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J J Fox

Publications and source records attributed to J J Fox.

At least 37 records · Page 2Linked to original sources
PubMed1987

Nucleosides. 139. Synthesis and anticytomegalovirus and antiherpes simplex virus activity of 5'-modified analogues of 2'-fluoroarabinosylpyrimidine nucleosides.

In order to determine if modification of the 5'-position reduces or abolishes the antiviral activity of 2'-fluoro-5-iodo-ara-C (FIAC), 2'-fluoro-5-iodo-ara-U (FIAU), or 2'-fluoro-5-methyl-ara-U (FMAU) against human cytomegalovirus (HCMV) and herpes simplex virus (HSV), the 5'-deoxy, 5'-mercapto, and 5'-amino analogues of these nucleosides were prepared. 5'-Deoxy-FIAC and 5'-deoxy-FIAU were prepared by catalytic hydrogenation of 5'-iodo-FIAC and 5'-iodo-FIAU to 5'-deoxy-FAC and 5'-deoxy-FAU, respectively, followed by reiodination at C-5. Reduction of 5'-iodo-FMAU afforded 5'-deoxy-FMAU. These 5'-deoxy nucleosides were found to be inactive against HCMV, indicating that the conversion to 5'-phosphate by the cellular enzyme(s) is a requirement for antiviral activity against this virus. Other 5'-modified (NH2 and SH) analogues were also prepared from 5'-O-tosyl-FIAC and 5'-O-tosyl-FMAU. Treatment of these tosylates with LiN3 in DMF afforded the corresponding 5'-N3 products. Catalytic hydrogenation of 5'-N3-FMAU afforded 5'-NH2-FMAU, whereas 5'-NH2-FIAC was obtained by treatment of 5'-N3-FIAC with Ph3P in pyridine. 5'-Mercapto analogues were prepared by treatment of 5'-O-tosyl-3'-O-acetyl nucleosides with KSAc followed by deacetylation. 5'-NH2-FMAU was the only compound that showed good activity against HSV-1 and HSV-2 in vitro. However, this compound was less potent and had a lower therapeutic index than FMAU.

Animals↗
PubMed1987

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

2'-Fluoro-5-ethyl-1-beta-D-arabinofuranosyluracil (FEAU) was synthesized, and its biological activities were compared with those of 2'-fluoro-5-methyl-1-beta-D-arabinofuranosyluracil (FMAU). Earlier studies indicated that both compounds showed potent anti-herpes simplex virus activity, with a 50% effective dose (ED50) of less than 0.25 microM. In the present study the cell growth inhibitory activity of FEAU (ED50, 200 to 2,060 microM) was found to be about 100-fold less than that of FMAU. With an ED50 ranging from 630 to 3,700 microM, FEAU only weakly inhibited thymidine incorporation into DNA, as compared with FMAU with an ED50 of 9 to 28 microM. Following exposure to [2-14C]FEAU (100 microM), 0.48 pmol/10(6) cells per h was incorporated into the DNA of herpes simplex virus type 1-infected Vero cells, whereas no detectable incorporation was found in uninfected Vero cells or L1210 cells. The Ki of FEAU for thymidine kinase purified from human leukemic cells was greater than 150 microM. For herpes simplex virus type 1- and 2-encoded thymidine kinases, the Kis were 0.6 and 0.74 microM, respectively. Both FEAU and FMAU were relatively nontoxic for mice, with a 50% lethal dose of greater than 800 mg/kg per day (four intraperitoneal doses). However, the lethal dose of FEAU for dogs was 100 mg/kg per day (10 intravenous doses), a dose which is 40- to 80-fold greater than the toxic dose of FMAU. These results suggest that FEAU is a worthy candidate for further development as an antiherpetic agent.

Antiviral Agents↗
PubMed1986

Nucleosides. 136. Synthesis and antiviral effects of several 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-5-alkyluracils. Some structure-activity relationships.

