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

Herein, regiospecific nucleophilic ring-opening of spiroaziridine oxindoles has been established to afford 3substituted-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 & PLUSMN; 0.36 and 6.64 & PLUSMN; 0.95 & mu;M, 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 & PLUSMN; 0.18 & mu;M. This inhibition of tubulin polymerase was further supported by binding interactions of 9c with tubulin through docking studies on PDB ID: 3E22.

Automated summary

In this study, regiospecific nucleophilic ring-opening of spiroaziridine oxindoles was performed to synthesize 3-substituted-thiooxindole derivatives as anticancer agents. Among the new compounds, 7d and 9c showed promising cytotoxic activity against HCT-116 cells with IC50 values of 6.73 ± 0.36 and 6.64 ± 0.95 μM, respectively. Further studies demonstrated significant alterations in nuclear and morphological characteristics, loss of mitochondrial membrane potential, and cell cycle arrest in G2-M phase for compound 9c. In addition, compound 9c exhibited tubulin polymerase inhibition with an IC50 value of 9.73 ± 0.18 μM, supported by docking interactions with tubulin.