Design, synthesis and crystal structure determination of dinuclear copper-based potential chemotherapeutic drug entities; in vitro DNA binding, cleavage studies and an evaluation of genotoxicity by micronucleus test and comet assay

Abstract

Copper-based potential chemotherapeutic complexes 1 and 2 were designed, synthesized and evaluated for in vitro DNA binding, cleaving capability and in vivo genotoxicity. The structural elucidation of complexes was done using elemental and spectroscopic data while the (R)-enantiomer of Cu(II) complex 1 was studied by single crystal diffraction. In vitro DNA binding profiling of both (R)- and (S)-enantiomers of complexes 1 and 2 was carried out to evaluate their enantioselectivity, exhibiting a remarkable degree of enantioselectivity in their interaction with DNA, with the (R)-enantiomer exhibiting greater DNA binding propensity. Interaction between complexes and pBR322 DNA was evaluated by agarose gel electrophoresis assay; both the (R)-enantiomeric complexes exhibit effective DNA cleavage and proceed via an oxidative pathway. Furthermore, the in vivo genotoxicity of the (R)-enantiomer of complex 1 was evaluated by micronucleus testing on bone marrow cells and comet assay in peripheral blood lymphocytes. These results support our contention that the (R)-enantiomer of complex 1 is a suitable chemotherapeutic drug candidate showing reduced toxic effects on normal cells as compared to cisplatin and an antioxidant (EVOO).