In order to study structure-activity relationships between antiherpetic activity and the size of the C-5 alkyl substituents of 2'-fluoro-ara-U derivatives, six new nucleosides (1c-h) were synthesized. The 5-allyl analogue 1c was prepared by a Pd(II)-catalyzed reaction of 5-(chloromercuri)-1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)uracil with allyl chloride. Partial hydrogenation of 1c afforded the 5-n-propyl derivative 1d (FPAU). Nucleosides 1e-h were obtained by condensation of 3-O-acetyl-5-O-benzoyl-2-deoxy-2-fluoro-D-arabinosyl bromide with the corresponding 5-substituted uracils. Preliminary in vitro data show that, as the alkyl side chain is increased by one carbon unit, the antiherpetic potency is decreased by approximately 1 log order. The cytotoxicity also diminishes as the size of the 5-substituent is increased. FPAU exerts good activity against HSV-1 and HSV-2. FiPAU still shows good therapeutic indices, whereas the higher alkyl analogues are essentially inactive.

Arabinonucleosides↗
PubMed1986

Synthesis and biological activities of 5-deaza analogues of aminopterin and folic acid.

N-[p-[[(2,4-Diaminopyrido[2,3-d]pyrimidin-6-yl)methyl] amino]benzoyl]-L-glutamic acid (1a, 5-deazaaminopterin) and the 5-methyl analogue (1b) were synthesized in 14 steps from 5-cyanouracil (4a) and 5-cyano-6-methyluracil (4b), respectively, by exploitation of the novel pyrimidine to pyrido[2,3-d]pyrimidine ring transformation reaction. The 5-cyanouracils 4 were treated with chloromethyl methyl ether to the 1,3-bis(methoxymethyl)uracils (5, which were treated with malononitrile in NaOEt/EtOH to give the pyrido[2,3-d]pyrimidines 6. Diazotization of 6 in concentrated HCl afforded the 7-chloro derivatives 8 in high yield. After reduction of 8, the 7-unsubstituted products 9 were reduced in the presence of Ac2O and the products, 6-(acetamidomethyl)pyridopyrimidines 10, were converted into the 6-acetoxymethyl derivatives 12 via nitrosation. After removal of the N-methoxymethyl groups from 12, the 6-(acetoxymethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-diones 14 were converted into 2,4-diamino-6-(hydroxymethyl)pyrido[2,3-d]pyrimidine (15a) and its 5-methyl analogue 15b by the silylation-amination procedure. Compounds 15 were brominated to the 6-bromomethyl derivatives 16, which were treated with diethyl (p-aminobenzoyl)-L-glutamate, and the products 17 were saponified to afford 5-deazaaminopterin (1a) and its 5-methyl analogue 1b. Compound 1b was also prepared by an alternative procedure in 10 steps from cyanothioacetamide and ethyl beta-(ethoxymethylene)acetoacetate via 2,4-diamino-6-(hydroxymethyl)-5-methylpyrido[2,3-d]pyrimidine (15b). 5-Deaza-5-methylfolic acid (2) was also prepared in four steps from 15b. The aminopterine analogues 1 showed significant anticancer activity in vitro and in vivo, whereas the folic acid analogue 2 did not exhibit any significant toxicity.

Aminopterin↗
PubMed1986

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.

