Ding Yuxin, Wang Enxiao, Xing Lin, Zhang Chaoyan, Sheng Ruilong, Wu Wenhui, Guo Ruihua
College of Food Science and Technology, Shanghai Ocean University, Shanghai 201306, China.
CQM - Centro de Química da Madeira, Universidade da Madeira, Campus da Penteada, 9000-390 Funchal, Portugal.
Bioorg Med Chem Lett. 2025 Aug 15;124:130261. doi: 10.1016/j.bmcl.2025.130261. Epub 2025 Apr 29.
Isosteviol is a tetracyclic diterpenoid from the hydrolysis of steviosidic acid, it exhibits a moderate inhibitory impact on tumor proliferation across various cancer types. Herein, we improved antitumor efficacy of isosteviol by modifying its reactive groups at C-16 and C-19 positions. A series of isosteviol derivatives 2-17, were synthesized and characterized. Their anti-proliferative activities were evaluated in three human cancer cell lines (HCT116, SKOV3 and HepG2) by CCK-8 assay. The results showed that derivative 10 has strong cancer cell inhibitory activities (with IC = 24.98 ± 1.82 μM for HCT116, IC = 26.15 ± 0.05 μM for SKOV3 and IC = 23.09 ± 0.31 μM for HepG2 cells). Accordingly, structure-activity relationships (SARs) of these isosteviol derivatives in ovarian cancer SKOV3 cells were discussed in detail. Moreover, derivative 10 has concentration-dependent cell cycle arrest at S-G2/M phases in SKOV3 cells, and it could greatly induce apoptosis. In addition, the targets of isosteviol against ovarian cancer were predicted and analyzed via network pharmacology. Then, molecular docking analysis showed that derivative 10 could interact with HSP90AA1 through its LYS-58 residues (docking energy: -8.96 kal/mol). The results suggested that derivative 10 might be employed as a promising drug candidate for anticancer chemotherapy.
异甜菊醇是甜菊糖苷酸水解产生的四环二萜类化合物，对多种癌症类型的肿瘤增殖具有中等抑制作用。在此，我们通过修饰异甜菊醇在C-16和C-19位的反应基团来提高其抗肿瘤疗效。合成并表征了一系列异甜菊醇衍生物2-17。通过CCK-8法在三种人癌细胞系（HCT116、SKOV3和HepG2）中评估了它们的抗增殖活性。结果表明，衍生物10具有很强的癌细胞抑制活性（对HCT116细胞的IC = 24.98 ± 1.82 μM，对SKOV3细胞的IC = 26.15 ± 0.05 μM，对HepG2细胞的IC = 23.09 ± 0.31 μM）。因此，详细讨论了这些异甜菊醇衍生物在卵巢癌SKOV3细胞中的构效关系（SARs）。此外，衍生物10在SKOV3细胞中能使细胞周期在S-G2/M期呈浓度依赖性阻滞，并且能极大地诱导细胞凋亡。另外，通过网络药理学预测并分析了异甜菊醇针对卵巢癌的靶点。然后，分子对接分析表明，衍生物10可通过其LYS-58残基与HSP90AA1相互作用（对接能量：-8.96千卡/摩尔）。结果表明，衍生物10可能是一种有前景且可用于抗癌化疗的候选药物。
