Fegade Bharti S, Chaudhari Somadatta Y, Likhar Rupali V, Bhole Ritesh P, Uttekar Pravin S, Pathare Sandeep S, Maitra Swastika, Uti Daniel Ejim, Zaki Magdi E A, Alum Esther Ugo
Department of Pharmaceutical Chemistry, LSHGCT Gahlot Institute of Pharmacy, Koparkhairane, Navi Mumbai, Maharashtra, 400709, India.
Department of Pharmaceutical Chemistry, Modern College of Pharmacy, Sector 21, Yamuna Nagar, Nigdi, Pune, Maharashtra, 411044, India.
Discov Oncol. 2025 May 15;16(1):773. doi: 10.1007/s12672-025-02491-6.
The present study aimed to synthesize flavone hybrids with 3-methoxy substitution and an N-heterocyclic ring at the 4' 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. HNMR, 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 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 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.
本研究旨在合成在黄酮B环4'位具有3-甲氧基取代和N-杂环的黄酮杂化物，并测试它们对癌症的疗效。
研究了3-甲氧基黄酮在雌激素受体α（ER-α）和表皮生长因子受体（EGFR）上的分子对接。通过查尔酮环化反应合成了各种黄酮醇衍生物，并通过黄酮醇甲基化反应制备了3-甲氧基黄酮。合成了用吗啉、哌啶、N-甲基哌嗪、吡咯烷、三唑、咪唑和苯并咪唑等各种杂环取代的3-甲氧基黄酮衍生物。通过核磁共振氢谱（HNMR）、核磁共振碳谱（CNMR）、红外光谱（IR）和质谱对所有化合物的结构进行了验证。采用噻唑蓝（MTT）法和磺酰罗丹明B（SRB）法在乳腺癌细胞（MCF-7和MDA-MB-231）上评估3-甲氧基黄酮衍生物的抗癌潜力。还对活性化合物在人雌激素受体α和表皮生长因子受体上进行了分子动力学模拟研究。
成功合成了3-甲氧基黄酮衍生物，并通过光谱研究进行了评估。在MCF-7细胞系上进行的MTT试验显示，化合物Ciii和Civ具有显著的细胞毒性活性，其半数抑制浓度（IC）值分别为13.08±1.80和20.3±1.47μg/ml。在MDA-MB-231细胞上进行的SRB试验显示，化合物Cii、Cv和Cvi有较强的反应，其IC值分别为5.54±1.57、5.44±1.66和8.06±1.83μg/ml。总体结果表明，在所有细胞系中，3-甲氧基黄酮的有效取代基是N-甲基哌嗪和哌啶，而三唑取代在MDA-MB-231细胞中有效。分子动力学研究证明了合成化合物的配体-蛋白质复合物的稳定性。黄酮衍生物的构效关系表明，供电子基团增加了MDA-MB-231中衍生物的抗癌活性，而在MCF-7细胞系中未体现这一点。
本研究为设计含N-杂环的黄酮衍生物作为抗癌药物提供了基础。