As measured by plaque and yield reduction assays, several metabolites of 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-5-iodocytosine (FIAC) were highly active against herpes simplex virus types 1 and 2. These metabolites included the 2'-deoxy-2'-fluoroarabinosyl derivatives of 5-iodouracil (FIAU), cytosine (FAC), uracil (FAU), and thymine (FMAU). In mice inoculated intracerebrally with herpes simplex virus type 2, the relative order of potency of these compounds and licensed antiviral drugs was as follows: FMAU much greater than FIAC approximately equal to FIAU greater than acyclovir approximately equal to vidarabine much greater than FAC approximately equal to FAU. One of the main metabolites of FMAU, 2'-fluoro-5-hydroxymethyl-arabinosyluracil, was essentially inactive in vivo. FIAC-, FIAU-, FMAU-, FAC-, and FAU-resistant herpes simplex virus variants prepared in cell culture were found to be (i) devoid of viral thymidine kinase, (ii) cross-resistant to one another and resistant to drugs requiring viral thymidine kinase for activation, and (iii) sensitive to vidarabine or phosphonoformate. These results indicate that FIAC, FIAU, and FMAU require the virally encoded thymidine kinase for activation and suggest that the antiviral activity of FAU and FAC in cell cultures is also mediated by this enzyme. The interaction of the fluoroarabinosyl pyrimidine nucleosides with herpes simplex virus thymidine kinase in a cell-free system is also described.

Animals↗
PubMed1985

Nucleosides. 133. Synthesis of 5-alkenyl-1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)cytosines and related pyrimidine nucleosides as potential antiviral agents.

The synthesis of 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)cytosines with a halovinyl or vinyl substituent at C-5 was accomplished from the corresponding 5-iodo (FIAC, 1) and/or 5-chloromercuri nucleoside analogues with use of Li2PdCl4- and Pd(OAc)2-mediated coupling reactions. Thiation of the benzoylated derivative of the 5-ethyluracil nucleoside 3 followed by S-methylation and then ammonolysis provided 5-ethyl-2'-fluoro-ara-C. 5-Ethynyl-2'-fluoro-ara-C (19a) and 5-ethynyl-2'-fluoro-ara-U (19b) were also obtained from the persilylated 5-iodo nucleosides 1 and 16, respectively, by PdII/CuI catalyzed coupling with (trimethylsilyl)acetylene. With use of selective sugar deprotection of the initial coupling products with H2O/Me2SO, the corresponding 5-[2-(trimethylsilyl)ethynyl] derivatives 18a and 18b could be isolated. Most of the new compounds showed activity in vitro against both HSV-1 and HSV-2, as did the known corresponding 5-alkenyluracil nucleosides synthesized earlier. The 5-vinylcytosine and -uracil nucleosides 10 and 24, respectively, were highly effective against HSV-1 (ED90 = 0.40 and 0.043 microM, respectively) and HSV-2 (ED90 = 0.59 and 0.56 microM, respectively). Unlike BVDU, the 2'-fluoroarabinosyl derivatives of 5-(halovinyl)cytosine and -uracil showed activity against both types of herpes simplex virus. The therapeutic indices of these compounds are in some cases superior to those of 2'-fluoro-5-methyl-ara-U (FMAU, 2). Moderate antileukemic activity was observed in vitro for the 5-alkynyl and 5-vinyl compounds. The competition of these compounds with thymidine for viral-induced thymidine kinases was also studied.

Animals↗
PubMed1985

Biotransformation and elimination of [2-14C]-1-(2-deoxy-2'-fluoro-beta-D -arabinofuranosyl)-5-iodocytosine in immunosuppressed patients with herpesvirus infections.

