Enzyme-mediated enantioselective preparation of pure enantiomers of the antiviral agent 2',3'-dideoxy-5-fluoro-3'-thiacytidine (FTC) and related compounds

Hoong, Lee K.; Strange, Luise E.; Liotta, Dennis; Koszalka, George W.; Burns, C. L.; Schinazi, Raymond F.

doi:10.1021/jo00047a004

Cited by 94 publications

(48 citation statements)

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“…The 3' -thia-2' ,3'-dideoxycytidine nucleosides were synthesized in our laboratories as described previously (Choi et al, 1991). The detailed synthesis of the (-)-enantiomer of FTC has been reported recently (Hoong et al, 1993) The intensity data were measured on an Enraf-Nonius CAD4 diffractomer, using Ni-filtered CuKex radiation (A = 1.5418A). The intensity data in the range of 2 < e< 75°were measured in three shells.…”

Section: Materials and Experimental Proceduresmentioning

confidence: 99%

Absolute Configuration of the Antiviral Agent (−)-cis-5-Fluoro-1-[2-Hydroxymethyl)-1,3-Oxathiolan-5-yl]Cytosine

Roey

Pangborn

Schinazi

et al. 1993

Antivir Chem Chemother

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The structure and absolute configuration of (−)- cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine (FTC), has been determined by X-ray crystallographic analysis. The results confirm that the L-isomer of the nucleoside analogue is the most active enantiomer and that the correct absolute configuration of (−)-FTC is 5-fluoro-(2′R,5′S)-(−)-1-[2-hydroxymethyl)oxathiolan-5-yl]-fluorocytosine. The two molecules in the asymmetric unit show conformations that combine conformational features of two other classes of potent antiviral nucleosides. Both oxathiolane rings have the 3′-sulphur atom in nearly perfect S3′- exo envelope conformations, similar to what is observed for 3′-azido-3′-deoxythymidine (AZT) and 2′,3′-dideoxycytidine. One of the two molecules has a glycosylic link conformation in which the base is eclipsed with the C5′-O1′ bond. This mimics the high- anti conformation that has been observed in the structures of several 2′,3′-didehydro-2′,3′-dideoxypyrimidine nucleosides but is inaccessible for saturated pyrimidine nucleosides. However, the observed conformations cannot be superimposed adequately with other active antiviral nucleosides to suggest a common ‘active site’ conformation.

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Section: Materials and Experimental Proceduresmentioning

confidence: 99%

Absolute Configuration of the Antiviral Agent (−)-cis-5-Fluoro-1-[2-Hydroxymethyl)-1,3-Oxathiolan-5-yl]Cytosine

Roey

Pangborn

Schinazi

et al. 1993

Antivir Chem Chemother

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“…FTC and 2,3'-dideoxy-5-fluoro-3'-thiauridine (FTU) were synthesized in our laboratories as described by Choi et al (5). The detailed synthesis and characterization of these new compounds are described elsewhere (13). 3'-Deoxy-2',3'-didehydrothymidine was synthesized as described previously (8).…”

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confidence: 99%

Pharmacokinetics and metabolism of racemic 2',3'-dideoxy-5-fluoro-3'-thiacytidine in rhesus monkeys

