恩替卡韦4'-氨基酸酯化衍生物的合成及生物活性评价

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

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。

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. 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 and1 HNMR,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.