Guaianolide二聚体代表了一类独特的具有抗癌活性的天然产物,但是它们在植物中的低含量限制了深入的药理学研究。LavandiolideI是从蒿属物种中分离出的愈创醇内酯二聚体,并以十克的规模分四步合成,总收率为60%,它对HepG2、Huh7和SK-Hep-1细胞系显示出有效的抗肝癌活性,IC50值为12.1、18.4和17.6µM,分别。为了探索更活跃的二聚体,设计了33种lavandiolideI衍生物,合成,并评估其对人肝癌细胞系的抑制活性。其中,10种衍生物在三种细胞系上比lavandiolideI和索拉非尼更具活性。一级结构-活性关系得出结论,醛的引入,酯,叠氮化物,酰胺,愈创木内酯二聚体C-14上的氨基甲酸酯和脲官能团显着增强了抗肝癌活性。在这些化合物中,衍生物25、27和33的抗肝癌活性比lavandiolideI增强1.2-5.8倍以上,并显示出对人类肝细胞系(THLE-2)的低毒性和良好的安全性,选择性指数在1.3至3.4之间,而lavandiolideI对THLE-2细胞的毒性更大。这项工作为提高抗肝癌疗效和降低倍半萜二聚体的毒性提供了新的见解。
Guaianolide dimers represent a unique class of natural products with anticancer activities, but their low content in plants has limited in-depth pharmacological studies. Lavandiolide I is a guaianolide dimer isolated from Artemisia species, and had been synthesized on a ten-gram scale in four steps with 60 % overall yield, which showed potent antihepatoma activity on the HepG2, Huh7, and SK-Hep-1 cell lines with IC50 values of 12.1, 18.4, and 17.6 µM, respectively. To explore more active dimers, 33 lavandiolide I derivatives were designed, synthesized, and evaluated for their inhibitory activity on human hepatoma cell lines. Among them, 10 derivatives were more active than lavandiolide I and sorafenib on the three cell lines. The primary structure-activity relationship concluded that the introduction of aldehyde, ester, azide, amide, carbamate and urea functional groups at C-14\' of the guaianolide dimer significantly enhanced the antihepatoma activity. Among these compounds, derivatives 25, 27, and 33 enhanced antihepatoma activity more than 1.2-5.8 folds than that of lavandiolide I, and demonstrated low toxicity to the human liver cell lines (THLE-2) and good safety profiles with selective index ranging from 1.3 to 3.4, while lavandiolide I was more toxic to THLE-2 cells. This work provides new insights into enhancing the antihepatoma efficacy and reducing the toxicity of sesquiterpenoid dimers.