Abstract
Xanthone, an oxygenated heterotricyclic phytochemical, has recently emerged as a promising scaffold in cancer research due to its multitargeted anticancer potential. Recent studies demonstrate its affinity for G-quadruplex (G4) DNA structures. In this context, herein, we describe the design and synthesis of a series of xanthone-benzimidazole conjugates to investigate their specific cytotoxic effects on cancer cells through the stabilization of telomeric G4 DNA structures. Comprehensive in vitro biophysical and cellular experiments were performed to screen the most effective compounds for targeting telomeric G4 DNA structures among them. The structure-activity relationship (SAR) of quadruplex-compound interactions was documented as well. The current study reveals that two compounds, XDBHEP and XDBAEP, exhibit maximum binding affinity and selectivity toward the antiparallel telomeric form of G4 DNA. These compounds stabilize this G4 DNA structure through binding within the DNA groove loci and exhibit a 1:1 molar binding stoichiometry. The specific cytotoxic effect of these compounds on different types of cancer cells, including A549, T-47D, and MCF-7, and their apoptotic-mediated cell death was further demonstrated by several in vitro cellular experiments. In addition, blood compatibility, ADME studies, pharmacokinetics, and biodistribution studies were also performed to assess the potential of these compounds for further in vivo and clinical investigations. Based on the current study, the selective antiparallel telomeric G4 DNA targeting properties and specific cancer cell cytotoxicity effects of xanthone-benzimidazole conjugates could provide valuable information to support the research community in the future development of new anticancer drugs through G4 DNA stabilization based on this pharmacophore.