title: Elucidation of the pharmacophore of echinocystic acid, a new lead for blocking HCV entry.
abstract: To elucidate the pharmacophore of echinocystic acid (EA), an oleanane-type triterpene displaying substantial inhibitory activity on HCV entry, two microbial strains, Rhizopus chinensis CICC 3043 and Alternaria alternata AS 3.4578, were utilized to modify the chemical structure of EA. Eight new metabolites with regio- and stereo-selective introduction of hydroxyl and lactone groups at various inert carbon positions were obtained. The anti-HCV entry activity of the metabolites 2-13, along with their parental compound EA and other analogs 14-15, were evaluated. Most of the metabolites showed no improvement but detrimental effect on potency except compound 5 and 6, which showed similar and even a litter higher anti-HCV entry activity than that of EA. The results demonstrated that ring A, B, C and the left side of ring E of EA are highly conserved, while ring D and the right side of ring E of EA are flexible. Introduction of a hydroxyl group at C-16 enhanced the triterpene potency. Further analysis indicated that the hemolytic effect of EA disappeared upon such modifications.
authors: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, 38 Xueyuan Road, Beijing 100191, China.
authors: Han
authors: H
authors: Wang
authors: Qi
authors: Q
authors: Wang
authors: Su-Long
authors: SL
authors: Xiao
authors: Fei
authors: F
authors: Yu
authors: Min
authors: M
authors: Ye
authors: Yong-Xiang
authors: YX
authors: Zheng
authors: Chuan-Ke
authors: CK
authors: Zhao
authors: Di-An
authors: DA
authors: Sun
authors: Li-He
authors: LH
authors: Zhang
authors: De-Min
authors: DM
authors: Zhou
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016174:Hepacivirus / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D008968:Molecular Conformation; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
chemical_list: D019380:Anti-HIV Agents; D009828:Oleanolic Acid; C022999:echinocystic acid