Design, Synthesis, and Anticancer Activities of Cyclometalated Tris(2-phenylpyridine)iridium(III) Complexes with Cationic Peptides at the 4′-Position of the 2-Phenylpyridine Ligand

Abstract

We previously reported the design and synthesis of amphiphilic Ir complex–cationic peptide hybrids (2a–2f), which contain basic peptide sequences such as KKGG (K = lysine, G = glycine) at the 5′-positions (para position with respect to the C–Ir bond) of three 2-(4′-tolyl)pyridine (tpy) ligands. Among them, 2c–2e induced the necrosis-like cell death of Jurkat cells through a calcium-dependent pathway, possibly involving a Ca2+–calmodulin (CaM) complex. Herein, we report the synthesis of amphiphilic Ir(ppy)3 complexes (ppy = 2-phenylpyridine) containing the KKGG sequence at the 4′-position of the ppy moiety (4a–4d) to examine the effect of the position of the cationic peptide sequence on the cytotoxicities of the complexes against Jurkat cells. The results of 3-(4,5-dimethly-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assays and a mechanistic study indicate that 4b and 4c, which contain C6 and C8 linkers, induce cell death through a calcium-dependent pathway accompanied by membrane disruption in a manner similar to that of 2c–2e but with smaller half-maximal effective concentration (EC50) values than those of 2c–2e. The results of the photoaffinity labeling of Jurkat cells with 5b containing a photoreactive 3-trifluoromethyl-3-phenyldiazirine (TFPD) unit and co-staining experiments with specific probes for intracellular organelles suggest that 4b and 4c bind to Ca2+–CaM and are localized in the mitochondria during cell death.