Activities of 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-5-iodocytosine and its metabolites against herpes simplex virus types 1 and 2 in cell culture and in mice infected intracerebrally with herpes simplex virus type 2

Schinazi, Raymond F.; Fox, Jack J.; Watanabe, K. A.; Nahmias, A. J.

doi:10.1128/aac.29.1.77

Cited by 35 publications

(16 citation statements)

References 25 publications

(35 reference statements)

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“…This result compared favorably with those of earlier studies, in which the ED50s were 2.8 ,uM for FMAU and >200 ,uM for FEAU (7,11,12). The ED50s of FEAU against HSV-1 and HSV-2 were 0.024 and 0.24 ,uM, respectively.…”

Section: Resultssupporting

confidence: 79%

Synthesis and biological effects of 2'-fluoro-5-ethyl-1-beta-D-arabinofuranosyluracil

Chou

Kong

Fanucchi

et al. 1987

Antimicrob Agents Chemother

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2'-Fluoro-5-ethyl-1-4-D-arabinofuranosyluracil (FEAU) was synthesized, and its biological activities were compared with those of 2'-fluoro-5-methyl-1-oi-D-arabinofuranosyluracil (FMAU). Earlier studies indicated that both compounds showed potent anti-herpes simplex virus activity, with a 50% effective dose (EDSO) of <0.25 ,uM. In the present study the cell growth inhibitory activity of FEAU (ED50, 200 to 2,060 ,uM) was found to be about 100-fold less than that of FMAU. With an ED50 ranging from 630 to 3,700 ,uM, FEAU only weakly inhibited thymidine incorporation into DNA, as compared with FMAU with an ED50 of 9 to 28 ,uM A series of studies on the structure-activity relationships of pyrimidine nucleoside analogs indicated that the antiherpes simplex virus effect was greatly increased by 2'-fluoro-arabinosyl group substitution and by 5-iodo or 5-methyl group substitution (7,11,13). 2'-Fluoro-5-methyl-1-p-D-arabinofuranosyluracil (FMAU) emerged as the most potent anti-herpes simplex virus agent in a mouse model (13). However, subsequent studies indicated that FMAU caused neurotoxicity in humans (6) and was incorporated into mammalian cell DNA as well as into viral DNA (8).Earlier studies of FMAU showed that the 50% effective doses (ED50s) for inhibiting herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) replication in vitro are 0.006 and 0.023 ,uM, respectively, whereas the ED50 for inhibiting the growth of Vero cells is 2.8 ,uM (1). Preliminary studies of 2'-fluoro-5-ethyl-1-,-D-arabinofuranosyluracil (FEAU) indicated that the ED50s for the inhibition of HSV-1 and HSV-2 replication are 0.024 and 0.24 ,uM, respectively. However, the ED50 for the inhibition of Vero cell growth by FEAU is >200 FiM (7,10,13). FMAU, therefore, is 4-and 10-fold more potent than FEAU against HSV-1 and HSV-2 replication, respectively, but 71-fold more toxic than FEAU toward host cells.In this study, FEAU is compared with FMAU for cytotoxicity in a variety of mammalian cells, kinetic constants for host and viral thymidine kinases, metabolic properties which may be modulated to reduce toxicity toward host cells, and toxicity in several animal species. The detailed synthesis procedure for FEAU is also reported. * Corresponding author. MATERIALS AND METHODSSynthesis of FEAU. The chemical synthesis of FEAU was performed by two different procedures (11, 13): (i) catalytic reduction of 5-vinyl-1-(2'-deoxy-2'-fluoro-,-D-arabinofuranosyl) uracil and (ii) condensation of 5-ethyluracil with 3-O-acetyl-5-O-benzoyl-2-deoxy-2-fluoro-D-arabinofuranosyl bromide. The latter method is more practical than the former. It should be noted that condensation of the silylated 5-ethyluracil with the 2-fluoro-arabinosyl bromide without the Lewis acid catalyst in methylene chloride at room temperature yielded and desired P-nucleoside as the major product, and very little formation of the ax-isomer was observed. Saponification of the condensation product with methanolic ammonia yielded FEAU, which was directly crystallized from a mixture of chloroform and aceton...

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Section: Resultssupporting

confidence: 79%

Synthesis and biological effects of 2'-fluoro-5-ethyl-1-beta-D-arabinofuranosyluracil

Chou

Kong

Fanucchi

et al. 1987

Antimicrob Agents Chemother

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“…In contrast, 3TC-treated cells did not induce any apparent morphological changes under the same conditions (data not shown). of herpes simplex virus and cytomegalovirus infections (18,29) was recently reported to be also effective against HBV replication (3,4). The anti-HBV activity of the 5 '-triphosphate form of FIAU is assumed to result from its selective inhibition of viral targets, possibly HBV DNA polymerase (30).…”

Section: Resultsmentioning

confidence: 99%

“…The human hepatoma HepG2 cell line isolated by Aden et al (12) and the 2.2.15 cell line which consists of HepG2 cells transfected with HBV (13) were selected for these investigations since the HepG2 cell line retains many characteristics of hepatocytes, is an adequate in vitro model in which to examine liver functions (14,15), and can be transfected with HBV leading to production of infectious virions (13). Only scant data have been reported on the in vitro and in vivo metabolism of FIAU but more extensive investigations have been carried out with FIAC, a nucleoside extensively deaminated in vivo to FIAU (16)(17)(18). From these studies, it is clear that several metabolites of FIAU can be formed including FAU, FMAU, FHMAU and glucuronides of FIAU and FMAU (16)(17)(18).…”

