恩替卡韦4′-氨基酸酯化衍生物的合成及生物活性评价

恩替卡韦是一种常用的治疗乙型肝炎病毒的拟核苷类药物,可以显著的抑制病毒HBV-DNA在人体内的复制水平,降低HBV-DNA在人体血浆中的含量;但临床实验表明恩替卡韦在人体中的口服生物利用度偏低,稳定性不好。选择性的合成了8种恩替卡韦4'-氨基酸酯化衍生物,以期提高其在体内的吸收效率;并保留其抗HBV活性。所有的化合物之前均未见报道,其结构经ESI-MS和1HNMR确证,同时其对于Caco-2细胞的膜渗透活性及其在HepG 2.2.15细胞中的抗HBV活性都在体外进行了进一步的评价。结果表明与恩替卡韦相比,所有的4'-氨基酸酯化衍生物的膜渗透活性都有一定程度的提高,同时化合物5c还表现出了与恩替卡韦相接近的抗HBV活性。

The Synthesis of Enticavir 4'-amino Acid Ester Derivatives and Biological Evaluation

Enticavir can significantly inhibit the replication of HBV-DNA, reduce the HBV-DNA level in blood serum.But because of it suffers from low oral bioacailability,enticavir has low intestinal membrane permeability and poor metablic stability.In this study,8 different types of enticavir amino acid ester derivatives were regioselective synthesized, in order to ameliorate their pharmacokinetic properties and remain their anti-HBV activity.All the compounds were reported firstly, the structure of the target compound was confirmed by means of ESI-MS and 1HNMR, and their apical-to-basolateral permeability across Caco-2 cells and HBV-DNA inhibitory efficacies in HepG 2.2.15 cells were evaluated.Most of the compounds showed highly permeability across Caco-2 cells compared with enticavir,and compounds 5c also exhibited comparable ant-HBV activity with that of enticavir, especially.