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

• Published in: RSC advances Vol. 8; no. 26; pp. 14335 - 14346
• Main Authors: Barakat, Assem, Islam, Mohammad Shahidul, Ghawas, Hussien Mansur, Al-Majid, Abdullah Mohammed, El-Senduny, Fardous F, Badria, Farid A, Elshaier, Yaseen A. M. M, Ghabbour, Hazem A
• Format: Journal Article
• Language: English
• Published: England Royal Society of Chemistry 17-04-2018; The Royal Society of Chemistry
• Subjects: Alkenes; Anticancer properties; Cancer; Chemical compounds; Chemistry; Colon; Cycloaddition; Cytotoxicity; Liver; Pharmacology; Prostate; Selectivity; Stomach; Toxicity
• ISSN: 2046-2069; 2046-2069
• DOI: 10.1039/c8ra02358a

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.
Spirooxindole is a promising chemo therapeutic agent. Possible targets include cancers of the liver, prostate, lung, stomach, colon, and breast.