Regioselective synthesis and in vitro cytotoxicity evaluation of 3-thiooxindole derivatives: Tubulin polymerization inhibition and apoptosis inducing studies

  • Bioorg Med Chem. 2023 Jul 15:90:117297. doi: 10.1016/j.bmc.2023.117297.
Akash P Sakla  1 ,  Biswajit Panda  2 ,  Ashutosh Mahale  3 ,  Pravesh Sharma  3 ,  Kritika Laxmikeshav  1 ,  Mursalim Ali Khan  1 ,  Onkar Prakash Kulkarni  3 ,  Chandraiah Godugu  4 ,  Nagula Shankaraiah  5
Affiliations
  • 1. Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500037, India.
  • 2. Department of Biological Sciences (Regulatory Toxicology), National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500037, India.
  • 3. Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Hyderabad Campus, Hyderabad 500 078, India.
  • 4. Department of Biological Sciences (Regulatory Toxicology), National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500037, India. Electronic address: [email protected].
  • 5. Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500037, India. Electronic address: [email protected].
PMID: 37343499 DOI: 10.1016/j.bmc.2023.117297
Abstract

Herein, regiospecific nucleophilic ring-opening of spiroaziridine oxindoles has been established to afford 3-substituted-thiooxindole derivatives as Anticancer agents. Among the new series, compounds 7d and 9c exhibited promising cytotoxic activity toward HCT-116 cells with IC50 values of 6.73 ± 0.36 and 6.64 ± 0.95 µM, respectively. Further, AO/EB, DCFDA, and DAPI staining studies were executed to establish the underlying Apoptosis mechanism which displayed significant nuclear and morphological alterations. JC-1 staining and annexin V binding assay inferred the loss of mitochondrial membrane potential in HCT-116 Cancer cells. Cell cycle analysis showed the treatment of 9c against HCT-116 cells, arrested the cell cycle in G2-M phase. In addition, tubulin binding assay revealed that compound 9c exhibited tubulin polymerase inhibition with IC50 value of 9.73 ± 0.18 μM. This inhibition of tubulin polymerase was further supported by binding interactions of 9c with tubulin through docking studies on PDB ID: 3E22.

Keywords
3-Thiooxindoles; Anticancer; Apoptosis; Spiroaziridine oxindole; Tubulin polymerase inhibitors.