3'-氟-2',3'-二脱氧胸苷（FLT）的5'-O-肉豆蔻酰类似物衍生物作为FLT潜在双功能前药的合成、体外抗HIV活性及生物稳定性

Synthesis, in vitro anti-HIV activity, and biological stability of 5'-O-myristoyl analogue derivatives of 3'-fluoro-2',3'-dideoxythymidine (FLT) as potential bifunctional prodrugs of FLT.

作者信息

Parang K, Knaus E E, Wiebe L I

机构信息

Faculty of Pharmacy, University of Alberta, Edmonton, Canada.

出版信息

Nucleosides Nucleotides. 1998 Jun;17(6):987-1008. doi: 10.1080/07328319808004216.

DOI:10.1080/07328319808004216

PMID:9708320

Abstract

A group of 5'-O-myristoyl analogue derivatives of FLT (2) were evaluated as potential anti-HIV agents that were designed to serve as prodrugs to FLT. 3'-Fluoro-2',3'-dideoxy-5'-O-(12-methoxydodecanoyl)thymidine (4) (EC50 = 3.8 nM) and 3'-fluoro-2',3'-dideoxy-5'-O-(12-azidododecanoyl)thymidine (8) (EC50 = 2.8 nM) were the most effective anti-HIV-1 agents. There was a linear correlation between Log P and HPLC Log retention time for the 5'-O-FLT esters. The in vitro enzymatic hydrolysis half-life (t1/2), among the group of esters (3-8) in porcine liver esterase, rat plasma and rat brain homogenate was longer for 3'-fluoro-2',3'-dideoxy-5'-O-(myristoyl)thymidine (7), with t1/2 values of 20.3, 4.6 and 17.5 min, respectively.

摘要

对一组FLT（2）的5'-O-肉豆蔻酰类似物衍生物进行了评估，它们被设计为FLT的前药，作为潜在的抗HIV药物。3'-氟-2'，3'-二脱氧-5'-O-（12-甲氧基十二烷酰基）胸苷（4）（EC50 = 3.8 nM）和3'-氟-2'，3'-二脱氧-5'-O-（12-叠氮基十二烷酰基）胸苷（8）（EC50 = 2.8 nM）是最有效的抗HIV-1药物。5'-O-FLT酯的Log P与HPLC保留时间对数之间存在线性关系。在猪肝脏酯酶、大鼠血浆和大鼠脑匀浆中，酯类（3-8）中3'-氟-2'，3'-二脱氧-5'-O-（肉豆蔻酰基）胸苷（7）的体外酶促水解半衰期（t1/2）较长，t1/2值分别为20.3、4.6和17.5分钟。