Issue 26, 2018

Substituted spirooxindole derivatives as potent anticancer agents through inhibition of phosphodiesterase 1

Abstract

Spirooxindole is a promising chemo therapeutic agent. Possible targets include cancers of the liver, prostate, lung, stomach, colon, and breast. Here, we demonstrate a one-pot three-component reaction via a [3 + 2] cycloaddition/ring contraction sequence of a dipolarophile (activated alkene) with in situ-generated azomethine ylide (1,3-dipoles) without the use of any catalyst. The reaction provides efficient access to synthetically useful and biologically important spirooxindoles in high yield (69–94%) with high diastereoselectivity. The synthesized compounds were subjected to cytotoxicity evaluation using colorectal cancer (HCT-116), hepatocellular carcinoma (HepG2), and prostate cancer (PC-3) cells. Compounds 4i, 4j, and 4k showed potent cytotoxic activity and high selectivity against HCT-116 cells when compared to cisplatin. Meanwhile compound 4d retained high cytotoxic activity and selectivity against HepG2 and PC-3 cells in comparison to cisplatin. The mechanism of compound 4d was further studied using phosphodiesterase 1 enzyme and showed 74.2% inhibitory activity. A possible binding mode for compound 4d to PDE-1 was investigated by molecular modeling using OpenEye software. Pose predictions for the active compounds were demonstrated by ROCS alignments. Compound 4d has a special geometry and differs from other active compounds.

Graphical abstract: Substituted spirooxindole derivatives as potent anticancer agents through inhibition of phosphodiesterase 1

Supplementary files

Article information

Article type
Paper
Submitted
17 mar 2018
Accepted
02 apr 2018
First published
17 apr 2018
This article is Open Access
Creative Commons BY license

RSC Adv., 2018,8, 14335-14346

Substituted spirooxindole derivatives as potent anticancer agents through inhibition of phosphodiesterase 1

A. Barakat, M. S. Islam, H. M. Ghawas, A. M. Al-Majid, F. F. El-Senduny, F. A. Badria, Y. A. M. M. Elshaier and H. A. Ghabbour, RSC Adv., 2018, 8, 14335 DOI: 10.1039/C8RA02358A

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