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愈创木烷倍半萜 ludartin 衍生物合成与抗 肝癌活性研究
Thesis Advisor陈纪军
KeywordLudartin 衍生物合成 Synthesis of ludartin derivatives, Antihepatoma activity, HepG2 cells, Huh7 cells 抗肝癌活性 HepG2 细胞 Huh7 细胞
Abstract肝细胞癌 (Hepatocellular carcinoma, HCC) 是最常见的原发性肝癌,严重危 害人类健康, 目前治疗肝细胞癌的药物有酪氨酸激酶抑制剂索拉非尼、 瑞格非尼、 乐伐替尼、 卡博替尼、 雷莫芦单抗以及免疫检查点抑制剂纳武单抗和帕姆单抗。 此外, 程序性死亡蛋白配体 1 (PD-L1) 抑制剂阿替利珠单抗联合抗血管生成药物 贝伐单抗、 纳武单抗联合伊匹单抗在治疗晚期或转移性肝细胞癌方面也有很好的 效果。 由于目前治疗肝细胞癌的药物化学结构和作用靶点较单一, 数量有限, 存 在价格昂贵,毒副作用明显等缺点, 仍需要开发结构新颖和作用机制不同的抗肝 癌药物。 天然产物对抗肿瘤药物的研发有重要作用, 我们研究组前期从野艾蒿 (Artemisia lavandulaefolia) 中分离得到的高含量愈创木烷倍半萜 ludartin 对 HepG2和Huh7细胞有中等强度的细胞毒活性, IC50值分别为32.7 μM和34.3 μM。 为了探讨 ludartin 的构效关系, 寻找结构新颖,活性显著的抗肝癌活性化合物, 对 ludartin 进行结构修饰,通过环氧开环、 酯化等反应合成了 39 个衍生物。 采用 MTT 法, 以索拉非尼为阳性对照, 测定了它们对 HepG2 和 Huh7 的细胞毒活性, 结果表明: 与 ludartin 相比, 18 个化合物对 HepG2 的细胞毒活性增强, 21 个化 合物对 Huh7 的细胞毒活性增强, 15 个化合物对这两株肝癌细胞的细胞毒活性均 增强, 活性增强 2~6 倍。 特别是对苯二甲酸相连的二酯化衍生物 2-37 和 2-39 是 活性最强的两个化合物, 化合物 2-37 对两株肝癌细胞的抑制活性比 ludartin 增强 20 倍和 17 倍,是索拉非尼的 5 倍, IC50 值分别为 1.6 μM 和 2.0 μM; 化合物 2-39 对两株肝癌细胞的抑制活性比 ludartin 增强 19 倍和 13 倍,是索拉非尼的 5 倍和 4 倍, IC50 值分别为 1.7 μM 和 2.6 μM。 Ludartin 衍生物抗肝癌活性的构效关系可 总结为: (1) 环氧开环得到的氟,氯和甲酸酯取代的衍生物活性增强; (2) 对 C-3 酯化衍生物, 酯侧链的取代基对活性有显著影响; (3) 引入 α, β-不饱和酰胺和芳 香族二酯化衍生物活性显著提高。 本研究初步揭示了 ludartin 衍生物对 HepG2 和 Huh7 细胞增殖的抑制活性的 构效关系, 特别是化合物 2-37 的活性优于 ludartin 和索拉非尼, 值得作为一种潜 在的抗肝癌先导化合物进一步研究。; Hepatocellular carcinoma (HCC) is the common primary liver cancer and seriously endangers human health. At present, the drugs for the treatment of hepatocellular carcinoma include tyrosine kinase inhibitors sorafenib, regafinib, lovatinib, cabotinib, ramoruzumab and immune checkpoint inhibitors navuzumab and pamumab. In addition, programmed death protein ligand 1 (PD-L1) inhibitor atilizumab combined with antiangiogenic drug bevacizumab, navuzumab combined with ipimab also have a good effect in the treatment of advanced or metastatic hepatocellular carcinoma. Currently, the chemical structure and action target of drugs for the treatment of hepatocellular carcinoma are relatively single, the number is limited, and there are some disadvantages, such as expensive price and obvious toxicity and side effects. Thus, it is still necessary to develop antihepatoma drugs with novel structure and different action mechanism. Natural products play an important role in the development of antitumor drugs. The high content of guaiacane sesquiterpene ludartin isolated from Artemisia lavandulaefolia in the early stage of our research group showed moderate cytotoxic activity against HepG2 and Huh7 cells, with IC50 values of 32.7 μM and 34.3 μM respectively. In order to explore the structure-activity relationship of ludartin and find novel active antihepatoma compounds with significant activity, the structure of ludartin was modified, and 39 derivatives were synthesized by epoxy ring opening and esterification. Using MTT assay and sorafenib as positive control, their cytotoxic activities against HepG2 and Huh7 were measured. The results showed that compared with ludartin, 18 compounds increased cytotoxic activities against HepG2, 21 compounds increased cytotoxic activities against Huh7, and 15 compounds had increased cytotoxic activities against these two hepatoma cells by 2~6 fold. In particular, terephthalate derivatives 2-37 and 2-39 were demonstrated with the highest activity. The inhibitory activity of compound 2-37 against two hepatoma cells is 20 fold and 17 fold higher than that of ludartin, 5 fold that of sorafenib, and the IC50 values are 1.6 μM and 2.0 μM respectively. The inhibitory activity of compound 2-39 against two hepatoma cells is 19 fold and 13 fold higher than that of ludartin, 5 fold and 5 fold higher than that of sorafenib, and the IC50 values are 1.7 μM and 2.6 μM, respectively. The structure-activity relationship of the antihepatoma activity ofAbstract IV ludartin derivatives can be summarized as follows: (1) the activity of fluorine, chlorine and formate substituted derivatives obtained by epoxy ring opening is enhanced; (2) For C-3 esterification products, the substituents of ester side chain generate a significant effect on the activity; (3) Introduce of α, β- unsaturated ketones and aromatic diesterification derivatives significantly improved the activity
Degree Grantor中国科学院大学
Document Type学位论文
Recommended Citation
GB/T 7714
孙金金. 愈创木烷倍半萜 ludartin 衍生物合成与抗 肝癌活性研究[D]. 中国科学院大学,2022.
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