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)

Authors

Keykavous Parang, University of Rhode IslandFollow
Leonard I. Wiebe
Edward E. Knaus
Jyy-Shiang Huang
David L. Tyrrell

Document Type

Article

Date of Original Version

1998

Department

Medicinal Chemistry

Abstract

Purpose: 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 μM) and FLT (4, EC₅₀ = 2.8 ± 0.3 μM; CC₅₀ = 186 ± 20 μM) 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)₁₁CO_2- > N₃(CH₂)₁₁CO_2- and Br(CH₂)₁₁CO₂- > EtS(CH₂)_nCO₂-(n = 10 or 11) > Me(CH₂)₁₂CO_2- (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.

Citation/Publisher Attribution

Parang, K., Wiebe, L. I., Knaus, E. E., Huang, J., & Tyrrell, D. L. (1998). 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). J. Pharm. Pharmaceut. Sci., 1, 107-113.

Available at: http://www.ualberta.ca/~csps/JPPS1(3)/E.Knaus/hepatitis.htm