Synthesis, Molecular Docking, and Anticancer Activity of N-Heteroaryl Substituted Flavon Derivatives

Abstract

Background: Flavones are potential anticancer agents that act by different mechanisms and have multiple targets to exert anticancer effects. Nitrogen-containing heterocyclic rings have remarkable chemical characteristics as well as a wide range of biological activities. Substitution of the N-heterocyclic ring on the flavon structure may potentiate its anticancer effect. Objective: A series of flavon derivatives with an N-heteroaryl ring at the 4' position of the B ring of flavon were designed, prepared, and evaluated for anticancer activity. Methods: Different flavon derivatives were created by cyclizing chalcones, and chalcones were synthesized by Claisen-Schmidt condensation of substituted aldehydes and 2-hydroxyacetophenone. Structures of all compounds were confirmed by 1HNMR, 13CNMR, FTIR, and MS spectra. Molecular docking was used to study the binding interactions of the synthesized compounds with the multiple targets ER-α, EGFR, and VEGFR-2. Anticancer activity was evaluated by Brine shrimp assay, MTT assay, and SRB assay on breast cancer (MCF-7, MDA-MB-231, and MDA-MB-468) and cervical cancer (HeLa). An apoptosis study was carried out on MCF-7 cell lines for the active compounds. Results: Among all compounds, 6c and 5f showed potent growth inhibition of ER-positive breast cancer cell lines. Compounds 5b, 5c, 5g, and 6f displayed good anticancer activity against cervical cancer. In triple-negative breast cancer cell lines, compounds 5c, 6b, and 6c showed remarkable anticancer activity. The potent flavones identified against breast cancer cell lines were 5f and 6c. Anticancer study results were analogous to the results obtained by the molecular docking study. Conclusion: This study offers a viable reference point for improving the design of flavon-incorporated Nheterocyclic ring derivatives as anticancer compounds.