A new series of benzoxazole-based SIRT1 modulators for targeted therapy of non-small-cell lung cancer


ARCHIV DER PHARMAZIE, vol.354, no.1, 2021 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 354 Issue: 1
  • Publication Date: 2021
  • Doi Number: 10.1002/ardp.202000235
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, BIOSIS, CAB Abstracts, Chimica, EMBASE, International Pharmaceutical Abstracts, MEDLINE, Veterinary Science Database
  • Keywords: apoptosis, benzimidazole, benzoxazole, molecular docking, non-small-cell lung cancer, SIRT1
  • Eskisehir Osmangazi University Affiliated: No


In an attempt to identify potential anticancer agents for non-small-cell lung cancer (NSCLC) targeting sirtuin 1 (SIRT1), the synthesis of a new series of benzoxazoles (3a - i) was carried out through a facile and versatile synthetic route. The compounds were evaluated for their cytotoxic effects on A549 human lung adenocarcinoma and NIH/3T3 mouse embryonic fibroblast cells using the MTT assay. 2-[(5-Nitro-1H-benzimidazol-2-yl)thio]-N-(2-methylbenzoxazol-5-yl)acetamide (3e) and 2-[(5-chloro-1H-benzimidazol-2-yl)thio]-N-(2-methylbenzoxazol-5-yl)acetamide (3g) were the most potent and selective anticancer agents in this series against the A549 cell line, with IC(50)values of 46.66 +/- 11.54 and 55.00 +/- 5.00 mu M, respectively. The flow cytometry-based apoptosis detection assay was performed to determine their effects on apoptosis in A549 cells. Both compounds induced apoptosis in a dose-dependent manner. The effects of compounds3eand3gon SIRT1 activity were determined. On the basis of in vitro studies, it was observed that compound3gcaused a significant decrease in SIRT1 levels in a dose-dependent manner, whereas compound3eincreased the SIRT1 levels. According to molecular docking studies, the substantial alteration in the type of action could be attributed to the difference between the interactions of compounds3eand3gwith the same residues in the active site of SIRT1 (PDB code: 4IG9). On the basis of in silico ADME (absorption, distribution, metabolism, and excretion) studies, these compounds are predicted to possess favorable ADME profiles. According to the in vitro and in silico studies, compounds3eand3g, small-molecule SIRT1 modulators, were identified as potential orally bioavailable anticancer agents for the targeted therapy of NSCLC.