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

• Published in: European journal of inorganic chemistry 2017-12, Vol.2017 (44), p.5295-5309
• Main Authors: Yokoi, Kenta, Hisamatsu, Yosuke, Naito, Kana, Aoki, Shin
• Format: Article
• Language: English
• Subjects: Anticancer properties; Apoptosis; Calcium; Calmodulin; Cations; Cell death; Cytotoxicity; Disruption; Glycine; Inorganic chemistry; Iridium; Iridium compounds; Ligand design; Luminescence; Lysine; Mitochondria; Organelles; Peptides; Synthesis
• ISSN: 1434-1948; 1099-0682
• DOI: 10.1002/ejic.201700846

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. Amphiphilic iridium(III) complexes with cationic KKGG peptide sequences at the 4′‐position of the 2‐phenylpyridine (ppy) ligands are designed and synthesized to examine the effect of the position of the cationic peptide on the cytotoxicities of the complexes against Jurkat cells, and a mechanistic study of the cell death is reported.