Copper(ii) l/d-valine-(1,10-phen) complexes target human telomeric G-quadruplex motifs and promote site-specific DNA cleavage and cellular cytotoxicity - Université de Rennes Accéder directement au contenu
Article Dans Une Revue Dalton Transactions Année : 2020

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

Résumé

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 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 (kobs = 0.9432 min-1 for 1a and kobs = 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. © The Royal Society of Chemistry.

Dates et versions

hal-02931938 , version 1 (07-09-2020)

Identifiants

Citer

Farukh Arjmand, S. Sharma, S Parveen, Loic Toupet, Z. Yu, et al.. Copper(ii) l/d-valine-(1,10-phen) complexes target human telomeric G-quadruplex motifs and promote site-specific DNA cleavage and cellular cytotoxicity. Dalton Transactions, 2020, 49 (28), pp.9888-9899. ⟨10.1039/d0dt01527j⟩. ⟨hal-02931938⟩
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