Publication: Design, synthesis, and biological evaluation of new pyrimidine-5-carbonitrile derivatives as novel anti-cancer, dual EGFR WT/COX-2 inhibitors with docking studies
Design, synthesis, and biological evaluation of new pyrimidine-5-carbonitrile derivatives as novel anti-cancer, dual EGFR WT/COX-2 inhibitors with docking studies
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Publisher DOI
10.1039/d3ra06088h
Date
2023-11-02
Type
Article
Authors
Reda, Nada
Elshewy, Ahmed
EL-Askary, Hesham I.
Mohamed, Khaled O.
Helwa, Amira A.
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Publisher
Royal Society of Chemistry
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Source
https://pubs.rsc.org/en/content/articlehtml/2023/ra/d3ra06088h
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Abstract
A novel series of pyrimidine-5-carbonitrile derivatives was designed, synthesized, then evaluated for their cytotoxic activity as novel anti-cancer with dual EGFRWT/COX-2 inhibitors. Two compounds 4e and 4f disclosed the highest activity against all NCI60 panel cell lines. They were most potent against Colo 205 (IC50 = 1.66, and 1.83 μM), Sequentially. The most potent two compounds disturbed cell cycle of Colo-205 cells by blocking the G1 phase, coupled with increased annexin-Vstained cells which indicated the increasing in percentage of apoptosis. In addition, 4e and 4f increase the concentration of caspase-3 by 10, and 8-fold compared to control, respectively. Moreover, the two candidate compounds were screened for cytotoxicity on normal epithelial colon cells; fortunately, they were found to be safe. Molecular docking study displayed that these compounds bound to the active site as EGFRWT/COX-2 inhibitors. Furthermore, 3D pharmacophore mapping disclosed many shared features between the most potent candidates 4e and 4f and the standard EGFRWT/COX-2 inhibitors; erlotinib, and celecoxib, respectively. Finally, the physicochemical parameter was calculated for the most potent novel anticancer candidates and the SwissAdme parameter showed that the newly synthesized compounds have good drug-likeness properties.
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Keywords
Molecular, Pharmacophore, Physicochemical
Citation
Di Reda, N., Elshewy, A., El‐Askary, H. I., Mohamed, K. O., & Helwa, A. A. (2023, January 1). Design, synthesis, and biological evaluation of new pyrimidine-5-carbonitrile derivatives as novel anti-cancer, dual EGFRWT/COX-2 inhibitors with docking studies. RSC Advances. https://doi.org/10.1039/d3ra06088h
Journal Title
RSC Advances
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Volume
13
Issue
46
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© 2023 by the authors. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license.