New Anthraquinone & Xanthone based Ligands as Potential Anti Cancer Agents via Selective Stabilization of G Quadruplex DNA and Theoretical Insights into G Quadruplex RNA Binding with Certain Small Molecules

Abstract

In recent years, different small molecules have been synthesized for selective stabilization of G-quadruplex DNA structures over the most abundant double-stranded duplex DNA. Stabilization of G-quadruplex DNA by small molecules would regulate transcription as well as translation in cancer cells. To this aspect, we have synthesized different anthraquinone and xanthone based small molecules to selectively recognize G-quadruplex structures. The interaction was examined by UV-Vis spectroscopic titration, which was substantiated by fluorescence, CD, and melting experiments. Further, Taq polymerase stop assay also supported the G-quadruplex stabilizing effect of these ligands. Fluorescent intercalator displacement assay revealed the end-stacking binding mode of these compounds with G-quadruplex DNA that was further checked by docking and simulation studies. The synthesized compounds showed selective cancer cell cytotoxicity over normal cells. The cell death was governed by apoptosis mediated pathway as obtained from Annexin V-FITC and PI dual staining assay. Cellular morphological changes were obtained in the compound induced cells in a dose-dependent manner. Confocal microscopic images showed the nuclear condensation in the compound treated cells. Further, certain anthraquinone and benzimidazole based derivatives were docked with G-quadruplex RNA to know the plausible binding mode. Further, the most effective benzimidazole-based compound was simulated in order to get the proper binding mode with G-quadruplex RNA. This theoretical inspection will help the scientists to design G-quadruplex RNA binding small molecules which can be applied in quadruplex mediated anti-cancer therapeutics.