Design and synthesis of novel 5-substituted acyclic pyrimidine nucleosides as potent and selective inhibitors of hepatitis B virus.

Abstract

A novel class of 5-substituted acyclic pyrimidine nucleosides, 1-[(2-hydroxyethoxy)methyl]-5-(1-azidovinyl)uracil (9a), 1-[(2-hydroxy-1-(hydroxymethyl)ethoxy)methyl]-5-(1-azidovinyl)uracil (9b), and 1-[4-hydroxy-3-(hydroxymethyl)-1-butyl]-5-(1-azidovinyl)uracil (9c), were synthesized by regiospecific addition of bromine azide to the 5-vinyl substituent of the respective 5-vinyluracils (2a-c) followed by treatment of the obtained 5-(1-azido-2-bromoethyl) compounds (3a-c) with t-BuOK, to affect the base-catalyzed elimination of HBr. Thermal decomposition of 9b and 9c at 110 degrees C in dioxane yielded corresponding 5-[2-(1-azirinyl)]uracil analogues (10b,c). The 5-(1-azidovinyl)uracil derivatives 9a-c were found to exhibit potent and selective in vitro anti-HBV activity against duck hepatitis B virus (DHBV) infected primary duck hepatocytes at low concentrations (EC(50) = 0.01-0.1 microg/mL range). The most active anti-DHBV agent (9c), possessing a [4-hydroxy-3-(hydroxymethyl)-1-butyl] substituent at N-1, exhibited an activity (EC(50) of 0.01-0.05 microg/mL) comparable to that of reference compound (-)-beta-L-2',3'-dideoxy-3'-thiacytidine (3-TC) (EC(50) = 0.01-0.05 microg/mL). In contrast, related 5-[2-(1-azirinyl)]uracil analogues (10b,c) were devoid of anti-DHBV activity, indicating that an acyclic side chain at C-5 position of the pyrimidine ring is essential for anti-HBV activity. The pyrimidine nucleosides (9a-c, 10b,c) exhibited no cytotoxic activity against a panel of 60 human cancer cell lines. All of the compounds investigated did not show any detectable toxicity to several stationary and proliferating host cell lines or to mitogen stimulated proliferating human T lymphocytes, up to the highest concentration tested.

• Authors: Rakesh Kumar, Mahendra Nath, D Lorne J Tyrrell
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 45 Issue 10 Pg. 2032-40 (May 09 2002) ISSN: 0022-2623 [Print] United States
• PMID: 11985471 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Antiviral Agents
• Pyrimidine Nucleosides
• DNA

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Antiviral Agents (chemical synthesis, chemistry, pharmacology, toxicity)
• Cell Division
• Cells, Cultured
• DNA (biosynthesis)
• Drug Screening Assays, Antitumor
• Ducks
• Hepatitis B Virus, Duck (drug effects)
• Hepatitis B virus (drug effects)
• Hepatocytes (drug effects, virology)
• Humans
• Pyrimidine Nucleosides (chemical synthesis, chemistry, pharmacology, toxicity)
• Structure-Activity Relationship
• T-Lymphocytes (cytology, drug effects, metabolism)