The metabolism of the drug [2-14C]-1-(2'-deoxy-2'-fluoro-beta-D -arabinofuranosyl)-5-iodocytosine (FIAC), a potent inhibitor of herpesvirus replication, was studied in immunosuppressed patients with herpesvirus infections. FIAC was administered intravenously by 15-min infusion and by mouth 24 h later to four patients at doses of 50 or 100 mg/m2. FIAC was cleared from the plasma primarily by biotransformation in liver, kidney, and peripheral blood, with a terminal-phase half-life of 0.92 to 1.80 h (mean, 1.36 h) after intravenous administration. The area under the concentration-time curve from zero to infinity (AUC0-infinity) for FIAC was 1.6 to 4.7% (mean, 3.4%) of the AUC0-infinity for total radioactivity. 1-(2'-Deoxy-2'-fluoro-beta-D-arabinofuranosyl)-5-iodouracil (FIAU) was the major metabolite; the AUC0-infinity for FIAU was 54.3 to 72.5% (mean, 63.4%) of the AUC0-infinity for total radioactivity. The terminal-phase half-life for FIAU was 3.32 to 4.49 h (mean, 3.91 h); FIAU was cleared from plasma by renal elimination and further biotransformation. lesser amounts of 1-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)uracil, 1-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)cytosine, the glucuronide conjugates of these metabolites, and the glucuronide conjugates of FIAC and FIAU were also formed. A comparison of the AUC0-infinity for total radioactivity after intravenous and oral administration suggested that nearly all of the oral dose was absorbed. Plasma levels of FIAU, also a potent inhibitor of herpesvirus replication in vitro, exceeded the 50% effective dose for herpes simplex virus and varicella-zoster virus as late as 12 h after administration of FIAC.

Adult↗
PubMed1985

Phase I trial of 1-(2'-deoxy-2'-fluoro-1-beta-D-arabinofuranosyl)-5-methyluracil (FMAU).

1-(2'-Deoxy-2'-fluoro-1-beta-D-arabinofuranosyl)-5-methyluracil (FMAU), a new pyrimidine nucleoside, is of potential clinical interest both as an anticancer and as an antiviral drug. FMAU is active in vitro and in vivo against P815 and L1210 cell lines resistant to cytarabine. Moreover, in mice inoculated ic with herpes simplex virus Type II, FMAU is 100-fold more potent than vidarabine or acyclovir. We have conducted a phase I trial of FMAU in 17 patients with advanced cancer. The dose levels studied were 2, 4, 8, 16, 32, 64, and 128 mg/m2/day iv for 5 days. The dose-limiting toxic effect was drug-induced central nervous system dysfunction. Although 32 mg/m2/day for 5 days produced only transient, mild symptoms, severe encephalopathy with extrapyramidal dysfunction occurred at 64 and 128 mg/m2/day for 5 days and contributed to two deaths. No toxicity was observed at less than 32 mg/m2. A dose of 32 mg/m2/day for 5 days is suggested for phase II study. Because of its potent and selective antiviral activity, future trials of low doses of FMAU in immunosuppressed patients with herpes virus infections are under consideration.

Adult↗
PubMed1984

Diagnostic imaging of herpes simplex virus encephalitis using a radiolabeled antiviral drug: autoradiographic assessment in an animal model.

To develop a new approach to the diagnosis of herpes simplex encephalitis, we used a radiolabeled antiviral drug, 2'-fluoro-5-methyl-1-beta-D-arabinosyluracil labeled with carbon 14 ([14C]FMAU), as a probe for selectively imaging brain infection in a rat model by quantitative autoradiography. A high correlation was found between focal infection, as defined by immunoperoxidase viral antigen staining, and increased regional [14C]FMAU uptake in brain sections. Two potential sources of false-positive imaging were defined: high concentrations of drug in the choroid plexus because of its higher permeability compared with brain, and drug sequestration by proliferating uninfected cell populations. Our results support the soundness of the proposed strategy of using a labeled antiviral drug that is selectively phosphorylated by herpes simplex virus type 1 thymidine kinase in conjunction with scanning methods for human diagnosis, and also define some of the factors that must be taken into account when planning clinical application.

Animals↗
PubMed1984

Nucleosides. 129. Synthesis of antiviral nucleosides: 5-alkenyl-1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)uracils.

Synthesis of 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)uracils containing a vinyl (4a), 2-halovinyl (4b-d), or ethyl substituent at C-5 was achieved. These nucleosides were found to be about a log order less active than 2'-fluoro-5-iodo-ara-C (FIAC) against HSV-1, but they are much less cytotoxic against normal human lymphocytes than FIAC. Nucleosides 4a and 4e showed good activity against HSV-1 (ED50 = 0.16 and 0.24 microM, respectively) and HSV-2 (ED50 = 0.69 and 0.65 microM) with very little cytotoxicity (ID50 greater than 100 microM).

