5-Propyl-2'-deoxyuridine: a specific anti-herpes agent

Clercq, Erik De; Descamps, J.; Shugar, David

doi:10.1128/aac.13.3.545

Cited by 35 publications

(12 citation statements)

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“…Cidofovir (CFV) was a gift from Gilead Sciences Inc. Authors contributed the following experimental compounds: 9-(4-hydroxybutyl)guanine (HBG), 9-(4-hydroxybutyl)-N 2 -phenylguanine (HBPG), and related TK inhibitors (G. E. Wright) (13, 22); 5-ethyl-2Ј-deoxyuridine (Et-dU, ␣ and ␤ anomers) and ␤-5-propyl-2Ј-deoxyuridine (Pr-dU) (D. Shugar) (5,18) (16,17). Structures of compounds used in this work are shown in Fig.…”

Section: Methodsmentioning

confidence: 99%

Sensitivity of Monkey B Virus ( Cercopithecine herpesvirus 1) to Antiviral Drugs: Role of Thymidine Kinase in Antiviral Activities of Substrate Analogs and Acyclonucleosides

Focher

Lossani

Verri

et al. 2007

Antimicrob Agents Chemother

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Herpes B virus (B virus [BV]) is a macaque herpesvirus that is occasionally transmitted to humans where it can cause rapidly ascending encephalitis that is often fatal. To understand the low susceptibility of BV to the acyclonucleosides, we have cloned, expressed, and characterized the BV thymidine kinase (TK), an enzyme that is expected to "activate" nucleoside analogs. This enzyme is similar in sequence and properties to the TK of herpes simplex virus (HSV), i.e., it has a broad substrate range and low enantioselectivity and is sensitive to inhibitors of HSV TKs. The BV enzyme phosphorylates some modified nucleosides and acyclonucleosides and L enantiomers of thymidine and related antiherpetic analogs. However, the potent anti-HSV drugs acyclovir (ACV), ganciclovir (GCV), and 5-bromovinyldeoxyuridine were poorly or not phosphorylated by the BV enzyme under the experimental conditions. The antiviral activities of a number of marketed antiherpes drugs and experimental compounds were compared against BV strains and, for comparison, HSV type 1 (HSV-1) in Vero cell cultures. For most compounds tested, BV was found to be about as sensitive as HSV-1 was. However, BV was less sensitive to ACV and GCV than HSV-1 was. The abilities of thymidine analogs and acyclonucleosides to inhibit replication of BV in Vero cell culture were not always proportional to their substrate properties for BV TK. Our studies characterize BV TK for the first time and suggest new lead compounds, e.g., 5-ethyldeoxyuridine and pencyclovir, which may be superior to ACV or GCV as treatment for this emerging infectious disease.Herpes B virus (Cercopithecine herpesvirus 1) (BV) is an alphaherpesvirus that naturally infects members of the genus Macaca. In macaques, infection with BV is usually asymptomatic but can present as lesions on the face, in the mouth, or in the genital region. The lesions heal spontaneously but may appear again sporadically in the same way that oral and genital herpes simplex do in humans. However, when transmitted to humans, BV causes an acute ascending encephalitis that is usually fatal if not treated immediately (19). Transmission of BV to humans usually occurs through monkey bites or contact with infected monkey tissues or fluids. BV has been classified as a select agent by the U.S. Public Health Service (42CFR73.3).Although BV is highly lethal in humans, the infrequency of human BV infections has not encouraged development of drugs specifically targeted to this virus. However, the extreme severity of BV infections makes this virus the primary zoonotic concern for persons working with macaques. Acyclovir (ACV), a drug widely used to treat herpes simplex virus (HSV) infections, is currently recommended for treatment of BV infections as well (3). However, BV is about 10 times less susceptible than HSV is to ACV and the related drug ganciclovir (GCV) (1, 3). No studies have examined the comparative sensitivity of BV to other antiherpes drugs, nor has the molecular basis of the lower susceptibility of BV to ACV or GCV been st...

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Section: Methodsmentioning

confidence: 99%

Sensitivity of Monkey B Virus ( Cercopithecine herpesvirus 1) to Antiviral Drugs: Role of Thymidine Kinase in Antiviral Activities of Substrate Analogs and Acyclonucleosides

Focher

Lossani

Verri

et al. 2007

Antimicrob Agents Chemother

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“…5-Methyluracil arabinonucleosides have been reported to selectively inhibit HSV-1 and HSV-2 (16). 5-Propyluracil nucleosides have been reported to possess antiviral activity (17,18). The (E)-5-(2-bromovinyl)uracil nucleosides have significant inhibitory activity against HSV-1.…”

Section: Introductionmentioning

confidence: 99%

Uracil analogues of the acyclonucleoside 9-[[2-hydroxy-1-(hydroxymethyl)ethoxy]- methyl]guanine (BIOLF-62)

Ogilvie¹,

Hamilton²,

Gillen³

et al. 1984

Can. J. Chem.