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confidence: 99%

“…Only scant data have been reported on the in vitro and in vivo metabolism of FIAU but more extensive investigations have been carried out with FIAC, a nucleoside extensively deaminated in vivo to FIAU (16)(17)(18). From these studies, it is clear that several metabolites of FIAU can be formed including FAU, FMAU, FHMAU and glucuronides of FIAU and FMAU (16)(17)(18). Unpublished data from our laboratory substantiates these previous reports and LC/MS/MS analysis of biological specimens of FIAU-treated patients from the last clinical trial demonstrates that FIAU is substantially metabolized to FAU and FMAU (19).…”

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confidence: 99%

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Cellular and molecular events leading to mitochondrial toxicity of 1-(2-deoxy-2-fluoro-1-beta-D-arabinofuranosyl)-5-iodouracil in human liver cells.

Cui¹,

Yoon²,

Schinazi³

et al. 1995

J. Clin. Invest.

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121

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We have explored the mechanism(s) related to FIAU-induced liver toxicity, particularly focusing on its effect on mitochondrial function in a human hepatoma cell lineHepG2. The potential role of FMAU and FAU, metabolites detected in FIAU-treated patients were also ascertained. FIAU and FMAU inhibited cell growth and were effectively phosphorylated. A substantial increase in lactic acid production in medium of cells incubated with 1-10 ,uM FIAU or FMAU was consistent with mitochondrial dysfunction. Slot blot analysis demonstrated that a two week exposure to 10 ,uM FIAU or FMAU was not associated with a decrease in total mitochondrial (mt) DNA content. However, FIAU and FMAU were incorporated into nuclear and mtDNA and relative values suggest that both compounds incorporate at a much higher rate into mtDNA. Electron micrographs of cells incubated with 10 ,IM FIAU or FMAU revealed the presence of enlarged mitochondria with higher cristae density and lipid vesicles. In conclusion, these data suggest that despite the lack of inhibition of mtDNA content, incorporation of FIAU and FMAU into mtDNA of HepG2 cells leads to marked mitochondrial dysfunction as evidenced by disturbance in cellular energy metabolism and detection of

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“…We have studied several licensed and experimental drugs which could be candidates for this purpose. Based on animal studies with ara-A, ACV, several 2'-fluoroarabinosyl pyrimidine nucleosides, including 2'-fluoro-5-methylarabinosyluracil (FMAU) and 2'-fluoro-5-iodoarabinosylcytosine (FIAC) (10,20,22), and congeners of acyclovir, such as 9-[(2,3-dihydroxypropoxy)methyl]guanine (DHPG; also known as 2'-NDG, BIOLF-62, and BW759) (27) and buciclovir (9; unpublished data), we concluded that FMAU was the best candidate to be evaluated in humans with severe herpetic infection (20).…”

mentioning

confidence: 99%

Delayed treatment with combinations of antiviral drugs in mice infected with herpes simplex virus and application of the median effect method of analysis

Schinazi¹,

Chou²,

Scott³

et al. 1986

Antimicrob Agents Chemother

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Mice were inoculated intracerebrally with a lethal dose of herpes simplex virus type 2. Three days later, the mice were treated intraperitoneally, twice daily for 4 days, with the following drugs alone or in combination: acyclovir (ACV), vidarabine (ara-A), 2'-fluoro-5-iodoaracytosine (FIAC), and 2'-fluoro-5-methylarauracil (FMAU). Despite delayed treatment, most of the animals receiving low doses of FMAU alone or in combination with ACV or ara-A survived. In contrast, significantly higher mortality rates were noted in mice receiving ara-A, ACV, or FIAC alone. The data were analyzed for quantitation of synergism, additivity, and antagonism of multiple drug effect by the median effect method. The median effective doses (in nanomoles per kilogram per day) calculated in this manner were: FMAU, 22.5; FIAC, 510; ara-A, 901; ACV, 7,587; ACV-ara-A (drug ratio, 1:1), 550; FIAC-ara-A (1:1), 376; FIAC-ACV (1:1), 133; FMAU-ACV (1:8), 60.3; and FMAU-ara-A (1:8), 65.2. Marked synergy was found throughout a wide range of effect levels with the five different combinations, with no increased toxicity over the single-drug treatments. Similar results were obtained when the data were analyzed by the isobologram method. Since many patients with severe herpetic infections, such as herpes encephalitis, have a poor prognosis despite single-drug therapy, the possible use of combinations including low doses of FMAU deserves further investigation.

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Activities of 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-5-iodocytosine and its metabolites against herpes simplex virus types 1 and 2 in cell culture and in mice infected intracerebrally with herpes simplex virus type 2

Cited by 35 publications

References 25 publications

Synthesis and biological effects of 2'-fluoro-5-ethyl-1-beta-D-arabinofuranosyluracil

Synthesis and biological effects of 2'-fluoro-5-ethyl-1-beta-D-arabinofuranosyluracil

Cellular and molecular events leading to mitochondrial toxicity of 1-(2-deoxy-2-fluoro-1-beta-D-arabinofuranosyl)-5-iodouracil in human liver cells.

Delayed treatment with combinations of antiviral drugs in mice infected with herpes simplex virus and application of the median effect method of analysis

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