Synthetic approaches, anticancer potential, HSP90 inhibition, multitarget evaluation, molecular modeling and apoptosis mechanistic study of thioquinazolinone skeleton: Promising antibreast cancer agent

Bioorg Chem. 2020 Aug:101:103987. doi: 10.1016/j.bioorg.2020.103987. Epub 2020 Jun 1.


New series of compounds bearing 2-thioquinazolinone scaffold were designed, synthesized as HSP90 inhibitors. Anti-proliferative activity of the synthesized compounds was evaluated against HCT-116, Hela and MCF-7 cell lines and compound 5k was found to be the most active member of the entire study with IC50 of 4.47, 7.55 and 4.04 μM, respectively, compared to DOX (IC50 of 5.23, 5.57 and 4.17 μM, respectively). Most of the tested compounds revealed lower cytotoxicity against normal fibroblast cells WI-38. Compounds 5b, 5k and 8a showed potent HSP90 inhibitory activities with IC50 values in nanomolar range; 71.32, 25.07 and 56.78 nm, respectively, against Tanespimycin (IC50 of 86.45 nm). Their HSP90 inhibitory activities were confirmed by their down regulation of HSP90 client protein Her2 and up regulation of chaperone HSP70 levels. Compound 5k had shown potent multi-target inhibitory activities against EGFR, VEGFR-2 and Topoisomerase-2 with IC50 values in nanomolar range; 38.5, 126.95 and 25.85 nm, respectively. Compound 5k was further evaluated for cell cycle distribution and apoptosis induction on MCF-7 cells using flow cytometry. Compound 5k arrested the cell cycle on MCF-7 at a G2/M phase by 35.06% and induced apoptosis by 19.82%. Mechanistic evaluation of apoptosis induction was studied by following ways triggering mitochondrial apoptotic pathway through inducing ROS accumulation, increasing Bax/Bcl-2 ratio and activation of caspases 6, 7 and 9. Comparative molecular modeling study was performed between active and inactive HSP90 inhibitors. Docking studies into the active site of HSP90 N-terminal domain showed good agreement with the obtained biological results. ADMET analysis and parameters of Lipinski's rule of five were calculated where compound 5k had reasonable drug-likeness with acceptable physicochemical properties so it could be used as promising orally absorbed antibreast targeted therapy.

Keywords: 2-Thioquinazoline-4-one; Anticancer activity; Apoptosis; HSP70; HSP90; Her2; Molecular modeling.

MeSH terms

  • Apoptosis
  • Breast Neoplasms / drug therapy*
  • Female
  • Humans
  • Molecular Structure
  • Quinazolines / pharmacology
  • Quinazolines / therapeutic use*
  • Structure-Activity Relationship


  • Quinazolines