新型非环核苷膦酸L-氨基酸酯类化合物的设计、合成与抗乙型肝炎病毒活性  

Design,synthesis and anti-HBV activity of L-amino acid ester prodrugs of acyclic nucleoside phosphonates

作　　者：傅晓钟[1] 江赛红[2] 杨玉社[2] 嵇汝运[2] 

机构地区：[1]贵阳医学院药学院,贵州贵阳550004 [2]中国科学院上海生命科学研究院上海药物研究所,新药研究国家重点实验室,上海201203

出　　处：《药学学报》2008年第5期495-503,共9页Acta Pharmaceutica Sinica

摘　　要：设计合成具有抗乙型肝炎病毒活性的非环核苷膦酸双L-氨基酸酯系列衍生物。以adefovir dipivoxil为先导化合物,根据核苷L-氨基酸酯前药提高生物利用度及抗病毒活性的研究结果对先导化合物进行结构优化,设计并合成一系列新型非环核苷膦酸双L-氨基酸类化合物,确定其结构,并通过测定其对HepG2 2.2.15细胞分泌的HBV-DNA的抑制作用评价其体外抗病毒活性。结果发现8个adefovir双L-氨基酸类化合物可显示不同程度活性,其中化合物11的抗病毒活性最强、选择性指数最高(EC500.095 2μmol.L-1,SI 69523)。以上研究提示L-氨基酸酯策略可适用于非环核苷膦酸的前药修饰,以期发现有效抗HBV药物。To design and synthesis a series of novel L-amino acid esters prodrugs of acyclic nucleoside phosphonates with more potent anti-HBV activity, adefovir dipivoxil was used as lead compound, according to the results of enhanced oral bioavailability and antiviral activities of nucleoside L-amino acid ester prodrugs. Eleven novel L-amino acid ester prodrugs of acyclic nucleoside phosphonates were designed and synthesized, their anti-HBV activities were evaluated in HepG2 2.2.15 cells. Eight compounds exhibited antiviral activity, and compound 11 showed the most potent anti-HBV activity and highest selective index in vitro （EC50 0. 095 2 μmol · L^-1, SI 69523）. Moreover, by analyzing the primary structure and activity relationship of these compounds, it could be suggested that L-amino acid ester strategy has significant potential in the acyclic nucleoside phosphonates prodrug design.

关 键 词：非环核苷膦酸 L-氨基酸 前药 

分 类 号：R916.2[医药卫生—药学]