Design, synthesis and characterization of novel chromone based-copper(ii) antitumor agents with N,N-donor ligands: comparative DNA/RNA binding profile and cytotoxicity

新型色酮基铜(II)抗肿瘤药物的设计、合成与表征:DNA/RNA结合谱和细胞毒性比较

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Abstract

A series of new chromone based-Cu(ii) complexes 1-3 derived from bioactive pharmacophore, 3-formylchromone and N,N-donor ligands viz., 1,10-phenanthroline, 2,2'-bipyridine and 1R,2R-DACH were synthesized as potential antitumor agents and thoroughly characterized by UV-vis, FT-IR, EPR, ESI-MS and elemental analysis. Single X-crystal diffraction studies of complex 2 revealed triclinic P1̄ space group with square pyramidal geometry around the Cu(ii) center. Comparative in vitro binding studies with ct-DNA and tRNA were carried out using absorption and emission titration experiments which revealed intercalative mode of binding with higher binding propensity of complexes 1-3 towards tRNA as compared to ct-DNA. Additionally, complex 1 exhibited high binding affinity among all the three complexes due to the involvement of phen co-ligands via π-stacking interactions in between nucleic acid base pairs. Furthermore, Hirshfeld surface analysis was carried out for complex 2 to investigate various intra and intermolecular non-covalent interactions (H-bonding, C-H⋯π etc.) accountable for stabilization of crystal lattice. The cleavage activity of complex 1 was performed by gel electrophoretic assay with pBR322 DNA and tRNA which revealed efficient DNA/tRNA cleaving ability of complex, suggesting tRNA cleavage both concentration and time dependent. Furthermore, in vitro cytotoxic activity of complexes 1-3 on a selected panel of human cancer cell lines was performed which revealed that all three complexes exhibited remarkably good cytotoxic activity with GI(50) value < 10 μg mL(-1) (<20 μM).

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