阿德福韦单L-氨基酸酯、单非甾体抗炎药羧酸酯前药的设计、合成与抗乙肝病毒活性研究  

Design,synthesis and anti-HBV evaluation of adefovir mono-L-amino acid ester,mono non-steroidal anti-inflammatory drugs carboxylic ester prodrugs

作　　者：傅晓钟[1] 王永林[1] 兰燕宇[1] 王爱民[1] 欧瑜[1] 罗春[1] 李燕[2] 

机构地区：[1]贵阳医学院药学院,贵州贵阳550004 [2]中国医学科学院、北京协和医学院药物研究所,北京100050

出　　处：《药学学报》2010年第8期1017-1024,共8页Acta Pharmaceutica Sinica

基　　金：贵州省科学技术基金资助项目(黔科合J字[2008]2140号)

摘　　要：为寻找新的抗乙肝病毒活性化合物,设计合成了新型阿德福韦单L-氨基酸酯、单非甾体药物羧酸酯衍生物。以阿德福韦双L-氨基酸酯为先导化合物,采用拼合设计原理在先导化合物膦酸基上引入非甾体抗炎药物结构片段,设计合成阿德福韦单L-氨基酸酯、单非甾体药物羧酸酯前药。采用HepG22.2.15细胞株进行化合物体外抗HBV活性评价。结果发现5个化合物显示不同程度抗HBV活性,其中化合物18活性最强、选择性指数较高(EC503.92μmol·L-1,SI9.97)。采用HK-2细胞模型评价了目标化合物的肾细胞毒性,结果发现目标化合物的肾细胞毒性均较阳性对照阿德福韦酯小。以上研究提示膦酸单L-氨基酸酯、单非甾体抗炎药物羧酸酯前药设计策略可适用于非环核苷膦酸的前药修饰,以期发现肾细胞毒性降低的有效抗HBV药物。A series of adefovir mono-L-amino acid esters,mono non-steroidal anti-inflammatory drugs carboxylic ester prodrugs with more potent anti-HBV activity and lower nephrotoxicity were designed and synthesized. Adefovir bis （L-amino acid） ester was used as lead compound,according to pathological and pharmacological findings that non-steroidal anti-inflammatory drugs can effectively inhibit the organic anion transporter 1 （hOAT1）-mediated adefovir phosphonic acid pairs of anion transport across tubular basement membrane thereby reducing the nephrotoxicity of adefovir. Flatten design principle was used to introducing non-steroidal anti-inflammatory drugs structural fragments to design and synthesize target adefovir mixture ester prodrugs. HepG2 2.2.15 cell line was used as in vitro anti-HBV activity evaluation model. Five compounds exhibited antiviral activity,and compound 18 showed the most potent anti-HBV activity and relatively high selective index （EC50 3.92 μmol·L-1,SI 9.97）. HK-2 cell line was used as in vitro model to evaluate nephrotoxicity. Results suggested the target compounds have lower cytotoxicity than the positive control. Moreover,by analyzing the primary structure and activity relationship of these compounds,it could suggest that mono-L-amino acid ester,mono non-steroidal anti-inflammatory drugs carboxylic ester prodrugs strategy has significant potential in the acyclic nucleoside phosphonates prodrug design.

关 键 词：非环核苷膦酸 L-氨基酸 非甾体抗炎药物 前药 

分 类 号：R916[医药卫生—药学]