Use of 2'-fluoro-5-methyl-beta-L-arabinofuranosyluracil as a novel antiviral agent for hepatitis B virus and Epstein-Barr virus

Abstract

A novel anti-hepatitis B virus (anti-HBV) agent, 2-fluoro-5-methyl-␤-L-arabinofuranosyluracil (L-FMAU), was synthesized and found to be a potent anti-HBV and anti-Epstein-Barr virus agent. Its in vitro potency was evaluated in 2.2.15 and H1 cells for anti-HBV and anti-Epstein-Barr virus activities, respectively. In vitro cytotoxicity in MT2, CEM, 2.2.15, and H1 cells was also assessed, and the results indicated high antiviral selectivities of L-FMAU in these cells.A number of nucleosides have been reported to be antihepatitis B virus (anti-HBV) agents, although none of them have yet been proven to be clinically useful. As a part of our antiviral drug discovery program for HBV, we recently have reported the syntheses and anti-HBV activities of dioxolane (14, 15) and oxathiolane (1,8,13) nucleosides. (Ϫ)-␤-L-Dioxolane-cytosine has been found to be the most potent anti-HBV agent (50% effective concentration ϭ 0.0005 M in 2.2.15 cells), although the compound was the most toxic (50% inhibitory concentration ϭ 0.26 M in CEM cells) among those tested (15). Among the oxathiolane cytosine nucleosides we evaluated, (Ϫ)-␤-L-oxathiolane-cytosine has the most potent anti-HBV activity (50% effective concentration ϭ 0.01 M) and a favorable cytotoxicity (Ͼ50 M in CEM cells) (1). Interestingly, the (Ϫ)-␤-L isomer of this compound resisted deoxycytidine deaminase, while the (ϩ)-␤-D isomer was deaminated under similar conditions (3).Recently, an increasing number of L nucleosides have been reported to be antiherpesvirus (23), anti-human immunodeficiency virus (anti-HIV) (2,6,13,14,16,19), and anti-HBV (1,7,8,10,11,15,16) agents. Furthermore, some of the L nucleosides have been found to be more potent than the corresponding D nucleosides (6,13,14). Previously, 2Ј-fluoro-5-methyl-␤-D-arabinofuranosyluracil (FMAU) and 2Ј-fluoro-5-ethyl-␤-Darabinofuranosyluracil (FEAU) were reported (5, 24, 27) to be extremely potent antiviral agents against herpesvirus and HBV, respectively. However, the myelosuppression and neurotoxicity of FMAU limit its usefulness as a clinically effective antiviral agent. In view of the discovery that several nucleosides with the unnatural L configuration are selective antiviral agents, it was of interest to synthesize several 2Ј-fluoro-substituted (arabino configuration) nucleosides with the L configuration as potential antiviral agents, anticipating that these nucleosides will give lower toxicities than the corresponding D isomers. Thus, we report here the preliminary syntheses and antiviral activities of several pyrimidine nucleosides for which the corresponding D isomers have been known to exhibit potent antiviral activities.Synthesis. 1-O-Acetyl-2,3,5-tri-O-benzoyl-␤-L-ribofuranose (compound 1) was prepared from L-ribose (Fig. 1). The fully protected L-ribose compound 1 was selectively debenzoylated at the C-2 position and then was converted to the 2-fluorinated sugar (compound 3) according to the method described for the corresponding D isomer (25). The 2-fluorosugar (arabino configuration) compound 3 was c...

A 12-week clevudine therapy showed potent and durable antiviral activity in HBeAg-positive chronic hepatitis B

“…4,5 Moreover, it has no effect on mitochondrial structure, or DNA content or function. 6,7 In woodchucks infected with woodchuck hepatitis virus (WHV), clevudine led to a decrease in the plasma WHV DNA of up to a thousand-fold.…”

Identification and Characterization of Clevudine-Resistant Mutants of Hepatitis B Virus Isolated from Chronic Hepatitis B Patients

“…Clevudine [1-(2-deoxy-2-fluoro-␤-arabinofuranosyl)thymine, L-FMAU] (CLV) is a pyrimidine analog with potent antiviral activity against HBV (4). CLV inhibits the DNA-dependent DNA activity of HBV polymerase, as well as reverse transcription and priming (1,16).…”

Design and Synthesis of Novel 2'(β)-Fluoro-3'(α)-hydroxy-threose Nucleosides: Iso-FMAU Analogues as Potent Antiviral Agents

“…Because of the broad spectrum of biological activities of 2'-F-arabinofuranosyl nucleoside, a number of structural modifications of these analogues have been carried out. Chu and coworkers have demonstrated that the enantiomer of FMAU, L-FMAU (2) is a promising agent against HBV [5] . It showed low toxicity in rates and woodchucks, potent in vivo antiviral activity against chronically infected woodchucks (WHV), respectable bioavailability and showed no significant virus rebound up to 36 weeks after cessation of the drug treatment.…”