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Antiproliferative activity and possible mechanism of action of certain 5-methoxyindole tethered C-5 functionalized isatins

Authors Almutairi MS, Hassan ES, Keeton AB, Piazza GA, Abdelhameed AS, Attia MI

Received 10 March 2019

Accepted for publication 19 August 2019

Published 27 August 2019 Volume 2019:13 Pages 3069—3078


Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 2

Editor who approved publication: Dr Sukesh Voruganti

Maha S Almutairi,1 Eman S Hassan,2 Adam B Keeton,3 Gary A Piazza,3 Ali S Abdelhameed,1 Mohamed I Attia1,4

1Department 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, Egypt

Correspondence: Mohamed I Attia
Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box. 2457, Riyadh 11451, Saudi Arabia
Tel +966 1 467 7337
Fax +966 1 467 6220

Background: 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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