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Functionalized Spirocyclic Heterocycle Synthesis and Cytotoxicity Assay
Published on: February 9, 2021
Antitumor activity, multitarget mechanisms, and molecular docking studies of quinazoline derivatives based on a
Adel S El-Azab1, Alaa A-M Abdel-Aziz1, Nawaf A AlSaif1
1Department of Pharmaceutical Chemistry, College of Pharmacy, P.O. Box 2457, King Saud University, Riyadh 11451, Saudi Arabia.
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.
Insights
Substituted quinazolinones show significant antitumor potential, with compounds 3, 4, 9, and 10 demonstrating potent activity against cancer cell lines and key enzymes like COX-2 and EGFR. Further research is warranted for these promising anticancer agents.
Area of Science:
- Medicinal Chemistry
- Pharmacology
- Cancer Research
Background:
- Quinazolinone derivatives are recognized for their diverse biological activities.
- Developing novel anticancer agents with improved efficacy and specific targets remains a critical area of research.
- Understanding structure-activity relationships is key to designing effective therapeutics.
Purpose of the Study:
- To evaluate the in vitro cytotoxicity of novel substituted quinazolinones (compounds 1-15) against a panel of human cancer cell lines.
- To identify potent compounds and investigate their inhibitory effects on key enzymes involved in cancer progression, including COX-2, EGFR, HER2, and CDK9.
- To explore the mechanism of action for promising candidates through molecular docking studies.
Main Methods:
- Cytotoxicity was assessed using the National Cancer Institute (NCI) 59-cell line panel assay at 10 µM concentration.
- Enzymatic inhibitory assays were performed for selected potent compounds against COX-2, EGFR, HER2, and CDK9 kinases.
- Molecular docking simulations were conducted for compounds 3 and 4 with target enzymes (COX-2, EGFR, CDK9) to predict binding interactions.
Main Results:
- Compounds 3, 4, 7, 9, and 10 displayed significant antitumor activity, with positive cytotoxic effects (PCE) ranging from 17/59 to 44/59.
- Compounds 3, 4, 9, and 10 showed potent inhibition against EGFR, HER2, CDK9, and COX-2 enzymes.
- Compound 3 exhibited good COX-2 inhibition (IC50 = 0.775 μM), while compounds 4 and 9 demonstrated potent activity against EGFR and HER2 tyrosine kinases, comparable to reference drugs.
- Compound 4 showed comparable potency against CDK9 kinase (IC50 = 67.04 nM) to the reference dinaciclib.
- Compound 9 induced apoptosis in MCF-7 cells, inhibiting cell growth at the G2/M phase.
Conclusions:
- Novel substituted quinazolinones, particularly compounds 3, 4, and 9, exhibit significant in vitro anticancer potential.
- These compounds target key oncogenic pathways, including COX-2, EGFR, HER2, and CDK9, suggesting their promise as lead compounds for anticancer drug development.
- Molecular docking studies provide insights into the binding modes of active compounds with their respective targets.
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