Synthesis of novel spirooxindole-pyrrolidines and evaluation of their cytotoxic activity

Abstract

Background: A variety of spirooxindoles have demonstrated cytotoxic activity toward several cancer cell lines. This study investigates the cytotoxicity of five novel spirooxindole-pyrrolidines by using the Vero and HeLa cell lines.

Methods: Vero and HeLa cells were treated with the synthesized spirooxindoles, and the cytotoxicity was evaluated by using the AlamarBlue Cell Viability Reagent and live/dead assay.

Results: A series of poly-substituted pyrrolidines differing in nature and in substituent positions were obtained, with yields of 42-63%. Of the synthesized cycloadducts, 3-picolinoyl-4-(2,4-dichlorophenyl)-5-phenylspiro[indoline-3,2'-pyrrolidine]-2'-one (4) was the most cytotoxic (IC₅₀ < 20 μg/ml for both cell lines). Besides, 3-picolinoyl-4-(2-chlorophenyl)-5-phenylspiro[indoline-3,2'-pyrrolidine]-2'-one (1) was three times more toxic to the HeLa cancer cell line (IC₅₀ = 70 μg/ml) than it was to the Vero healthy cell line. The cytotoxicity of compounds 1 and 4 was confirmed with a live/dead assay. The cytotoxicity of a molecule was found to depend on the substitution nature on the benzene ring at the C-4 atom.

Conclusion: 3-Picolinoyl-4-(2-chlorophenyl)-5-phenylspiro[indoline-3,2'-pyrrolidine]-2'-one (1) can be used as a source for the synthesis of novel therapeutic agents against cancer.

Keywords: 1,3-dipolar cycloaddition; Azomethine ylide; Cytotoxicity; HeLa; Spirooxindole-pyrrolidines.