作为强效抗乙肝病毒药物的β-L-FD4C的双-S-酰基-2-硫代乙基（SATE）磷酸前药。

Bis-S-acyl-2-thioethyl (SATE)-bearing monophosphate prodrug of beta-L-FD4C as potent anti-HBV agent.

作者信息

Li X, Carmichael E, Feng M, King I, Doyle T W, Chen S H

机构信息

Vion Pharmaceuticals, Inc., New Haven, CT 06511, USA.

出版信息

Bioorg Med Chem Lett. 1998 Jan 6;8(1):57-62. doi: 10.1016/s0960-894x(97)10178-0.

DOI:10.1016/s0960-894x(97)10178-0

PMID:9871628

Abstract

The S-acyl-2-thioethyl (SATE)-bearing 5'-monophosphate prodrug of beta-L-FD4C (8) was synthesized and evaluated for its activity against HBV in the 2.2.15 cell line. This pronucleotide (8) exhibited an excellent inhibitory effect against HBV with an EC50 value that is more than eight fold lower than that of the parent nucleoside (4) under some assay conditions. It is also important to note that pronucleotide (8) was capable of inhibiting HBV replication by 90%; whereas its parent, beta-L-FD4C (4), could only inhibit virus replication no greater than 70% in the same assay. When evaluated in the standard cytotoxicity assay in CEM cell line, pronucleotide (8) exhibited an IC50 value of 52 microM, which was four times less toxic than parent beta-L-FD4C (4) (IC50 = 13 microM).

摘要

合成了β-L-FD4C（8）的含S-酰基-2-硫代乙基（SATE）的5'-单磷酸前药，并在2.2.15细胞系中评估了其抗乙肝病毒（HBV）的活性。在某些检测条件下，这种前体核苷酸（8）对HBV表现出优异的抑制效果，其半数有效浓度（EC50）值比母体核苷（4）低八倍多。同样重要的是要注意，前体核苷酸（8）能够抑制90%的HBV复制；而在相同检测中，其母体β-L-FD4C（4）只能抑制不超过70%的病毒复制。在CEM细胞系的标准细胞毒性检测中进行评估时，前体核苷酸（8）的半数抑制浓度（IC50）值为52微摩尔，其毒性比母体β-L-FD4C（4）（IC50 = 13微摩尔）低四倍。