2. Academic Validation
  3. Antitumor activity, multitarget mechanisms, and molecular docking studies of quinazoline derivatives based on a benzenesulfonamide scaffold: Cell cycle analysis

Antitumor activity, multitarget mechanisms, and molecular docking studies of quinazoline derivatives based on a benzenesulfonamide scaffold: Cell cycle analysis

  • Bioorg Chem. 2020 Nov;104:104345. doi: 10.1016/j.bioorg.2020.104345.
Adel S El-Azab 1,  Alaa A-M Abdel-Aziz 2,  Nawaf A AlSaif 2,  Hamad M Alkahtani 2,  Mohammed M Alanazi 2,  Ahmad J Obaidullah 2,  Razan O Eskandrani 2,  Amal Alharbi 2
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, College of Pharmacy, P.O. Box 2457, King Saud University, Riyadh 11451, Saudi Arabia. Electronic address: [email protected].
  • 2 Department of Pharmaceutical Chemistry, College of Pharmacy, P.O. Box 2457, King Saud University, Riyadh 11451, Saudi Arabia.
PMID: 33142413 DOI: 10.1016/j.bioorg.2020.104345
Abstract

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 (IC50 = 0.775 μM) compared to the reference drug, celecoxib (IC50 = 0.153 μM). Compounds 4 and 9 were closely potent to the reference compounds against EGFR and (HER2) tyrosine kinases, with IC50 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 IC50 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 (IC50 = 67.04 nM) like the reference compound, dinaciclib (IC50 = 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.

Keywords

Apoptosis; CDK9 and COX-2 inhibitors; Cytotoxicity; EGFR and HER2 tyrosine kinase inhibitors; Quinazolinone derivatives.

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