Benzoxazole derivatives as new generation of anti-breast cancer agents

Area of Science:

• Medicinal Chemistry
• Molecular Biology
• Pharmacology

Background:

• Breast cancer remains a leading cause of mortality worldwide, necessitating novel therapeutic strategies.
• Targeting key signaling pathways like EGFR and ARO offers a promising approach for cancer treatment.

Purpose of the Study:

• To synthesize and evaluate novel 2-substituted benzoxazole derivatives for anti-cancer properties.
• To investigate the mechanism of action, including apoptosis induction and enzyme inhibition.

Main Methods:

• Synthesis of benzoxazole derivatives.
• In vitro screening for anti-proliferative and cytotoxic activities against various cancer cell lines (MCF-7, MDA-MB-231, A431, HCC827).
• Enzyme inhibition assays for wild-type and mutated EGFR, and aromatase (ARO).
• Apoptosis assays (caspase-9, Annexin V) and cell cycle analysis.
• Chemo-informatic analysis and molecular docking studies.

Main Results:

• Compounds 4b, 4d, and 11c demonstrated significant activity against MCF-7 cells.
• Compound 11c potently inhibited EGFR(WT), while 4b and 4d showed superior inhibition against EGFR(L858R) compared to erlotinib.
• Compounds 4a, 6c, and 8a were cytotoxic to MDA-MB-231 cells, with 4a and 6c showing moderate ARO inhibition.
• All tested compounds induced apoptosis and G2/M cell cycle arrest.
• Docking studies confirmed favorable binding interactions with EGFR and ARO enzymes.

Conclusions:

• Benzoxazole derivatives 11c and 6c are potent apoptosis-inducing anti-breast cancer agents.
• These compounds exert their effects through the inhibition of EGFR and ARO enzymes, respectively.
• The synthesized derivatives possess acceptable physicochemical properties for further drug development.