用于抗丙型肝炎病毒（HCV）进入抑制剂的A环和/或C环扩展与开环海胆酸衍生物的合成及生物学评价
Synthesis and biological evaluation of ring A and/or C expansion and opening echinocystic acid derivatives for anti-HCV entry inhibitors.
作者信息
Wang Han, Yu Fei, Peng Yiyun, Wang Qi, Han Xu, Xu Renyang, Zhou Xiaoshu, Wan Chuanxing, Fan Zibo, Jiao Pingxuan, Zhang Yongmin, Zhang Lihe, Zhou Demin, Xiao Sulong
机构信息
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China; Medical Faculty of Kunming University of Science and Technology, Kunming 650500, China.
出版信息
Eur J Med Chem. 2015 Sep 18;102:594-9. doi: 10.1016/j.ejmech.2015.08.034. Epub 2015 Aug 18.
Echinocystic acid (EA), a naturally occurring oleanane-type triterpene isolated from Dipsacus asperoides, was found to have anti-HCV entry activity in our previous study. Expansion of triterpene structural diversity, including the ring A and/or C expansion and opening, was performed. To elucidate the pharmacophore of EA, seven lactones (8, 16, 17, 24, 26, 35 and 41), three 3,28-dioic acids (9, 36 and 42) and two pentols (10 and 27) were synthesized. The anti-HCV entry activities of those derivatives, along with their parental compound EA and analogs α,β-unsaturated ketone (18), were evaluated. All the products showed no improvement but detrimental effect on potency of EA. The results demonstrated that ring A and C of EA are highly conserved, indicating the steric effects of the rigid skeleton have a profound effect on the potency.
刺囊酸（EA）是从川续断中分离得到的一种天然齐墩果烷型三萜，在我们之前的研究中发现其具有抗丙型肝炎病毒（HCV）进入活性。我们进行了三萜结构多样性的扩展，包括A环和/或C环的扩展与开环。为阐明EA的药效团，合成了七种内酯（8、16、17、24、26、35和41）、三种3,28 - 二酸（9、36和42）以及两种戊醇（10和27）。评估了这些衍生物以及它们的母体化合物EA和类似物α,β - 不饱和酮（18）的抗HCV进入活性。所有产物均未显示出活性提高，反而对EA的效力有不利影响。结果表明，EA的A环和C环高度保守，这表明刚性骨架的空间效应对效力有深远影响。
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