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New Isatin–Indole Conjugates: Synthesis, Characterization, and a Plausible Mechanism of Their in vitro Antiproliferative Activity

Authors Al-Wabli RI, Almomen AA, Almutairi MS, Keeton AB, Piazza GA, Attia MI

Received 19 August 2019

Accepted for publication 9 January 2020

Published 3 February 2020 Volume 2020:14 Pages 483—495


Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 2

Editor who approved publication: Professor Jianbo Sun

Reem I Al-Wabli, 1 Aliyah A Almomen, 1 Maha S Almutairi, 1 Adam B Keeton, 2 Gary A Piazza, 2 Mohamed I Attia 1, 3

1Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; 2Department of Oncologic Sciences and Pharmacology, Drug Discovery Research Center, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604-1405, USA; 3Medicinal 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 +966-146-77337
Fax +966-146-76220

Background: Cancer remains the leading cause of human morbidity universally. Hence, we sought to assess the in vitro antiproliferative activity of new isatin-based conjugates ( 5a–s) against three human cancer cell lines.
Methods: The antiproliferative activities of compounds 5a–s were evaluated in vitro and their ADME (absorption, distribution, metabolism and excretion) was carried out using standard protocols. Subsequently, Western blot analysis was conducted to elucidate the potential antiproliferative mechanism of compounds 5a–s.
Results: The in vitro antiproliferative activities of compounds 5a–s against the tested cancer cell lines ranged from 20.3 to 95.9%. Compound 5m had an IC 50 value of 1.17 μM; thus, its antiproliferative potency was approximately seven-fold greater than that of sunitinib (IC 50 = 8.11 μM). In-depth pharmacological testing was conducted with compound 5m to gain insight into the potential antiproliferative mechanism of this class of compounds. Compound 5m caused an increase in the number of cells in the G1 phase, with a concomitant reduction of those in the G2/M and S phases. Additionally, compound 5m significantly and dose-dependently reduced the amount of phosphorylated retinoblastoma protein detected. Compound 5m enhanced expression of B cell translocation gene 1, cell cycle-associated proteins (cyclin B1, cyclin D1, and phosphorylated cyclin-dependent kinase 1), and a pro-apoptotic protein (Bcl-2-associated X protein gene), and activated caspase-3. ADME predictions exposed the oral liability of compounds 5a-s.
Conclusion: Herein, we revealed the antiproliferative activity and ADME predictions of the newly-synthesized compounds 5a–s and provided a detailed insight into the pharmacological profile of compound 5m. Thus, compounds 5a–s can potentially be exploited as new antiproliferative lead compounds for cancer chemotherapeutic.

Keywords: synthesis, isatin, indole, antiproliferative, cancer cell line

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