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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-HIV Agents / chemical synthesis*
  • Anti-HIV Agents / pharmacokinetics
  • Anti-HIV Agents / pharmacology*
  • CD4-Positive T-Lymphocytes / drug effects
  • CD4-Positive T-Lymphocytes / virology
  • Cell Line
  • Dideoxynucleosides / chemistry*
  • Dideoxynucleosides / pharmacology
  • HIV-1 / drug effects
  • HIV-1 / physiology
  • Half-Life
  • Magnetic Resonance Spectroscopy
  • Molecular Structure
  • Prodrugs / chemical synthesis*
  • Prodrugs / pharmacokinetics
  • Prodrugs / pharmacology*
  • Rats
  • Swine
  • Virus Replication / drug effects

Substances

  • Anti-HIV Agents
  • Dideoxynucleosides
  • Prodrugs
  • alovudine