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 platinumcontaining 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 (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'] 2 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, II, and cathepsin B inhibition and ROS generation are presented.

Luminescent PtII and PtIV Platinacycles with Anticancer Activity Against Multiplatinum‐Resistant Metastatic CRC and CRPC Cell Models

“…Furthermore, several cyclometallated Pt II anticancer agents exhibit luminescence properties which make them potential luminescent probes for DNA in living cells and also allows easy tracing of their cellular uptake and distribution by fluorescence microscopy . Surprisingly, little attention has been devoted to Pt IV compounds containing a metallacycle in spite of their promising properties …”

“…[5][6][7] On the other hand,c yclometallated Pt II compounds containing bidentate (C,N) or tridentate (C,N,N')l igands display interestingp roperties. [13] Within the last few years, we have attempted to optimize the ligand design of cyclometallated Pt II and Pt IV compounds to maximize their efficacy and selectivitya gainst cancer cells. In addition, covalent coordinationt o DNA is favoured since the strong PtÀCb ondi ncreasest he lability of the ligand in a trans position.…”

“…[11,12] Surprisingly,l ittle attention has been devoted to [ Pt IV compounds containing am etallacycle in spite of their promisingp roperties. [13] Within the last few years, we have attempted to optimize the ligand design of cyclometallated Pt II and Pt IV compounds to maximize their efficacy and selectivitya gainst cancer cells.…”

One‐Pot Synthesis of New Organometallic Compounds with Platinum‐Carbon Bond

“…[10] Cyclometalated complexes, in which is present a σ(Pt-C) bond and the metal core is in both the oxidation states II and IV, have also been considered for possible anticancer activity. [11][12][13][14] In particular, cyclometalated C-N and C-N-N Pt II complexes have been designed with the aim of either interact with DNA through different binding modes or target alternative cellular machinery such as proteins. [15,16] C-N Pt II labile ligands, compound 3 has Cl and DMSO ligands that can be released, allowing the formation of cross-links with DNA.…”

“…Structurally different platinum compounds may lead to a complementary or different biological activity with respect to that of cisplatin and its homologues which is known to be triggered by a cross‐linking of nuclear DNA . Cyclometalated complexes, in which is present a σ(Pt–C) bond and the metal core is in both the oxidation states II and IV, have also been considered for possible anticancer activity . In particular, cyclometalated C–N and C–N–N Pt II complexes have been designed with the aim of either interact with DNA through different binding modes or target alternative cellular machinery such as proteins , .…”