title: In vitro anti-hepatitis B virus activities of 5"-O-myristoyl analogue derivatives of 3"-fluoro-2",3"-dideoxythymidine (FLT) and 3"-azido-2",3"-dideoxythymidine (AZT).
abstract: OBJECTIVE
  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 anti-hepatitis 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, EC(50) = 2. 7 +/- 0.3 microM; CC(50)= 727 +/- 19 microM) and FLT (4, EC(50)= 2.8 +/- 0.3 microM; CC(50)= 186 +/- 20 microM) 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(CH(2))(11)CO(2)- > N(3)(CH(2))(11)CO(2)- and Br(CH(2))(11)CO(2)- > EtS(CH(2))(n)CO(2)- (n = 10 or 11) > Me(CH(2))(12)CO(2)- (myristoyl).
  
  
  CONCLUSIONS
  The in vitro data suggest that the 5'-O-myristoyl analogue prodrug concept offers a potential drug design approach to design dual acting antiviral 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.
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: K
authors.initials: K
authors.lastname: Parang
authors.forename: L I
authors.initials: LI
authors.lastname: Wiebe
authors.forename: E E
authors.initials: EE
authors.lastname: Knaus
authors.forename: J S
authors.initials: JS
authors.lastname: Huang
authors.forename: D L
authors.initials: DL
authors.lastname: Tyrrell
mesh_terms: D000217:Acyltransferases / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D002460:Cell Line; D015224:Dideoxynucleosides / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D006515:Hepatitis B virus / Q000187:drug effects*; D006801:Humans; D020128:Inhibitory Concentration 50; D009226:Myristates / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D011355:Prodrugs / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D013329:Structure-Activity Relationship; D014779:Virus Replication; D015215:Zidovudine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity
chemical_list: D000998:Antiviral Agents; D015224:Dideoxynucleosides; D004791:Enzyme Inhibitors; D009226:Myristates; D011355:Prodrugs; D018894:Reverse Transcriptase Inhibitors; D015215:Zidovudine; D000217:Acyltransferases; C050480:glycylpeptide N-tetradecanoyltransferase; C002854:alovudine