去氢胆酸肟类衍生物的设计、合成与体外抗乙肝病毒活性研究  

Design,synthesis and anti-HBV evaluation in vitro of oxime derivatives of dehydrocholic acid

作　　者：韦卓才 韦万兴[1] 崔新华[1] 谭洁[1] 周敏[1] WEI Zhuo-cai;WEI Wan-xing;CUI Xin-hua;TAN Jie;ZHOU Min(School of Chemistry and Chemical Engineering,Guangxi University,Nanning 530004,China)

机构地区：[1]广西大学化学化工学院,广西南宁530004

出　　处：《广西大学学报（自然科学版）》2018年第2期775-786,共12页Journal of Guangxi University（Natural Science Edition）

基　　金：国家自然科学基金资助项目(81060261);广西自然科学基金资助项目(2012GXNSFAA053021);广西壮族自治区教育厅广西高等学校高水平创新团队及卓越学者计划(2015年起)

摘　　要：为进一步研究新型抗乙肝病毒活性药物,根据活性片段拼接原理设计了一系列新型结构的去氢胆酸肟类衍生物,并预测其抗乙肝病毒活性。以去氢胆酸为原料经过酯化(或酰胺化)、肟化等反应合成8种新化合物和1种已知化合物,其中,肟类3种,肟醚类6种,均为E构型。以1H NMR、13C NMR和MS测定其结构,发现肟化反应均发生在去氢胆酸3位的羰基上。体外抗乙肝病毒活性测试结果表明部分目标产物对乙肝e型抗原HBe Ag的分泌具有抑制活性,其中,化合物2a和2c的活性较好,其半数抑制浓度IC50分别为170.36μmol/L和97.34μmol/L。初步分析化合物的构效关系,发现甲氧肟醚类化合物活性最好。研究结果为该类结构的新药的研究提供了理论依据。A series of new oxime derivatives of dehydrocholic acid(DHCA)were designed for new anti-HBV drugs according to assemble principles of active chemical fragments.The anti-HBV activities of target compounds were predicted by the Molecular Operating Environment(MOE)software.Nine target compounds with E-configuration were synthesized from DHCA by esterification(or amidation)and oximation.The structures were elucidated by 1 H NMR,13 C NMR and MS data.The data revealed that oximation reactions occurred on C-3 of DHCA.The results of anti-HBV eveluation showed that a part of target compounds displayed obvious inhibitory activities to HBeAg secretion.The IC 50 on HBeAg inhibition of compound 2a and 2c were respectively 170.36μmol/L and 97.34μmol/L.Preliminary structure-activity relationship study showed that methyl oxime ethers displayed better anti-HBV activities than the oximes and benzyl oxime ethers.The results provide a theoretical basis for the study of new drugs with this structure.

关 键 词：去氢胆酸 肟类衍生物 合成 抗乙肝病毒活性 

分 类 号：O629.22[理学—有机化学]