论文部分内容阅读
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。
In order to find a new anti-HBV active compound, a new adefovir dipivoxil L-amino acid ester and a single non-steroidal drug carboxylate derivative were designed and synthesized. Using adefovir dipivoxil L-amino acid ester as the lead compound, the non-steroidal anti-inflammatory drug structure fragment was introduced into the phosphonate group of the lead compound by the principle of split design, and the synthesis and synthesis of adefovir L-amino acid ester, Carboxylic acid ester prodrugs. HepG22.2.15 cell lines were used to evaluate the anti-HBV activity of the compounds in vitro. Five compounds showed different levels of anti-HBV activity. Compound 18 showed the strongest activity and higher selectivity index (EC503.92μmol·L-1, SI9.97). The cytotoxicity of the target compound was evaluated using the HK-2 cell model and found that the target compound had less renal cell toxicity than the positive control adefovir dipivoxil. The above studies suggest that phosphonic acid mono-L-amino acid esters, single non-steroidal anti-inflammatory drug carboxylate prodrug design strategy can be applied to prodrug modification of non-cyclic nucleoside phosphonic acid in order to find effective anti-HBV drugs with reduced renal cell toxicity .