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

Assem Barakat; Mohammad Shahidul Islam; Hussien Mansur Ghawas; Abdullah Mohammed Al-Majid; Fardous F El-Senduny; Farid A Badria; Yaseen A M M Elshaier; Hazem A Ghabbour

doi:10.1039/c8ra02358a

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

RSC Adv. 2018 Apr 17;8(26):14335-14346. doi: 10.1039/c8ra02358a.

Authors

Assem Barakat^{1

2}, Mohammad Shahidul Islam¹, Hussien Mansur Ghawas¹, Abdullah Mohammed Al-Majid¹, Fardous F El-Senduny³, Farid A Badria⁴, Yaseen A M M Elshaier⁵, Hazem A Ghabbour^{6

7}

Affiliations

¹ Department of Chemistry, College of Science, King Saud University P. O. Box 2455 Riyadh 11451 Saudi Arabia ambarakat@ksu.edu.sa +966-11467-5992 +966-11467-5901.
² Department of Chemistry, Faculty of Science, Alexandria University P.O. Box 426, Ibrahimia Alexandria 21321 Egypt.
³ Department of Chemistry, Faculty of Science, Mansoura University Mansoura Egypt.
⁴ Department of Pharmacognosy, Faculty of Pharmacy, Mansoura University Mansoura 35516 Egypt.
⁵ Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Al-Azhar University Assuit 71524 Egypt.
⁶ Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University P. O. Box 2457 Riyadh 11451 Saudi Arabia.
⁷ Department of Medicinal Chemistry, Faculty of Pharmacy, University of Mansoura Mansoura 35516 Egypt.

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.