Copper(ii) l/d-valine-(1, 10-phen) complexes target human telomeric G-quadruplex motifs and promote site-specific DNA cleavage and cellular cytotoxicity. Issue 28 (8th July 2020)

• Record Type: Journal Article
• Authors: Arjmand, Farukh; Sharma, Surbhi; Parveen, Sabiha; Toupet, Loic; Yu, Zhen; Cowan, J. A.
• Is Part Of: Dalton transactions. Volume 49:Issue 28(2020)
• Page Start: 9888
• Page End: 9899
• Publication Date: 2020-07-08
• Subjects: Chemistry, Inorganic -- Periodicals; Chemistry, Physical and theoretical -- Periodicals; Chemistry, Inorganic -- Periodicals; 546.05
• DOI: 10.1039/d0dt01527j
• Languages: English
• ISSNs: 1477-9226

Abstract

Abstract : Chiral l -/d -valine-(1, 10-phen)-Cu(ii ) complexes that target G-quadruplex DNA were synthesized and thoroughly characterized. The cytotoxic activity of 1a and 1b on some of the notably important cancer cell lines was evaluated by MTT assay. Abstract : 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 P 21/ c and C 2 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 1a exhibited 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) μM h −1 ) than 1b (4.29 (±0.11) μM 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 μM) for all tested cancer strains.