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 (4Å) 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 µM, 3.9 µM, 14.9 µM and 8.2 µM 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