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Structural optimization of 4-(imidazol-5-yl)pyridine derivatives affords broad-spectrum anticancer agents with selective B-RAFV600E/p38α kinase inhibitory activity: Synthesis, in vitro assays and in silico study

Ali, Eslam M.H.; Mersal, Karim I.; Ammar, Usama M.; Zaraei, Seyed-Omar; Abdel-Maksoud, Mohammed S.; El-Gamal, Mohammed I.; Haque, Md Mamunul; Das, Tanuza; Kim, Eunice EunKyeong; Lee, Jun-Seok; Lee, Kwan Hyi; Kim, Hee-Kwon; Oh, Chang-Hyun

Authors

Eslam M.H. Ali

Karim I. Mersal

Seyed-Omar Zaraei

Mohammed S. Abdel-Maksoud

Mohammed I. El-Gamal

Md Mamunul Haque

Tanuza Das

Eunice EunKyeong Kim

Jun-Seok Lee

Kwan Hyi Lee

Hee-Kwon Kim

Chang-Hyun Oh



Abstract

In the current article, we introduce design of a new series of 4-(imidazol-5-yl)pyridines with improved anticancer activity and selective B-RAF V600E /p38α kinase inhibitory activity. Based on a previous work, a group of structural modifications were applied affording the new potential antiproliferative agents. Towards extensive biological assessment of the target compounds, an in vitro anticancer assay was conducted over NCI 60-cancer cell lines panel representing blood, lung, colon, CNS, skin, ovary, renal, prostate, and breast cancers. Compounds 7c, 7d, 8b, 9b, 9c, 10c, 10d, and 11b exhibited the highest potency among the tested compounds and demonstrated sub-micromolar or one-digit micromolar GI 50 values against the majority of the employed cell lines. Compound 10c emerged as the most potent agent with nano-molar activity over most of the cells and incredible activity against melanoma (MDA-MB-435) cell line (GI 50 70 nM). It is much more potent than sorafenib, the clinically used anticancer drug, against almost all the NCI-60 cell lines. Further cell-based mechanistic assays showed that compound 10c induced cell cycle arrest and promoted apoptosis in K562, MCF-7 and HT29 cancer cell lines. In addition, compound 10c induced autophagy in the three cancer cell lines. Kinase profiling of 10c showed its inhibitory effects and selectivity towards B-RAF V600E and p38α kinases with IC 50 values of 1.84 and 0.726 µM, respectively. Docking of compound 10c disclosed its high affinity in the kinases pockets. Compound 10c represent a promising anticancer agent, that could be optimized in order to improve its kinase activity aiming at developing potential anticancer agents. The conformational stability of compound 10c in the active site of B-RAF V600E and p38α kinases was studied by applying molecular dynamic simulation of the compound in the two kinases for 600 ns in comparison to the native ligands.

Journal Article Type Article
Acceptance Date Dec 17, 2021
Online Publication Date Jan 4, 2022
Publication Date 2022-04
Deposit Date Dec 11, 2022
Publicly Available Date Dec 12, 2022
Journal European Journal of Pharmaceutical Sciences
Print ISSN 0928-0987
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 171
Article Number 106115
DOI https://doi.org/10.1016/j.ejps.2022.106115
Keywords Anticancer, Imidazolylpyridine, BRAFV600E, p38α, Cell cycle arrest, Molecular modeling
Public URL http://researchrepository.napier.ac.uk/Output/2973611

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