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The objective of this study was to evaluate a dual action prodrug concept wherein an unnatural myristic acid analogue is coupled via an ester moiety to the 5’-position of FLT or AZT. Subsequent intracellular cleavage of the prodrug ester would simultaneously release FLT or AZT that could inhibit reverse transcriptase (RT), and the myristic acid analogue that could inhibit myristoyl- CoA:protein N-myristoyltransferase (NMT). Methods: Cytotoxicity (2.2.15 cell culture), and antihepatitis B activity of 5’-O-myristoyl analogue prodrug derivatives of FLT and AZT (2-8) were evaluated in vitro using human liver hepatitis B virus (HBV) producing 2.2.15 cell lines. Results: The 5’- O-(12-methoxydodecanoyl) ester derivatives of AZT (2, EC50 = 2.7 ± 0.3 mM; CC50 = 727 ± 19 mM) and FLT (4, EC50 = 2.8 ± 0.3 mM; CC50 = 186 ± 20 mM) were the most effective anti-hepatitis B virus (anti-HBV) compounds of this series in a replication assay. In the series of 5’-O-myristic acid analogue ester prodrug derivatives of FLT, the relative anti-HBV potency order was MeO(CH2)11CO2- > N3(CH2)11CO2- and Br(CH2)11CO2- > EtS(CH2)nCO2-(n = 10 or 11) > Me(CH2)12CO2- (myristoyl). Conclusions: The in vitro data suggest that the 5’-Omyristoyl analogue prodrug concept offers a potential drug design approach to design dual acting antiiviral agents, with superior pharmacokinetic, biodistribution, reduced cytotoxicity and/or increased efficacy. In this regard, the 5’-O-(12-methoxydodecanoyl) prodrug ester of 3’-thia-3’-deoxythymidine (3TC) may offer the greatest potential for the treatment of HBV infection.


This article was originally published in Journal of Pharmacy & Pharmaceutical Sciences, volume 1, issue 3, in 1998.


Canadian Society for Pharmaceutical Sciences



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