Design, synthesis and cytotoxic activity of spiro(oxindole-3-3'-pyrrolidine) derivatives
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CitationKonyar, D., Andac, C. A., & Buyukbingol, E. (2018). Design, Synthesis and Cytotoxic Activity of Spiro (oxindole-3-3'-pyrrolidine) Derivatives. Letters in Drug Design & Discovery, 15(1), 37-45.
Background: Spiro[pyrrolidine-3,3'-oxindole] compounds are reported to be highly bioactive natural and synthetic products. Initially, spirooxindole alkaloids were isolated from plants of the Apocynaceae and Rubiaceae families, which were found to have a common scaffold, spiro[pyrrolidine-3,3'-oxindole], exhibiting anticancer activities., we specifically aimed at the synthesis, characterization and anticancer activity of novel spiro[pyrrolidine-3,3'-oxindole] derivatives, compounds 6a-c and 7. Methods: The synthesis was initiated by Knovenegal condensation of indole-2-one with an appropriate benzaldehyde in presence of piperidine to afford compounds 3a-c. Compounds 6a-c were synthesized by an asymmetric 1,3-dipolar cycloaddition between compounds 3a-c and (2S, 3R)-2, 3, 5, 6-tetrahydro-2, 3-diphenyl-1, 4-oxazin-6-one, which is an intermediate compound formed by the Schiff base reaction between 3-methyl-butanal and (2S, 3R)-2, 3, 5, 6-tetrahydro-2, 3-diphenyl-1,4- oxazin-6-one, in presence of molecular sieves (4A) under argon atmosphere. Compound 6a was then reacted with ethylamine-HCl in THF at room temperature to yield compound 7. Results: Cytotoxic effects of the compounds synthesized were determined on Huh7, MV, HCT116 and MCF7 cancer cell lines by the NCI-60 Sulforhodamine B Assay, using (S)-(+)-Camptothecin as a positive control. In general, target compounds showed better cytotoxic activities against the MCF7 and HCT116 cancer cell lines. It was found that compound 7 exhibited the most potent inhibitory activity with IC50 values of 4.8 mu M, 3.9 mu M, 14.9 mu M and 8.2 mu M against the MCF7, HCT116, MV and Huh7 cell lines, respectively. Conclusion: It was determined that compounds 6a&6b possess C6'(S)|C8'(R)|C9'(R) stereochemistry and compound 7 adopts C2'(S)|C4'(R)|C5'(R) stereochemistry. Cytotoxicity studies suggest that compound 7 gave rise to the highest anticancer activity against MCF7, HCT116, and Huh7 cancer cell lines.