinum(IV) compounds studies of DNA interaction, topoisomerase I, IIα, and cathepsin B inhibition and ROS generation are presented.