Design and synthesis of a DNA intercalative half-sandwich organoruthenium(ii)–chromone complex: cytotoxicity evaluation and topoisomerase Iα inhibition assay

Abstract

In the present study, we report the molecular design and synthesis of [Ru(η⁶-p-cymene)-(chromone)Cl] complex (1) as a potential topoisomerase I inhibitor. The structural elucidation of complex 1 was carried out by analytical, spectral and single crystal X-ray crystallographic techniques. Complex 1 crystallized in the monoclinic Pc space group with a Ru(II) ion coordinated to a p-cymene arene unit in a usual “piano-stool” geometry. In vitro binding interaction studies of complex 1 with ct-DNA and HSA were carried out and suggested a strong binding affinity towards DNA via an intercalative mode. DNA photocleavage activity was carried out with a pBR322 plasmid DNA substrate to ascertain the cleaving ability and the mechanistic pathway of the cleavage process. Topoisomerase I inhibition assay of complex 1 was performed via gel electrophoresis which revealed a significant inhibitory effect on the enzyme catalytic activity at a minimum concentration of 20 μM. Molecular docking studies of the complex were carried out with DNA, HSA and topoisomerase I to determine the specific binding preferences at the target site and complement the spectroscopic studies. Cytotoxic studies of complex 1 on a series of five human cancer cell lines, viz. A-498, HepG2, HeLa, MCF-7 and MIA-PA-CA-2, by the SRB assay revealed a moderate but selective activity towards pancreatic and cervical cancer cell lines.