Copper(II) Complexes of Indolo[2,3-c]quinoline-Derived Schiff Bases: Insight into the Mechanism of their Antiproliferative Activity

Bacher, Felix and Madejski, Christian and Kuznetcova, Irina and Dömötör, Orsolya and Gyurcsik, Béla and Nafaee, Zeyad H. and Igaz, Nóra and Bocz, Csenge and Péntek, Bálint and Csontné Kiricsi, Mónika and Raptova, Petra and Stoica, Alexandru-Constantin and Hejl, Michaela and Jakupec, Michael A. and Alfadul, Samah Mutasim and Babak, Maria V. and Rapta, Peter and Reynisson, Jóhannes and Sindlerova, Lenka and Enyedy, Éva Anna and Hamel, Ernest and Arion, Vladimir B. (2026) Copper(II) Complexes of Indolo[2,3-c]quinoline-Derived Schiff Bases: Insight into the Mechanism of their Antiproliferative Activity. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY. No.-118882. ISSN 0223-5234

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Abstract

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.

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