Design, synthesis and biological evaluation of iridium(III) complexes as potential antitumor agents.

Cisplatin and its analogs have been used for the treatment of various cancers, but their serious side effect has limited clinical application. Presently, scientists are developing other metal drugs as an alternative of cisplatin. In this paper, three new iridium(III) complexes [Ir(ppy)2(adppz)](PF6) (adppz = 7-aminodipyrido[3,2-a:2',3'-c]phenazine; ppy = 2-phenylpyridine 1), [Ir(bzq)2(adppz)](PF6) (bzq = benzo[h]quinolone 2) and [Ir(piq)2(adppz)](PF6) (piq = 1-phenylisoquinoline 3) were synthesized and characterized. The complexes can effectively inhibit the cell colonies. The cytotoxicity in vitro of the complexes against A549, HepG2, SGC-7901, BEL-7402 and normal NIH3T3 cells was evaluated by 3-(4,5-dimethylthiazole)-2,5-diphenyltetraazolium bromide (MTT) methods. The intracellular reactive oxygen species (ROS) levels and Ca2+ concentrations were assayed. The mitochondrial membrane potential, a release of cytochrome c and the expression of B-cell lymphoma/leukemia-2 (Bcl-2) family protein have been investigated. The data reveal that the complexes 1-3 can effectively inhibit the cell proliferation in A549 cells with low IC50 value of 3.2 ±â€¯0.4 µM, 4.8 ±â€¯0.5 µM and 1.2 ±â€¯0.2 µM, respectively. The antitumor in vivo shows that complex 3 can inhibit tumor growth with an inhibitory rate of 76.34%. The studies on the mechanism indicate that these complexes cause apoptosis in A549 cell via a ROS-mediated lysosomal-mitochondrial dysfunction pathway. In addition, the interaction of the complexes with BSA was explored.