Carbohydrate-based heteronuclear complexes as topoisomerase Iα inhibitor: approach toward anticancer chemotherapeutics

Abstract

<p>Due to the critical role of cellular enzymes necessary for cell proliferation by deciphering topological hurdles in the process of DNA replication, topoisomerases have been one of the major targets in the anticancer drug development area. A need, therefore, arises for new metallodrugs that specifically recognizes DNA and inhibits the activity of topoisomerase enzymes, herein, we report the synthesis and characterization of new metal-based glycoconjugate entities containing heterobimetallic core Cu^II–Sn^IV (<b>1</b>) and Ni^II–Sn^IV (<b>2</b>) derived from N-glycoside ligand (<b>L</b>). The optimized structure of complex <b>1</b> and other significant vibrational modes have been explained using dispersion corrected B3LYP/DFT calculations. <i>In vitro</i> DNA binding profile of the <b>L</b> and both the complexes <b>1</b> and <b>2</b> were done by various biophysical studies. Complex <b>1</b> breaks pBR322 DNA <i>via a</i> hydrolytic means which was validated by T4 DNA enzymatic assay. To get a mechanistic insight of mode of action topoisomerase I (Topo I) inhibition assay was carried out. Also, we have taken the help of molecular modeling studies in accordance with experimental findings. <i>In vitro</i> cytotoxicity of the complex <b>1</b> was evaluated against a panel of cancer cells which exhibited remarkably good anticancer activity (GI₅₀ values <10 μg/ml). Moreover, intracellular localization of the complex <b>1</b> was visualized by confocal microscopy against HeLa cells.</p