Anti-cancer gold, platinum and iridium compounds with porphyrin and/or N-heterocyclic carbene ligand(s)

Abstract

Metal complexes of d8 and d10 metal ions having planar coordination geometry provide diverse structural scaffolds for non-covalent and covalent interactions with bio-molecular targets. These complexes can be harnessed to design new diagnostics and therapeutics for the treatment of cancer. We have employed ligands with N donor and/or C donor atom(s), such as pincer cyclometalated (C∧N∧N) moieties, porphyrins and N-heterocyclic carbenes (NHCs), to prepare cationic Au(III), Au(I), Pt(II), Pd(II) and Ir(III) complexes, all of which display good stability under physiological conditions. Apart from the strong M–NHC bond(s) that lend the metal–NHC complexes a favorable stability against demetalation in solution, the coordination of metal ions with NHC ligand(s) can give rise to strongly luminescent behavior of the metal complexes due to the suppression of excited state structural distortion. The d8- and d10-metal complexes described herein exhibit potent cytotoxicity in cancer cells in culture as well as anti-tumor activity in mouse models of cancer. Chemical formulation strategies, such as bio-conjugation and encapsulation, can be used to deliver the cytotoxic, anti-cancer metal complexes to tumors with lower toxic side effects. The molecular targets of some of these metal complexes have been identified using clickable photo-affinity probes and cellular thermal-shift proteomics, revealing the engagement of multiple targets. These results account for the effective anti-cancer properties with a less likelihood of developing drug resistance.