Enantiomeric copper based anticancer agents promoting sequence-selective cleavage of G-quadruplex telomeric DNA and non-random cleavage of plasmid DNA.

Abstract

Copper-based binuclear enantiomeric complexes 1S and 1R were synthesized as anticancer chemotherapeutic agents to target G-quadruplex rich region of DNA and thoroughly characterized by various spectroscopic and single X-ray crystal diffraction studies. The structure elucidation of Schiff base ligand LS and complexes 1S & 1R, was carried out by single crystal X-ray studies which showed that ligand crystallized in the monoclinic P21/n space group while complexes 1S and 1R crystallized in triclinic space groups P1[combining macron] and P1, respectively with two copper units connected to each other via an alkoxide bridge to exhibit square planar geometry which is in good agreement with other spectroscopic studies {IR, ESI-MS, EPR and magnetic moment values}. In vitro binding studies of complexes 1S and 1R were carried out with G-quadruplex DNA and CT-DNA which showed higher binding affinity and selectivity toward quadruplex DNA over the duplex DNA. To validate the potential of complexes to act as therapeutic drug candidates, the cleavage studies of complexes 1S and 1R were carried out with G-quadruplex telomeric DNA by PAGE Gel assay which showed sequence selective cleavage of 22G4via oxidative cleavage pathway. The major cleavage sites identified were G15, T6, G8, G9, G14 for complex 1S whereas for 1R G15, G20, G21, G14 cleavage sites were observed. Furthermore, these complexes were capable of cleaving pUC19 plasmid DNA in double-stranded non-random fashion which is considered to be more potent than single-strand cleavage as a source of lethal DNA lesions. Cellular studies of 1S and 1R were performed on a panel of human cancer cell lines; Huh7, MCF7, BxPC3 and AsPC1, which displayed significant cytotoxicity and differential responses toward different cancer phenotypes.