Schinazi

Boudinot

Ibrahim

et al. 1992

Antimicrob Agents Chemother

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2',3'-Dideoxy-5-fluoro-3'-thiacytidine (FTC) is a nucleoside analog that selectively inhibits human immunodeficiency and hepatitis B viruses in vitro. In this study, the preclinical pharmacokinetics of racemic FTC in rhesus monkeys following intravenous and oral administration were characterized. The terminal half-life of FTC was independent of the route of administration and averaged 1.34 ± 0.18 h (mean ± standard deviation). Total clearance of FTC was moderate to high, averaging 1.49 ± 0.24 liters/h/kg. Qualitative assessment of urine samples suggests that renal excretion of unchanged FTC was the major route of elimination of the nucleoside. The compound was also eliminated by metabolism and the deaminated biotransformation product 2,3'-dideoxy-5-fluoro-3'-thiauridine (FT]U) was detected in serum and urine. This metabolite has no antiviral activity in human lymphocytes and liver cells. FTC and the metabolite FTU were conjugated, to a minor extent yielding the corresponding glucuronides. No 5-fluorouracil was detected in serum or urine. This is consistent with chromatographic studies using a chiral column that indicated that when racemic FTC is treated with cellular cytidine-deoxycytidine deaminase, the D-(+)-enantiomer of FTC is slowly deaminated to D-(+)-FTU, whereas the L-(-)-enantiomer is essentially resistant to this enzyme. The steady-state volume of distribution of FTC in serum averaged 2.23 ± 0.42 liters/kg, and the nucleoside analog was distributed into the cerebrospinal fluid, which suggests that this drug penetrated the blood-brain barrier. Absorption of FTC after oral administration was rapid, with bioavailabiity averaging 73 ± 6%. Taken together, the results indicate that the unusual L-(-)-enantiomer of FTC should be evaluated further in rhesus monkeys prior to determination of whether this compound is useful for treatment of human immunodeficiency and hepatitis B virus infections.

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“…(-)-FTC and its triphosphate were synthesized in our laboratories as described previously (Hoong et al, 1992). The chemical structure and purity of these compounds were confirmed by 1 H NMR spectra, mass spectrometry and chiral (high performance liquid chromatography) HPLC analysis.…”

Section: Chemicalsmentioning

confidence: 99%

Viral Pharmacodynamic Model for (–)-β-2′,3′-Dideoxy-5-Fluoro-3′-Thiacytidine (Emtricitabine) in Chronically Infected Woodchucks

Hurwitz

Tennant

Korba

et al. 2002

Antivir Chem Chemother

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There is a need for models that can be used to predict the dynamics of virus depletion in hepatitis B virus (HBV)-infected individuals for use in early dose-ranging studies with nucleoside analogues that inhibit virus polymerase/ reverse transcriptase (RT), such as the triphosphate of lamivudine and the diphosphate of adefovir. To date most models of virus dynamics were developed to gain understanding of the dynamics of the virus and infected target cells, and have not incorporated the pharmacokinetic and pharmacodynamic parameters of pharmacological agents used in their treatment. Consequently, these models were not designed to predict virus depletion profiles as a function of dose regimen.Woodchuck hepatitis virus (WHV) is a member of the hepadnavirus family that includes duck hepatitis virus, ground squirrel hepatitis virus and HBV (Mason & Taylor, 1989;Roggendorf & Tolle, 1995). WHV-infected woodchucks are one of the most useful animal models for studying the pathology of HBV and for the development of antiviral nucleosides for treating HBV infections (Korba et al., 1987(Korba et al., , 2000aMason & Taylor, 1989;Seeger et al., 1991;Kajino et al., 1994;Roggendorf & Tolle, 1995;Schinazi et al., 1997Schinazi et al., ,1999Hurwitz et al., 1998;Tennant et al., 1998). Nowak et al. (1996) used a system of three differential equations that incorporated viral loads, the number of

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Enzyme-mediated enantioselective preparation of pure enantiomers of the antiviral agent 2',3'-dideoxy-5-fluoro-3'-thiacytidine (FTC) and related compounds

Cited by 94 publications

References 0 publications

Absolute Configuration of the Antiviral Agent (−)-cis-5-Fluoro-1-[2-Hydroxymethyl)-1,3-Oxathiolan-5-yl]Cytosine

Absolute Configuration of the Antiviral Agent (−)-cis-5-Fluoro-1-[2-Hydroxymethyl)-1,3-Oxathiolan-5-yl]Cytosine

Pharmacokinetics and metabolism of racemic 2',3'-dideoxy-5-fluoro-3'-thiacytidine in rhesus monkeys

Viral Pharmacodynamic Model for (–)-β-2′,3′-Dideoxy-5-Fluoro-3′-Thiacytidine (Emtricitabine) in Chronically Infected Woodchucks

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