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Facile Preparation of 4-Substituted Quinazoline Derivatives
Published on: February 15, 2016
Design, Synthesis, Antiproliferative Potency and In Silico Studies of Novel Alkynyl Quinazolines as Potential EGFR
Apostolia Gkoutzivelaki1, Sotiria-Iro Triantopoulou2, Lykourgos Chiniadis3
1Laboratory of Organic Chemistry, Department of Chemistry, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece.
Abstract:
The epidermal growth factor receptor (EGFR) is a highly attractive and promising target for novel anticancer agents, particularly for non-small-cell lung cancer (NSCLC), due to its crucial role in regulating cell survival and proliferation. Despite the development of first-generation reversible inhibitors like Gefitinib and Erlotinib, acquired resistance necessitated the discovery of highly potent irreversible inhibitors effective against drug-resistant mutants. Molecular docking calculations utilizing both EGFR conformations identified five top-ranked compounds (QN012, QN017, QN019, QN022, and QN023) proposed for synthesis and biological evaluation. These in silico studies predicted high inhibitory activity against the active and inactive state of EGFR. Herein, we report the design, synthesis and biological evaluation of novel 4-anilino quinazoline derivatives, bearing various alkynyl substituents at position 6, expected to bind to the hinge Met793 residue of EGFR. The effects of the derivatives on various cancer cell lines in terms of cytotoxic/cytostatic activity, interference with cell cycle phase distribution, and suppression of EGFR phosphorylation set the basis for the design of more potent derivatives.
Insights
Researchers designed and synthesized novel anticancer compounds targeting the epidermal growth factor receptor (EGFR) to overcome drug resistance in non-small-cell lung cancer (NSCLC). These new EGFR inhibitors show promise for treating resistant cancers.
Area of Science:
- Medicinal Chemistry
- Oncology
- Molecular Biology
Background:
- Epidermal growth factor receptor (EGFR) is a key target for non-small-cell lung cancer (NSCLC) therapies.
- First-generation EGFR inhibitors face acquired resistance, necessitating development of potent irreversible inhibitors.
- Drug-resistant EGFR mutants require novel therapeutic strategies.
Purpose of the Study:
- To design, synthesize, and evaluate novel 4-anilino quinazoline derivatives as potential anticancer agents.
- To identify compounds with high inhibitory activity against active and inactive EGFR states.
- To explore derivatives targeting the Met793 hinge region of EGFR.
Main Methods:
- In silico molecular docking studies to predict inhibitory activity.
- Synthesis of novel 4-anilino quinazoline derivatives with alkynyl substituents.
- Biological evaluation of synthesized compounds against cancer cell lines.
Main Results:
- Five top-ranked compounds (QN012, QN017, QN019, QN022, QN023) were identified via molecular docking.
- Predicted high inhibitory activity against both active and inactive EGFR conformations.
- Synthesized derivatives demonstrated cytotoxic/cytostatic activity and suppressed EGFR phosphorylation.
Conclusions:
- Novel 4-anilino quinazoline derivatives show potential as anticancer agents against EGFR-driven cancers.
- The synthesized compounds interfere with cancer cell proliferation and EGFR signaling.
- These findings provide a basis for designing more potent EGFR inhibitors for resistant NSCLC.
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