Synthesis and in vitro antitumor activity evaluation of copper(II) complexes with 5-pyridin-2-yl-[1,3]dioxolo[4,5-g]isoquinoline derivatives

Seven Cu(II) complexes with 5-pyridin-2-yl-[1,3]dioxolo [4,5-g] isoquinoline derivatives as ligands: [Cu-2(L-1)(2)Cl-4] (1), [Cu(L-2)Cl-2] (2), [Cu(L-1)(NO3)(2)) ( 3 ), [Cu(L-2)(NO3)(2)) (4), [Cu(L-3)Cl-2] (5), [Cu(L-3)Br-2] (6) and [Cu(L-3) (NO3)(2)] (7) {L-1= 9-nitro-5-pyridin-2-yl- [1,3] dioxolo [4,5-g] isoquinoline, L-2= 4-nitro-5-pyridin-2-yl-[1,3]dioxolo [4,5-g] isoquinoline, L-3=9-bromo-5-pyridin-2-yl41,31dioxolo[4,5-g]isoquinolinel, were synthesized and characterized. Their in vitro anticancer activities against T-24, MGC-80-3, HeLa, Hep-G2, A549 and SK-OV-3 were evaluated. Compared with their corresponding ligands, most of these complexes exhibited enhanced anticancer activities in contrast to their corresponding ligands and copper salt. Among them, complexes 1 and 3 displayed selective cytotoxicity to HeLa cells comparing with normal liver cell HL-7702, with IC50 values of 5.03 +/- 1.20 mu M and 10.05 +/- 0.52 mu M, respectively. Complexes 1 and 3 inhibited telomerase activity by interacting with c-myc promoter elements, and therefore exerted their antitumor activity. Furthermore, complexes 1 and 3 could trigger cell apoptosis via disruption of mitochondrial pathway through notably increased reactive oxygen species (ROS) levels, loss of mitochondrial membrane potential (Delta psi(m)), increase of the cytochrome c and apaf-1, decrease of bcl-2, and activation of caspases 3/9. Complexes 1 and 3 exhibited enhanced cytotoxicity, presenting synergetic effect after the ligands coordinated to copper(II) center.