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.
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.
Faculty of Pharmacy, University of Alberta, Edmonton, Canada.
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Parang
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Knaus
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Wiebe
D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000821:virology; D002460:Cell Line; D015224:Dideoxynucleosides / Q000737:chemistry* / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology; D006207:Half-Life; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D011355:Prodrugs / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D013552:Swine; D014779:Virus Replication / Q000187:drug effects
D019380:Anti-HIV Agents; D015224:Dideoxynucleosides; D011355:Prodrugs; C002854:alovudine