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 )(NO ₃ ) ₂ ] (3), [Cu(L ² )(NO ₃ ) ₂ ] (4), [Cu(L ³ )Cl ₂ ] (5), [Cu(L ³ )Br ₂ ] (6) and [Cu(L ³ )(NO ₃ ) 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-yl-[1,3]dioxolo[4,5-g]isoquinoline}, 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 IC ₅₀ values of 5.03 ± 1.20 μM and 10.05 ± 0.52 μM, 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 (Δψ _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.
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