Discovery of novel benzimidazole acyclic C‐nucleoside DNA intercalators halting breast cancer growth

Breast cancer continues to be the most frequent cancer worldwide. In practice, successful clinical outcomes were achieved via targeting DNA. Along with the advances in introducing new DNA‐targeting agents, the “sugar approach” design was employed herein to develop new intercalators bearing pharmacophoric motifs tethered to carbohydrate appendages. Accordingly, new benzimidazole acyclic C‐nucleosides were rationally designed, synthesized and assayed via MTT (3‐[4,5‐dimethylthiazol‐2‐yl]‐2,5 diphenyl tetrazolium bromide) assay to evaluate their cytotoxicity against MCF‐7 and MDA‐MB‐231 breast cancer cells compared to normal fibroblasts (Wi‐38), compared to doxorubicin. (1S,2R,3S,4R)‐2‐(1,2,3,4,5‐Pentahydroxy)pentyl‐1H‐5,6‐dichlorobenzimidazole 7 and (1S,2R,3S,4R)‐2‐(1,2,3,4,5‐pentahydroxy)pentyl‐1H‐naphthimidazole 13 were the most potent and selective derivatives against MCF‐7 (half‐maximal inhibitory concentration [IC50] = 0.060 and 0.080 µM, selectivity index [SI] = 9.68 and 8.27, respectively) and MDA‐MB‐231 cells (IC50 = 0.299 and 0.166 µM, SI = 1.94 and 3.98, respectively). Thus, they were identified as the study hits for mechanistic studies. Both derivatives induced DNA damage at 0.24 and 0.29 μM, respectively. The DNA damage kinetics were studied compared to doxorubicin, where they both induced faster damage than doxorubicin. This indicated that 7 and 13 showed a more potent DNA‐damaging effect than doxorubicin. Docking simulations within the DNA double strands highlighted the role of both the heterocyclic core and the sugar side chain in exhibiting key H‐bond interactions with DNA bases. Employing the “sugar approach” design, new DNA intercalators bearing pharmacophoric motifs tethered to carbohydrate appendages were developed. The new rationally designed benzimidazole acyclic C‐nucleosides were synthesized and assayed for their cytotoxicity against breast cancer cells and normal fibroblasts. Compounds 7 and 13 were identified as the study hits for mechanistic studies, showing a more potent DNA‐damaging effect than doxorubicin.