Design, synthesis, molecular docking and molecular dynamics studies of some 3-methoxy flavone derivatives as an anti-breast cancer agent
Bharti Sachin Fegade, Somadatta Y. Chaudhari, Rupali Likhar, Ritesh Bhole, Pravin S. Uttekar, Sandeep S. Pathare, Swastika Maitra, Daniel Ejim Uti, Magdi E. A. Zaki, Esther Ugo Alum
Abstract
The present study aimed to synthesize flavone hybrids with 3-methoxy substitution and an N -heterocyclic ring at the 4ʹ position of the flavone B ring and test their effectiveness against cancer. Molecular docking of 3-methoxy flavone was studied on ER-α and EGFR. By cyclizing chalcones, various flavonol derivatives were synthesized and 3-methoxy flavones were produced by flavonol methylation. 3-methoxy flavone derivatives substituted with various heterocyclic rings like morpholine, piperidine, N -methyl piperazine, pyrrolidine, triazole, imidazole, and benzimidazole were synthesized. 1 HNMR, 13 CNMR, IR, and mass spectra verified all compound’s structures. 3-methoxy flavone derivatives evaluated for their anticancer potential by MTT assay and SRB assay on breast cancer (MCF-7 and MDA-MB-231). The molecular dynamics simulation was also studied for active compounds on the human estrogen receptor alpha and epidermal growth factor receptor. 3-methoxy flavone derivatives were successfully synthesized and evaluated by spectroscopic studies. The MTT assay on MCF-7 cell lines revealed significant cytotoxic activity of compounds Ciii and Civ by expressing IC 50 values of 13.08 ± 1.80 and 20.3 ± 1.47 µg/ml, respectively. The SRB assay on MDA-MB-231 showed a potent response by compounds Cii, Cv & Cvi with IC 50 values of 5.54 ± 1.57, 5.44 ± 1.66 and 8.06 ± 1.83 µg/ml, respectively. Overall results showed the effective substitution of 3-methoxy flavone was N -methyl piperazine and piperidine in all cell lines, while triazole substitution was effective in MDA-MB-231 cells. Molecular dynamics study proved the stability of synthesized compounds’ ligands-protein complexes. The structure–activity relationship of flavone derivatives suggests the electron donating group increases the anticancer activity of derivatives in MDA-MB-231, while the same is not reflected in MCF-7 cell lines. This study provides a foundation for designing flavone derivatives with N -heterocyclic ring incorporation as anticancer medicines.