DNA binding and evaluation of anticancer activity in vitro and in vivo of iridium(III) polypyridyl complexes

In this report, we synthesized three new iridium(III) complexes: [Ir(piq)2(apip)]PF6 (Ir1, piq = 1-phenylisoquinoline, apip = 2-aminophenyl-1H-imidazo[4,5-f][1,10]phenanthroline), [Ir(piq)2(maip)]PF6 (Ir2, maip = 3-aminophenyl-1H-imidazo[4,5-f][1,10]phenanthroline) and [Ir(piq)2(paip)]PF6 (Ir3, paip = 4-aminophenyl-1Himidazo[4,5-f][1,10]phenanthroline). The DNA binding was investigated. 3-(4,5-dimethylthiazol-2-yl)-2,5diphenyltetrazolium bromide (MTT) method was used to detect the cytotoxic activity of Ir1, Ir2 and Ir3, the complexes show highly active against B16 cells with IC50 values of 0.3 +/- 0.2 mu M, 3.7 +/- 0.2 mu M and 4.6 +/- 1.1 mu M, respectively. Subsequently, cellular uptake suggested that the cytotoxicity of the complexes is attributed to their differences in cellular uptake levels. In addition, complexes Ir1, Ir2 and Ir3 induce cell cycle arrest at the G0/G1 phase and regulate the cell cycle mediators such as cyclin D1, CDK6 (cyclin-dependent kinase 6), CDK4 and p21, leading to the inhibition of B16 cells proliferation. The autophagy was investigated by monodansylcadaverine (MDC) staining. The complexes can promote the change from LC3-I to LC3-II, up-regulate levels of Beclin-1 and down-regulate expression of p62. The complexes induced apoptosis by regulating the expression levels of related indicators such as PARP (poly ADP-ribose polymerase), PI3K (phosphoinositide-3 kinase), AKT (protein kinase B), Caspase, Bcl-2 (B-cell lymphoma-2), Bad (Bcl2 associated death promoter), Bax (Bcl2-associated X) and Cyto C (cytochrome C). Additionally, Ir1 exerted significant antitumor activity in the suppression of malignant melanoma proliferation in vivo. As indicated in the above results, these complexes were highly effective for malignant melanoma treatment through the intrinsic pathway and provided much insight into anticancer drugs for tumor therapy.