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

摘要

Copper-based binuclear enantiomeric complexes1(S)and1(R)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 ligandL(S)and complexes1(S)&1(R), was carried out by single crystal X-ray studies which showed that ligand crystallized in the monoclinicP21/nspace group while complexes1(S)and1(R)crystallized in triclinic space groupsP1 & x304; andP1, respectively with two copper units connected to each otherviaan 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 vitrobinding studies of complexes1(S)and1(R)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 complexes1(S)and1(R)were carried out with G-quadruplex telomeric DNA by PAGE Gel assay which showed sequence selective cleavage of ;22G4viaoxidative cleavage pathway. The major cleavage sites identified were G15, T6, G8, G9, G14 for complex1(S)whereas for1(R)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 of1(S)and1(R)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.