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“…These compounds include phosphonoacetic acid (3,4), phosphonoformic acid (5, 6), 9-f3-D-arabinofuranosyladenine (araA) (7,8), 5-iodo-5'-amino-2',5'-dideoxyuridine (AIDDU) (9, 10), 9-(2-hydroxyethoxymethyl)guanine (acycloguanosine) (11,12), 1-f3-D-arabinofuranosylthymine (araT) (13,14), 5-iodo-and 5-bromo-2'-deoxycytidine (15, 16), 5,6-dihydro-5-azathymidine (17,18), and erythro-9-[3-(2-hydroxynonyl)]adenine (EHNA) (19). Among the 5-substituted 2'-deoxyuridines, various compounds-namely, 5-methylamino-dUrd (20), 5-methoxymethyl-dUrd (21), 5-propyl-dUrd (22), and 5-propynyloxy-dUrd (23)-proved more inhibitory to herpes than to any other DNA (or RNA) virus. We now report on the synthesis and antiviral potency of two new anti-herpes compounds, (E)-5-(2-bromovinyl)-dUrd and (E)-5-(2-iodoThe publication costs of this article were defrayed in part by page charge payment.…”

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confidence: 99%

(E)-5-(2-Bromovinyl)-2'-deoxyuridine: a potent and selective anti-herpes agent.

Clercq¹,

Descamps²,

Somer³

et al. 1979

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

440

198

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Of a series of five newly synthesized 2'-deoxyuridine derivatives, including 5(1-chlorovinyl)-dUrd, (E--(2-bromovinyl)-dUrd, and (E)5-(2-iodovinyl).dUrd, the last two compounds were found to exert a marked inhibitory effect on the replication of herpes simplex virus type 1 [ID50 (mean inhibitory dose), 0.004-0.02 ;tg/mll.Both (E)5(2-bromovinyl).dUrd and (E>5S(2-iodovinyl).dUrd were highly selective in their anti-herpes activity in that they did not affect the growth or metabolism of the host (primary rabbit kidney) cells unless drug concentrations were used that were 5,000-to 10,000-fold greater than those required to inhibit virus multiplication. In this sense (E-5-2-bromovinyl Idoxuridine (5-iodo-2'-deoxyuridine) and trifluorothymidine (5-trifluoromethyl-2'-deoxyuridine) are among the best known antiviral agents currently used in the chemotherapy of-herpesvirus infections (1). Their clinical usefulness is restricted to the topical treatment of local herpes simplex virus (HSV) infections such as herpetic keratitis and "cold sores" (herpes labialis). The unfavorable therapeutic index of Idoxuridine when administered parenterally-as most dramatically exemplified by its inefficacy in patients with herpes simplex encephalitis (2)-has prompted the search for more effective and less toxic anti-herpes agents. In recent years several compounds have been described which are all endowed with selective anti-herpes properties. These compounds include phosphonoacetic acid (3, 4), phosphonoformic acid (5, 6), 9-f3-D-arabinofuranosyladenine (araA) (7, 8), 5-iodo-5'-amino-2',5'-dideoxyuridine (AIDDU) (9, 10), 9-(2-hydroxyethoxymethyl)guanine (acycloguanosine) (11, 12), 1-f3-D-arabinofuranosylthymine (araT) (13, 14), 5-iodo-and 5-bromo-2'-deoxycytidine (15, 16), 5,6-dihydro-5-azathymidine (17, 18), and erythro-9-[3-(2-hydroxy- vinyl)-dUrd. These compounds surpassed all previously described anti-herpes agents, including acycloguanosine, in both potency and selectivity, at least in primary rabbit kidney (PRK) cells infected with herpes simplex virus type 1 (HSV-1). Compounds 5-Vinyl-dUrd, 5-ethynyl-dUrd, (E)-5-(2-bromovinyl)-dUrd, and (E)-5-(2-iodovinyl)-dUrd were obtained by condensing the trimethylsilyl derivatives of the appropriate 5-substituted uracils with 2'-deoxy-3,5-di-0-p-toluoyl-a-D-erythropentofuranosyl chloride to give a mixture of the a-and f3-anomers of the protected nucleosides. T anomers were separated by chromatography on silica gel and the p-toluoyl protecting groups were removed by treatment with sodium methoxide in methanol. The results indicated for the biological experiments were all obtained by using the f3-anomers (Fig. 1). The a-anomers were also tested for biological activity, but they were inactive. The synthesis of 25). The synthesis of (E)-5-(2-bromovinyl)-dUrd, (E)-5-(2-iodovinyl)-dUrd, and 5-(1-chlorovinyl)-dUrd has been published elsewhere (ref. 26 and unpublished data). The structures assigned to these compounds were established by elemental analysis and UV and NMR spectroscopy.The sour...

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5-Propyl-2'-deoxyuridine: a specific anti-herpes agent

Cited by 35 publications

References 8 publications

Sensitivity of Monkey B Virus ( Cercopithecine herpesvirus 1) to Antiviral Drugs: Role of Thymidine Kinase in Antiviral Activities of Substrate Analogs and Acyclonucleosides

Sensitivity of Monkey B Virus ( Cercopithecine herpesvirus 1) to Antiviral Drugs: Role of Thymidine Kinase in Antiviral Activities of Substrate Analogs and Acyclonucleosides

Uracil analogues of the acyclonucleoside 9-[[2-hydroxy-1-(hydroxymethyl)ethoxy]- methyl]guanine (BIOLF-62)

(E)-5-(2-Bromovinyl)-2'-deoxyuridine: a potent and selective anti-herpes agent.

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