Department of Chemistry, Aligarh Muslim University, Aligarh 202002, Uttar Pradesh, India.
Department of Chemistry and Biochemistry, The Ohio State University, 100 West 18th Avenue, Columbus, OH 43210, USA.
Metallomics. 2020 Jun 24;12(6):988-999. doi: 10.1039/d0mt00084a.
Copper-based binuclear enantiomeric complexes 1S and 1R were synthesized as anticancer chemotherapeutic agents to target G-quadruplex rich region of DNA and thoroughly characterized by various spectroscopic and single X-ray crystal diffraction studies. The structure elucidation of Schiff base ligand LS and complexes 1S & 1R, was carried out by single crystal X-ray studies which showed that ligand crystallized in the monoclinic P21/n space group while complexes 1S and 1R crystallized in triclinic space groups P1[combining macron] and P1, respectively with two copper units connected to each other via an alkoxide bridge to exhibit square planar geometry which is in good agreement with other spectroscopic studies {IR, ESI-MS, EPR and magnetic moment values}. In vitro binding studies of complexes 1S and 1R were carried out with G-quadruplex DNA and CT-DNA which showed higher binding affinity and selectivity toward quadruplex DNA over the duplex DNA. To validate the potential of complexes to act as therapeutic drug candidates, the cleavage studies of complexes 1S and 1R were carried out with G-quadruplex telomeric DNA by PAGE Gel assay which showed sequence selective cleavage of 22G4via oxidative cleavage pathway. The major cleavage sites identified were G15, T6, G8, G9, G14 for complex 1S whereas for 1R G15, G20, G21, G14 cleavage sites were observed. Furthermore, these complexes were capable of cleaving pUC19 plasmid DNA in double-stranded non-random fashion which is considered to be more potent than single-strand cleavage as a source of lethal DNA lesions. Cellular studies of 1S and 1R were performed on a panel of human cancer cell lines; Huh7, MCF7, BxPC3 and AsPC1, which displayed significant cytotoxicity and differential responses toward different cancer phenotypes.
铜基双核对映体配合物 1S 和 1R 被合成作为抗癌化疗药物，以靶向富含 G-四链体的 DNA 区域，并通过各种光谱和单晶 X 射线衍射研究进行了彻底表征。席夫碱配体 LS 和配合物 1S 和 1R 的结构阐明通过单晶 X 射线研究进行，结果表明配体在单斜 P21/n 空间群中结晶，而配合物 1S 和 1R 分别在三斜空间群 P1[combining macron]和 P1 中结晶，两个铜单元通过烷氧基桥彼此连接，呈现出平面正方形几何形状，这与其他光谱研究（IR、ESI-MS、EPR 和磁矩值）一致。配合物 1S 和 1R 与 G-四链体 DNA 和 CT-DNA 的体外结合研究表明，它们对四链体 DNA 的结合亲和力和选择性高于双链 DNA。为了验证配合物作为治疗药物候选物的潜力，通过 PAGE 凝胶分析对配合物 1S 和 1R 进行了 G-四链体端粒 DNA 的切割研究，结果表明通过氧化切割途径对 22G4 进行了序列选择性切割。鉴定的主要切割位点为 1S 的 G15、T6、G8、G9、G14，而 1R 的 G15、G20、G21、G14 切割位点被观察到。此外，这些配合物能够以双链非随机方式切割 pUC19 质粒 DNA，这被认为比单链切割作为致死性 DNA 损伤的来源更有效。1S 和 1R 的细胞研究在一组人类癌细胞系（Huh7、MCF7、BxPC3 和 AsPC1）上进行，这些细胞系显示出对不同癌症表型的显著细胞毒性和不同反应。
