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Tytuł:
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Antitumor activity, multitarget mechanisms, and molecular docking studies of quinazoline derivatives based on a benzenesulfonamide scaffold: Cell cycle analysis.
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Autorzy:
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El-Azab AS; Department of Pharmaceutical Chemistry, College of Pharmacy, P.O. Box 2457, King Saud University, Riyadh 11451, Saudi Arabia. Electronic address: .
Abdel-Aziz AA; Department of Pharmaceutical Chemistry, College of Pharmacy, P.O. Box 2457, King Saud University, Riyadh 11451, Saudi Arabia.
AlSaif NA; Department of Pharmaceutical Chemistry, College of Pharmacy, P.O. Box 2457, King Saud University, Riyadh 11451, Saudi Arabia.
Alkahtani HM; Department of Pharmaceutical Chemistry, College of Pharmacy, P.O. Box 2457, King Saud University, Riyadh 11451, Saudi Arabia.
Alanazi MM; Department of Pharmaceutical Chemistry, College of Pharmacy, P.O. Box 2457, King Saud University, Riyadh 11451, Saudi Arabia.
Obaidullah AJ; Department of Pharmaceutical Chemistry, College of Pharmacy, P.O. Box 2457, King Saud University, Riyadh 11451, Saudi Arabia.
Eskandrani RO; Department of Pharmaceutical Chemistry, College of Pharmacy, P.O. Box 2457, King Saud University, Riyadh 11451, Saudi Arabia.
Alharbi A; Department of Pharmaceutical Chemistry, College of Pharmacy, P.O. Box 2457, King Saud University, Riyadh 11451, Saudi Arabia.
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Źródło:
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Bioorganic chemistry [Bioorg Chem] 2020 Nov; Vol. 104, pp. 104345. Date of Electronic Publication: 2020 Oct 08.
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Typ publikacji:
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Journal Article; Research Support, Non-U.S. Gov't
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Język:
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English
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Imprint Name(s):
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Publication: Amsterdam : Elsevier
Original Publication: New York, London, Academic Press.
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MeSH Terms:
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Antineoplastic Agents/*pharmacology
Quinazolines/*pharmacology
Sulfonamides/*pharmacology
Antineoplastic Agents/chemical synthesis ; Antineoplastic Agents/chemistry ; Apoptosis/drug effects ; Cell Cycle/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Dose-Response Relationship, Drug ; Drug Screening Assays, Antitumor ; Humans ; Models, Molecular ; Molecular Structure ; Quinazolines/chemical synthesis ; Quinazolines/chemistry ; Structure-Activity Relationship ; Sulfonamides/chemistry ; Benzenesulfonamides
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Contributed Indexing:
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Keywords: Apoptosis; CDK9 and COX-2 inhibitors; Cytotoxicity; EGFR and HER2 tyrosine kinase inhibitors; Quinazolinone derivatives
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Substance Nomenclature:
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0 (Antineoplastic Agents)
0 (Quinazolines)
0 (Sulfonamides)
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Entry Date(s):
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Date Created: 20201104 Date Completed: 20210330 Latest Revision: 20231213
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Update Code:
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20240105
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DOI:
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10.1016/j.bioorg.2020.104345
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PMID:
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33142413
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The in vitro cytotoxicity of some substituted quinazolinones, 1-15, was evaluated using NCI (10 µM) in a full NCI 59-cell line panel assay. Relative to the reference drug, imatinib (PCE = 20/59), compounds 3, 4, 7, 9, and 10 exhibited remarkable antitumor activity against the tested cell lines, with positive cytotoxic effects (PCE) of 29/59, 18/59, 17/59, 44/59, and 24/59 respectively. Enzymatic inhibitory assay conducted on 3, 4, 9, and 10 as the most potent antitumor agents against EGFR, HER2 and CDK9 kinases, and COX-2 enzyme. Compound 3 possessed good COX-2 inhibitory activity (IC 50 = 0.775 μM) compared to the reference drug, celecoxib (IC 50 = 0.153 μM). Compounds 4 and 9 were closely potent to the reference compounds against EGFR and (HER2) tyrosine kinases, with IC 50 values of 90.17 (and 131.39 for HER2) for 4 and 145.35 (and 129.07 for HER2) nM for 9; the reference drugs in this case, namely, gefitinib and erlotinib, exhibited IC 50 values of 55.58 (90) and 110 (79.28) nM against the EGFR and (HER2) tyrosine kinases, respectively. Compound 4 was approximately similar potent against CDK9 kinase (IC 50 = 67.04 nM) like the reference compound, dinaciclib (IC 50 = 53.12 nM). Compound 9 induced cytotoxicity in the MCF-7 cell line (GI % at 10.0 μM = 47%) through pre-G1 apoptosis, thereby inhibiting cell growth at the G2/M phase. Molecular docking models of 3 and 4 with COX-2, EGFR, and CDK9 were conducted to determine their binding mode within the putative binding pockets.
(Copyright © 2020 Elsevier Inc. All rights reserved.)
