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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
Author(s) -
Yokoi Kenta,
Hisamatsu Yosuke,
Naito Kana,
Aoki Shin
Publication year - 2017
Publication title -
european journal of inorganic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.667
H-Index - 136
eISSN - 1099-0682
pISSN - 1434-1948
DOI - 10.1002/ejic.201700846
Subject(s) - chemistry , jurkat cells , cationic polymerization , stereochemistry , peptide , moiety , ligand (biochemistry) , amphiphile , biochemistry , t cell , receptor , polymer chemistry , organic chemistry , immune system , copolymer , immunology , biology , polymer
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 Ca 2+ –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‐2 H ‐tetrazolium bromide (MTT) assays and a mechanistic study indicate that 4b and 4c , which contain C 6 and C 8 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 (EC 50 ) 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 Ca 2+ –CaM and are localized in the mitochondria during cell death.