Molecular drug design, synthesis and crystal structure determination of CuII–SnIV heterobimetallic core: DNA binding and cleavage studies

A novel heterobimetallic CuII–SnIV complex 1 bearing bioactive 1,10-phenanthroline pharmacophore ligand scaffold was synthesized and characterized by elemental analysis, IR, UV–vis spectroscopy, Mass (ESI and FAB) and X–ray crystallography. The in vitro DNA binding studies of complex 1 with CT DNA was carried out by various biophysical and molecular docking techniques which revealed that complex 1 binds to DNA through intercalation in the minor groove having AT-rich sequences. Complex 1 exhibits high chemical nuclease activity cleaving supercoiled pBR322 DNA via hydrolytic pathway which was further evidenced by T4 DNA ligase assay. The complex 1 shows high inhibitory activity against Topo I at a very low concentration (15 μM), suggesting that complex 1 is an efficient catalytic inhibitor of human Topo I and further validated by molecular docking studies.

Graphical abstractTo elucidate the molecular recognition toward the minor groove of DNA as Topo I inhibitor, molecular docking techniques were performed and further validated by various spectroscopic studies.Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Novel heterobimetallic CuII–SnIV complex 1 bearing bioactive 1,10-phenanthroline pharmacophore ligand scaffold. ► The in vitro DNA binding studies reveal that this complex bind to CT DNA via intercalation into the minor groove. ► Complex 1 shows efficient hydrolytic cleavage of pBR322 DNA as evidenced from the T4 DNA ligase experiments. ► The complex showed an IC50 of 15 μM, indicates that it has high potential to act as an anticancer drug.