Animals↗
PubMed1984

Effects of certain nucleoside analogues on human cytomegalovirus replication in vitro.

Four nucleoside analogues, 1-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)-5-methyluracil (FMAU), -5-iodouracil (FIAU), -5-methylcytosine (FMAC) and -5-iodocytosine (FIAC), were studied for their effect on human cytomegalovirus (HCMV) replication in vitro. FMAU, FIAU, FMAC and FIAC showed antiviral activities for four strains of HCMV (Major, Clegg, D550 and Towne) in a plaque reduction assay, with a dose required for 50% inhibition (ED50) in the range of 0.1 to 0.65 microM. At a concentration of 1 microM-FMAU or -FIAC, the synthesis of five virus-specific late polypeptides of molecular weights 150 000, 120 000, 67000, 54000 and 27000 was entirely blocked. Quantification of Towne viral DNA synthesis, using complementary RNA-DNA hybridization with a Towne-specific cRNA probe, demonstrated a complete inhibition of HCMV DNA replication at 1 microM of FMAU or FIAC. After the removal of the inhibitors, however, viral DNA synthesis resumed, and infectious virus reappeared, indicating that the inhibition of HCMV replication by these nucleoside analogues was of a virostatic reversible type.

Antiviral Agents↗
PubMed1984

Metabolic competition studies of 2'-fluoro-5-iodo-1-beta-d-arabinofuranosylcytosine in vero cells and herpes simplex type 1-infected vero cells.

2'-Fluoro-5-iodo-1-beta-D-arabinofuranosylcytosine (FIAC) is a potent antiviral agent with minimal cytotoxicity. In Vero cells, incorporation of labeled dCyd and dThd into the acid-insoluble DNA fraction was, respectively, competitively and noncompetitively inhibited by FIAC. In herpes simplex type 1 (HSV-1) infected Vero cells, these inhibition patterns became noncompetitive. The inhibition constants of FIAC on dThd and dCyd incorporation into the acid-insoluble fraction during a 15-min period were greater than 30 microM which were much higher than the antiviral concentration of FIAC (ED90 = 0.003-0.013 microM) for continuous exposure. Incorporation of dUrd into acid-insoluble DNA was inhibited by 10 microM FIAC in HSV-1-infected Vero cells, but not in uninfected cells. The radioactivity of [2-14C]FIAC was incorporated into the acid-insoluble DNA fraction, and this incorporation in uninfected cells was strongly inhibited by 10 microM dCyd but not by dThd. By contrast, the incorporation in HSV-1-infected Vero cells was strongly inhibited by 10 microM dThd but not by dCyd. These data indicate that FIAC behaves metabolically like dThd, dUrd, or 5-iodo-dUrd in HSV-1-infected cells but like dCyd in noninfected cells. Thus, combined use of dCyd and FIAC may reduce cytotoxicity of FIAC or incorporation of FIAC into host cell DNA without affecting its antiviral activity. This finding is of significance since, for practical reasons, incorporation of FIAC into host cell DNA needs to be reduced as much as possible.

Animals↗
PubMed1983

Comparison of 2'-fluoro-arabinosyl pyrimidine nucleosides and 1-beta-D-arabinofuranosylcytosine on immunological parameters in vitro.

1-beta-D-arabinofuranosylcytosine (ara C)3, 2'-fluoro-5-iodo-arabinofuranosyl-cytosine (FIAC) and 2'-fluoro-5-methyl-arabinofuranosyluracil (FMAU) were analyzed for immunosuppressive activity in vitro. In assay systems quantifying both humoral and cellular immune reactivity, FMAU and FIAC were less immunosuppressive than ara C by several orders of magnitude.

