Copper(ii) l/d-valine-(1,10-phen) complexes target human telomeric G-quadruplex motifs and promote site-specific DNA cleavage and cellular cytotoxicity.

Chiral L/D-valine-(1,10-phen)-Cu(II) complexes that target G-quadruplex DNA were synthesized and thoroughly characterized by UV-vis, IR, EPR, ESI-MS, elemental analysis and single crystal X-ray spectroscopy. Complexes 1a and 1b crystallized in the monoclinic P21/c and C2 space groups, respectively. On the basis of Wolfe-Shimer analyses, the binding affinities of 1a and 1b with G-quadruplex telomeric DNA were determined, and 1 aexhibited significantly higher binding as compared to 1b. Site selective cleavage of G4-DNA was demonstrated by employing the time-dependent PAGE assay, with 1a exhibiting a significantly higher cleavage rate from A1 to G22 (4.32 (+/- 0.13) mu M h(-1)) than 1b(4.29 (+/- 0.11) mu M h(-1)). The DNA cleavage profile demonstrated that both complexes perform non-random double-strand cleavage by following first-order kinetics (k(obs)=0.9432 min(-1) for 1a and k(obs)=0.6574 min(-1) for 1b). Molecular docking simulations were performed with both parallel and anti-parallel topologies of the quadruplex to provide a clear insight on G-quadruplex-complex interactions. Complexes 1a and 1b were found to interact strongly at the minor groove cavity of the quadruplex with preferential selectivity for the parallel vs. anti-parallel quadruplex. The cytotoxic activities of complexes 1a and 1b were evaluated on a few notably important human cancer cell lines,viz, breast (MCF-7), pancreatic strains (BxPC3, AsPC1) and liver (Huh7) by an MTT assay. Both 1a and 1b exhibited pronounced cytotoxic activity with remarkably low IC50 values (1-3 mu M) for all tested cancer strains.