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

Keykavous Parang, Edward E. Knaus, Leonard I. Wiebe

Research output: Contribution to journalArticlepeer-review

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 (t(1/2)), 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 t(1/2) values of 20.3, 4.6 and 17.5 min, respectively.

Original languageEnglish (US)
Pages (from-to)987-1008
Number of pages22
JournalNucleosides and Nucleotides
Volume17
Issue number6
StatePublished - 1998
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Genetics

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