title: Antioxidant, DNA interaction, VEGFR2 kinase, topoisomerase I and in vitro cytotoxic activities of heteroleptic copper(II) complexes of tetrazolo[1,5-a]pyrimidines and diimines.
abstract: A series of heteroleptic mononuclear copper(II) complexes of the type [Cu(L(1-3))(diimine)]ClO4 (1-6) containing three tetrazolo[1,5-a]pyrimidine core ligands, ethyl 5-methyl-7-(2-hydroxyphenyl)-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxylate (HL(1)), ethyl 5-methyl-7-(4-diethylamino-2-hydroxyphenyl)-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxylate (HL(2)) or ethyl 5-methyl-7-(2-hydroxy-4-nitrophenyl)-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxylate (HL(3)), and two diimine coligands, 2,2'-bipyridyl (bpy) or 1,10-phenanthroline (phen) have been synthesized and characterized by spectral methods. The geometry of complexes have been determined with the help of electronic absorption and EPR splitting patterns, which suggest four coordinated square planar geometry around copper(II) ion. The lowering of HOMO-LUMO band gap value of complex 4 implies its higher biological activity compared to other complexes. Antioxidant studies revealed that the complexes possess considerable radical scavenging potency against DPPH. The binding studies of the complexes with calf thymus DNA (CT-DNA) revealed groove mode of binding, which was further supported by docking simulation. The complexes 3 and 4 strongly inhibit the topoisomerase I, and also strongly interact with VEGFR2 kinase receptor via π-π, σ-π and hydrogen bonding interaction. Gel electrophoresis experiments demonstrated the ability of the complexes to cleave plasmid DNA in the absence of activators. In vitro cytotoxic activities of the complexes were examined on three cancerous cell lines such as human lung (A549), cervical (HeLa) and colon (HCT-15), and two normal cells such as human embryonic kidney (HEK) and peripheral blood mononuclear cells (PBMCs). The live cell and fluorescent imaging of cancer cells were observed with acridine orange/ethidium bromide staining assay. All encouraging chemical and biological findings indicate that the complex 4 is a suitable candidate for drug target.
authors: Post-Graduate and Research Department of Chemistry, The New College (Autonomous), Chennai 600 014, India.
authors: A
authors: A
authors: Haleel
authors: Post-Graduate and Research Department of Chemistry, The New College (Autonomous), Chennai 600 014, India.
authors: D
authors: D
authors: Mahendiran
authors: Department of Biotechnology, Pondicherry University, Pondicherry 605 014, India.
authors: V
authors: V
authors: Veena
authors: Department of Biotechnology, Pondicherry University, Pondicherry 605 014, India.
authors: N
authors: N
authors: Sakthivel
authors: Post-Graduate and Research Department of Chemistry, The New College (Autonomous), Chennai 600 014, India. Electronic address: akrahmanjkr@gmail.com.
authors: A Kalilur
authors: AK
authors: Rahiman
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000138:chemical synthesis / Q000737:chemistry; D002642:Chick Embryo; D003300:Copper / Q000737:chemistry*; D003603:Cytotoxins / Q000138:chemical synthesis / Q000737:chemistry; D004247:DNA / Q000737:chemistry*; D004264:DNA Topoisomerases, Type I / Q000737:chemistry*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D013777:Tetrazoles / Q000138:chemical synthesis / Q000737:chemistry; D059004:Topoisomerase I Inhibitors / Q000138:chemical synthesis / Q000737:chemistry; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000737:chemistry*
chemical_list: D000975:Antioxidants; D003603:Cytotoxins; D013777:Tetrazoles; D059004:Topoisomerase I Inhibitors; D003300:Copper; D004247:DNA; C427203:calf thymus DNA; C000588866:KDR protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2; D004264:DNA Topoisomerases, Type I
keywords: Apoptosis; DNA binding; DNA cleavage; HOMO–LUMO energy gap; Heteroleptic copper(II) complexes; Molecular docking; Tetrazolo[1,5-a]pyrimidines