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Facile Preparation of 4-Substituted Quinazoline Derivatives
Published on: February 15, 2016
Multi-Kinase Inhibition by New Quinazoline-Isatin Hybrids: Design, Synthesis, Biological Evaluation and Mechanistic
Mohammed M Alanazi1, Reem I Al-Wabli1
1Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.
Abstract:
Background/Objectives: Cancer is a worldwide health concern and is the second leading cause of death, responsible for nearly one in six deaths. Discovery of new anticancer agents is still a challenge for medicinal chemists and further research will improve patients' chances of survival. Protein kinases are among the most popular and successful biological targets for developing anticancer drugs. In this context, protein kinases were selected as targets, and a series of isatin-quinazoline hybrids were synthesized. Methods: Their antiproliferative activity was evaluated against four cancer cell lines (HepG2, MCF-7, MDA-MB-231, and HeLa) and one normal fibroblast cell line (WI38) using MTT assays. Results: The tested compounds showed variable cytotoxic effects on the four cancer cell lines. Compound 6c exhibited the most potent anticancer activity against all cancer cells. In addition, this compound was tested for the effect on the expression of anti-apoptotic Bcl-2 protein and pro-apoptotic proteins Bax, caspase-3, and caspase-9, which revealed induction of apoptosis similar to staurosporine. Furthermore, an annexin V-FITC/PI dual staining assay confirmed that compound 6c induced cell death by apoptosis. Flow cytometric analysis revealed that compound 6c induced cell cycle arrest at the sub-G1 and S phases in the HepG2 cell line. Moreover, compound 6c was found to be a multi-kinase inhibitor with potent inhibitory activity on CDK2, EGFR, VEGFR-2, and HER2, with IC50 values of 0.183 ± 0.01, 0.083 ± 0.005, 0.076 ± 0.004, and 0.138 ± 0.07 μM, respectively. Finally, a molecular docking simulation was conducted to predict possible binding interactions with the active site of CDK2. Conclusions: These findings suggest that compound 6c is a promising multi-kinase inhibitor with potent anticancer activity, warranting further investigation as a potential therapeutic agent.
Insights
A novel isatin-quinazoline hybrid, compound 6c, demonstrates potent anticancer activity by inhibiting multiple kinases and inducing apoptosis. This compound shows promise as a therapeutic agent for cancer treatment.
Area of Science:
- Medicinal Chemistry
- Molecular Biology
- Pharmacology
Background:
- Cancer remains a leading global cause of death, necessitating the development of novel anticancer agents.
- Protein kinases are validated targets for anticancer drug development.
- Isatin-quinazoline hybrids represent a class of compounds with potential therapeutic applications.
Purpose of the Study:
- To synthesize and evaluate a series of isatin-quinazoline hybrids as potential anticancer agents.
- To identify specific molecular targets and mechanisms of action for active compounds.
- To assess the therapeutic potential of lead compounds through in vitro assays and molecular simulations.
Main Methods:
- Synthesis of isatin-quinazoline hybrids.
- In vitro antiproliferative activity assessment using MTT assays against HepG2, MCF-7, MDA-MB-231, and HeLa cancer cell lines, and WI38 normal fibroblasts.
- Apoptosis induction analysis via Western blotting for Bcl-2, Bax, caspase-3, caspase-9, and Annexin V-FITC/PI staining.
- Cell cycle analysis using flow cytometry.
- In vitro kinase inhibition assays against CDK2, EGFR, VEGFR-2, and HER2.
- Molecular docking simulations against CDK2.
Main Results:
- Compound 6c exhibited significant antiproliferative activity across all tested cancer cell lines.
- Compound 6c induced apoptosis, evidenced by altered expression of apoptosis-related proteins and Annexin V/PI staining.
- Flow cytometry revealed that compound 6c causes cell cycle arrest at the sub-G1 and S phases in HepG2 cells.
- Compound 6c demonstrated potent multi-kinase inhibitory activity against CDK2, EGFR, VEGFR-2, and HER2 (IC50 values ranging from 0.076 to 0.183 μM).
- Molecular docking supported the binding interactions of compound 6c with the CDK2 active site.
Conclusions:
- Compound 6c is a potent multi-kinase inhibitor with significant anticancer properties.
- The mechanism of action involves the induction of apoptosis and cell cycle arrest.
- Compound 6c represents a promising lead candidate for further development as an anticancer therapeutic agent.
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