Synthesis and anticancer activity of mixed ligand 3d metal complexes

Our previously reported copper-based complexes of tropolone show nice antitumor effects, but with high cytotoxicity to normal cells, which is presumably caused by copper ions. Here, we managed to achieve this challenge by using other 3D metals to replace copper ions. We thus prepared four mononuclear 3D metal complexes [M(phen)L2] (M = Mn, Co, Ni, and Zn for 1-4, respectively). Complexes 1 and 4 show selectivity on different cancer cell lines with much lower cytotoxicity to normal cells than cisplatin. The anticancer effects for complexes 2 and 3 on the tested cancer cell lines are very poor. It revealed a tuning effect of different metal ions on the anticancer activities with those for Mn(II) and Zn(II) being much higher than those for Co(II) and Ni(II) in this system. Among them, complex 1 presents a best anticancer effect on HeLa cells comparable to cisplatin. It overcame the afore-mentioned shortage of high cytotoxicity to normal cells for the reported Cu(II) complexes. It revealed from the mechanistic studies that complex 1 mainly induces apoptosis through the mitochondrial pathway by increasing intracellular reactive oxygen species, releasing Ca2+, and activating Caspase 9 and proapoptotic gene Bax.