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Objective <p>The present study aimed to synthesize flavone hybrids with 3-methoxy substitution and an <i>N</i>-heterocyclic ring at the 4ʹ position of the flavone B ring and test their effectiveness against cancer.</p> Method <p>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, <i>N</i>-methyl piperazine, pyrrolidine, triazole, imidazole, and benzimidazole were synthesized. <sup>1</sup>HNMR, <sup>13</sup>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.</p> Results <p>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<sub>50</sub> values of 13.08 ± 1.80 and 20.3 ± 1.47&#xa0;µg/ml, respectively. The SRB assay on MDA-MB-231 showed a potent response by compounds Cii, Cv &amp; Cvi with IC<sub>50</sub> values of 5.54 ± 1.57, 5.44 ± 1.66 and 8.06 ± 1.83&#xa0;µg/ml, respectively. Overall results showed the effective substitution of 3-methoxy flavone was <i>N</i>-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.</p> Conclusion <p>This study provides a foundation for designing flavone derivatives with <i>N</i>-heterocyclic ring incorporation as anticancer medicines.</p>

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Design, synthesis, molecular docking and molecular dynamics studies of some 3-methoxy flavone derivatives as an anti-breast cancer agent

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月15日

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  • Bharti S. Fegade,
  • Somadatta Y. Chaudhari,
  • Rupali V. Likhar,
  • Ritesh P. Bhole,
  • Pravin S. Uttekar,
  • Sandeep S. Pathare,
  • Swastika Maitra,
  • Daniel Ejim Uti,
  • Magdi E. A. Zaki,
  • Esther Ugo Alum

摘要

Objective

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.

Method

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. 1HNMR, 13CNMR, 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.

Results

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 IC50 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 IC50 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.

Conclusion

This study provides a foundation for designing flavone derivatives with N-heterocyclic ring incorporation as anticancer medicines.