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Triazolo-linked benzimidazoles as tubulin polymerization inhibitors and DNA intercalators: Design, synthesis, cytotoxicity, and docking studies. | LitMetric

AI Article Synopsis

  • * Compound 12j had strong cytotoxic effects on SK-Mel-28 cancer cells, with an IC value of 4.17 µM, while being safe for normal BEAS-2B cells (IC > 100 µM).
  • * Mechanistic studies showed that 12j induced apoptosis and arrested cell growth in the G2/M phase, while also inhibiting tubulin polymerization and binding to tumor DNA, suggesting its effectiveness as a cancer treatment.

Article Abstract

A simple "click" protocol was employed in the quest of synthesizing 1,2,3-triazole-linked benzimidazoles as promising anticancer agents on various human cancer cell lines such as A549, HCT116, SK-Mel-28, HT-29, and MCF-7. Compound 12j demonstrated significant cytotoxic potential towards SK-Mel-28 cancer cells (IC : 4.17 ± 0.09 µM) and displayed no cytotoxicity (IC : > 100 µM) against normal human BEAS-2B cells inferring its safety towards normal healthy cells. Further to comprehend the underlying apoptosis mechanisms, AO/EB, dichlorodihydrofluorescein diacetate (DCFDA), and 4',6-diamidino-2-phenylindole (DAPI) staining were performed, which revealed the nuclear and morphological alterations. Compound 12j displayed impairment in cellular migration and inhibited colony formation. The annexin V binding assay and JC-1 were implemented to evaluate the scope of apoptosis and the loss of the mitochondrial transmembrane potential in SK-Mel-28 cells. Cell-cycle analysis revealed that compound 12j arrested the cells at the G2/M phase in a dose-dependent manner. Target-based assays established the inhibition of tubulin polymerization by 12j at an IC value of 5.65  ± 0.05 μM and its effective binding with circulating tumor DNA as a DNA intercalator. The detailed binding interactions of 12j with tubulin and DNA were examined by docking studies on PDB ID: 3E22 and DNA hexamer (PDB ID: 1NAB), respectively.

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Source
http://dx.doi.org/10.1002/ardp.202200449DOI Listing

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