Animals↗
PubMed1983

Nucleosides. 123. Synthesis of antiviral nucleosides: 5-substituted 1-(2-deoxy-2-halogeno-beta-D-arabinofuranosyl)cytosines and -uracils. Some structure-activity relationships.

The syntheses of several 2'-halogeno-5-substituted-arabinofuranosylcytosines and -uracils are described, and relationships of structure to anti herpes virus activity in vitro were examined. Those arabinonucleosides containing the 2'-fluoro function exhibit, generally, more potent anti herpes virus (HSV) activity than do their 2'-chloro of 2'-bromo analogues. The importance of the fluorine in the 2'-"up" (arabino) configuration for enhancement of antiviral effectiveness is demonstrated by the superior activity of 2'-fluoro-5-iodo-ara-C [3a, FIAC] to that of 2'-fluoro-5-iodo-ribo-C. Of all the nucleosides tested herein, FIAC exhibited the most potent in vitro activity against HSV. 2'-Chloro-5-iodo- and -5-methyl-ara-C (3b and 4b) were 37 to greater than 500 times more effective in vitro against HSV type 2 than against type 1, suggesting that these latter derivatives might serve clinically as useful probes to distinguish between HSV types 1 and 2 in the diagnosis of HSV infections in man.

Animals↗
PubMed1983

Mechanism of action of 2',5-difluoro-1-arabinosyluracil.

Results are described which demonstrate that the cytotoxic action of 2',5-difluoro-1-arabinosyluracil (FFara-Ura) involves conversion to the corresponding 5'-phosphate, FFara-UMP, and subsequent inhibition of thymidylate synthetase. The evidence for this is as follows: (a) cells lacking thymidine kinase are 120-fold more resistant to FFara-Ura; (b) FFara-Ura markedly inhibits the incorporation of 2'-deoxyuridine (dUrd) into DNA with little or no effect on 2'-deoxythymidine (dThd) incorporation; (c) FFara-Ura causes changes in deoxynucleoside triphosphate pool sizes, which are characteristic of specific inhibition of dTMP synthetase. Binding and spectroscopic studies demonstrate that FFara-UMP inactivates dTMP synthetase from Lactobacillus casei in a manner analogous to that described for FdUMP. Furthermore, FFara-Ura is not a substrate for the pyrimidine phosphorylases; the significance of this finding with regard to the possible chemotherapeutic utility of FFara-Ura is discussed.

Animals↗
PubMed1983

Activity of 1-(2'-fluoro-2'-deoxy-beta-D-arabinofuranosyl)thymine against herpes simplex virus in cell cultures and rabbit eyes.

A new antiviral compound 1-(2'-fluoro-2'-deoxy-beta-D-arabinofuranosyl)thymine (2'-fluoro-5-methyl-ara-uracil [FMAU]), was compared with acyclovir and idoxuridine in vitro against two strains of both herpes simplex virus type 1 (HSV-1) and HSV-2. Determinations of the 50% effective dose varied slightly with each strain and with the host cells employed. The 50% effective dose for FMAU and acyclovir against HSV-1 ranged from 0.1 microM to 0.5 to 0.6 microM in rabbit kidney cells and from 0.5 microM to 0.6 to 0.78 microM in Vero cells. Beginning 4 days post-inoculation, topical FMAU therapy given five times per day to rabbits with acute herpetic keratitis either suppressed or delayed the severity of corneal epithelial involvement, conjunctivitis, iritis, and corneal clouding. Responses to treatment with FMAU were similar to those obtained with acyclovir and significantly better than those attained with idoxuridine and vidarabine. At 30 to 40 days after the end of treatment, rabbit eyes were subjected to iontophoresis with epinephrine in an attempt to induce reactivation and enhance detection of previously latent HSV-1. Latent HSV-1 was detected in 67 to 92% of trigeminal ganglia in FMAU-treated animals and in 90% of placebo-treated animals.

Acyclovir↗