| Summary: | Maha S Almutairi,1 Eman S Hassan,2 Adam B Keeton,3 Gary A Piazza,3 Ali S Abdelhameed,1 Mohamed I Attia1,41Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; 2Department of Medical Laboratory Sciences, Al-Ghad International Medical Sciences College, Female Section, Riyadh 13315, Saudi Arabia; 3Department of Oncologic Sciences and Pharmacology, Drug Discovery Research Center, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604-1405, USA; 4Medicinal and Pharmaceutical Chemistry Department, Pharmaceutical and Drug Industries Research Division, National Research Centre (ID: 60014618), Giza 12622, EgyptCorrespondence: Mohamed I AttiaDepartment of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box. 2457, Riyadh 11451, Saudi ArabiaTel +966 1 467 7337Fax +966 1 467 6220Email mattia@ksu.edu.saBackground: Cancer is one of the most dreaded human diseases, that has become an ever-increasing health problem and is a prime cause of death globally. The potential antiproliferative activity of certain indole–isatin molecular hybrids 5a-w was evaluated in vitro against three human cancer cell lines.Methods: Standard protocols were adopted to examine the antiproliferative potential and mechanisms of compounds 5a-w. Western blot analysis was carried out on compound 5o.Results: Compounds 5a-w demonstrated in vitro antiproliferative activity in the range of 22.6–97.8%, with compounds 5o and 5w being the most active antiproliferative compounds with IC50 values of 1.69 and 1.91 μM, which is fivefold and fourfold more potent than sunitinib (IC50=8.11 μM), respectively. Compound 5o was selected for in-depth pharmacological testing to understand its possible mechanism of antiproliferative activity. It caused a lengthening of the G1 phase and a reduction in the S and G2/M phases of the cell cycle and had an IC50 value of 10.4 μM with the resistant NCI-H69AR cancer cell line. Moreover, compound 5o significantly decreased the amount of phosphorylated Rb protein in a dose-dependent fashion, which was confirmed via Western blot analysis.Conclusion: The current investigation highlighted the potential antiproliferative activity of compounds 5a-w as well as the antiproliferative profile of compound 5o. These compounds can be harnessed as new lead antiproliferatives in the preclinical studies of cancer chemotherapy.Keywords: isatin, indole, synthesis, antiproliferative, apoptosis
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