New series of isoxazole derivatives targeting EGFR-TK: Synthesis, molecular modeling and antitumor evaluation

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Cancer Research

Background:

• Developing novel antitumor agents is crucial for cancer therapy.
• Isoxazole derivatives represent a class of compounds with potential pharmacological activities.

Purpose of the Study:

• To synthesize and evaluate new isoxazole derivatives for in vitro antitumor activity.
• To identify potent and safe antitumor agents with specific molecular targets.

Main Methods:

• Synthesis of isoxazole derivatives.
• In vitro evaluation of antitumor activity against HepG2, MCF-7, and HCT-116 cancer cell lines.
• Cytotoxicity assessment against normal cells (WISH and WI38).
• Inhibition assays against EGFR-TK, VEGFR-2, CK2α, topoisomerase IIβ, and tubulin polymerization.
• Cell cycle analysis and apoptosis induction studies.
• Molecular docking studies.
• Analysis of Lipinski's rule and Veber's standards.

Main Results:

• Compounds 4b and 25a exhibited the most potent antitumor activity (IC50 = 6.38-9.96 μM).
• Compound 25a showed low cytotoxicity against normal cells and significant inhibitory activity against EGFR-TK, VEGFR-2, CK2α, and topoisomerase IIβ.
• Compound 25a induced cell cycle arrest at G2/M and pre-G1 phases, promoting apoptosis.
• Docking studies confirmed the binding of compound 25a to target proteins.
• Compound 25a is predicted to have good oral absorption.

Conclusions:

• The synthesized isoxazole derivatives, particularly compound 25a, show significant potential as antitumor agents.
• Compound 25a exhibits a favorable safety profile and multiple mechanisms of action, including enzyme inhibition and apoptosis induction.
• Further investigation of compound 25a is warranted for its development as a safe and effective cancer therapeutic.