Cui Hongjuan, Zhao Yan, Li Wei, Cui Huanjie, Han Jiahong, Cai Enbo
College of Chinese Medicinal Material, Jilin Agricultural University, 2888 Xincheng Street, Changchun 130118, China.
Int J Mol Sci. 2025 May 30;26(11):5280. doi: 10.3390/ijms26115280.
Formononetin is widely used in anti-tumor research, but its poor water solubility leads to low absorption and poor utilization efficiency in vivo, limiting further development. The triphenylphosphine cation was partially attached to the 7-position hydroxyl group of formononetin to specifically target it into the mitochondria of tumor cells to enhance the anti-tumor effect. Detailed structural characterization via H-NMR and C-NMR analysis confirmed the physical properties and chemical structures of 21 newly synthesized derivatives. The effects of these derivatives on tumor cells were assessed by in vitro and computational methods. MTT results from four tumor cell lines showed that formononetin derivatives containing triphenylphosphine had stronger anti-tumor activity than formononetin and exhibited more cytotoxic effects in cancer cells than in normal cells. In particular, the final product 2c (IC = 12.19 ± 1.52 μM) showed more potent anti-tumor activity against A549 cells. It was also superior to formononetin and 5-FU. To identify the potential biological targets, the core-expressed gene in lung cancer mitochondria was screened using network pharmacology technology, and molecular docking analysis confirmed the stable binding of the end products to the amino acid residues of the core genes through the formation of hydrogen bonds and via other interactions. In addition, molecular docking simulations further confirmed that the end product exhibited excellent stability when bound to . These results suggest that triphenylphosphine-containing formononetin derivatives are worthy of further exploration in the search for novel drug candidates for the treatment of cancer.
大豆苷元广泛应用于抗肿瘤研究，但其水溶性差导致体内吸收低且利用效率不佳，限制了其进一步发展。将三苯基膦阳离子部分连接到大豆苷元的7位羟基上，使其特异性靶向进入肿瘤细胞的线粒体以增强抗肿瘤效果。通过氢核磁共振（H-NMR）和碳核磁共振（C-NMR）分析进行的详细结构表征证实了21种新合成衍生物的物理性质和化学结构。通过体外和计算方法评估了这些衍生物对肿瘤细胞的影响。来自四种肿瘤细胞系的MTT结果表明，含三苯基膦的大豆苷元衍生物比大豆苷元具有更强的抗肿瘤活性，并且在癌细胞中比在正常细胞中表现出更多的细胞毒性作用。特别是，最终产物2c（IC = 12.19 ± 1.52 μM）对A549细胞显示出更强的抗肿瘤活性。它也优于大豆苷元和5-氟尿嘧啶（5-FU）。为了确定潜在的生物学靶点，使用网络药理学技术筛选了肺癌线粒体中的核心表达基因，分子对接分析证实了终产物通过形成氢键和其他相互作用与核心基因的氨基酸残基稳定结合。此外，分子对接模拟进一步证实终产物与……结合时表现出优异的稳定性。这些结果表明，含三苯基膦的大豆苷元衍生物在寻找治疗癌症的新型候选药物方面值得进一步探索。
