Synthesis, in vitro anti-human immunodeficiency virus structure-activity relationships and biological stability of 5'-O-myristoyl analogue derivatives of 3'-azido-2',3'-dideoxythymidine (AZT) as potential prodrugs.
5'-O-Myristoyl analogue derivatives of 3'-azido-2',3'-dideoxythymidine (AZT), designed as potential double-barrelled prodrugs to AZT and the myristic acid analogues, were synthesized. Their ability to protect CEM cells against human immunodeficiency virus (HIV)-induced cytopathogenicity was determined and structure-activity paradigms were developed. 3'-Azido-2',3'-dideoxy-5'-O-(4-oxatetradecanoyl)thymidine (EC50 = 1.4 nM) and 3'-azido-2',3'-deoxy-5'-O-(12-bromododecanoyl)thymidine (EC50 = 3.2 nM) were the most effective anti-HIV-1 agents, relative to AZT (EC50 = 10 nM). These myristoyl analogue derivatives were more lipophilic (calculated log P = 4.5-8.1 range) than the parent compound AZT (log P = 0.06), and a linear correlation between their log P and HPLC log retention times was observed. The ester cleavage half-lives (t1/2) for esters upon in vitro incubation with porcine liver esterase, rat plasma or rat brain homogenate was dependent on the steric bulk, and electronegative inductive effect of the alpha-substituent (H, Br, F), of the 5'-O-myristoyl analogue moiety. 3'-Azido-2',3'-dideoxy-5'-O-(11-(4-iodophenoxy) undecanoyl)-thymidine exhibited t1/2 values of 80.4, 3.7 and 150.0 min upon incubation with porcine liver esterase, rat plasma and rat brain homogenate, respectively.
Parang
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Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.
Wiebe
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Knaus
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D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000494:pharmacology; D002460:Cell Line; D004950:Esterases / Q000378:metabolism; D004952:Esters / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D015394:Molecular Structure; D009226:Myristates / Q000138:chemical synthesis / Q000494:pharmacology; D009705:Nucleosides / Q000138:chemical synthesis* / Q000494:pharmacology; D011355:Prodrugs / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D015215:Zidovudine / Q000031:analogs & derivatives*
D019380:Anti-HIV Agents; D000998:Antiviral Agents; D004952:Esters; D009226:Myristates; D009705:Nucleosides; D011355:Prodrugs; D015215:Zidovudine; D004950:Esterases