Copper(II) complexes of indolo[2,3-c]quinoline-derived Schiff bases: Insight into the mechanism of their antiproliferative activity.

Indoloquinolines are potent anticancer agents, but their poor aqueous solubility prevents clinical development. Indoloquinoline-based metal complexes offer an opportunity to circumvent this drawback. A series of new indolo[2,3-c]quinoline derivatives HL1-HL8 and their copper(II) complexes were synthesized, comprehensively characterized and tested for antiproliferative activity against MDA-MB-231, MCF-7, MCF-7 KCR, A549 and DU-145 cancer cells and compared to known isomeric indolo[3,2-c]quinolines (HL11-HL14 and 11-14). The Cu(II) complexes were generally as active, or slightly more so, than the proligands. Lead compounds HL8 and 8 showed superior anticancer activity compared to isomers HL14 and 14, respectively. Complex 8 was superior to HL8 in ROS generation in A549 cells, induced mitochondrial dysfunction as evidenced by JC-1 staining, induced lactate dehydrogenase release in medium, inhibited DNA synthesis and triggered apoptosis. DNA-binding studies, supported by molecular docking calculations, showed strong affinity of the compounds for double stranded DNA, to which they bind by intercalation.