Synthesis and computational insights of flavone derivatives as potential estrogen receptor alpha (ER-α) antagonist

Area of Science:

• Medicinal Chemistry
• Molecular Biology
• Pharmacology

Background:

• Hormone-related breast cancer is often driven by estrogen receptor alpha (ER-α) activity.
• Flavones are known to interact with ER-α, and structural modifications may enhance their anticancer potential.
• N-heterocyclic ring substitutions on flavones are explored to improve efficacy.

Purpose of the Study:

• To design, synthesize, and evaluate novel flavon derivatives with N-heterocyclic rings for in vitro breast cancer activity.
• To investigate the binding interactions of these compounds with ER-α using molecular docking and dynamics.
• To assess the anticancer efficacy and estrogen receptor binding potential of the synthesized compounds.

Main Methods:

• Synthesis of flavon derivatives via Claisen-Schmidt condensation and cyclization of chalcones.
• In vitro evaluation of breast cancer activity using MTT assay on MCF-7 cell lines.
• Molecular docking and molecular dynamics simulations to study protein-ligand complex stability and binding interactions with ER-α.

Main Results:

• Molecular docking indicated favorable binding scores for the tested compounds with ER-α.
• Molecular dynamics simulations revealed stable protein-ligand complexes with low binding energy.
• MTT assays identified PzF and IFL as the most potent compounds, exhibiting low IC50 values against MCF-7 cells.
• Estrogen receptor binding assays confirmed interactions between the compounds and ER-α.

Conclusions:

• The synthesized flavon derivatives, particularly PzF and IFL, exhibit significant in vitro anticancer activity against breast cancer cells.
• The N-heterocyclic ring modifications enhance the interaction with ER-α, suggesting a mechanism for their anticancer effects.
• These findings provide a foundation for developing novel flavon-based N-heterocyclic compounds as potential breast cancer therapeutics.