9-(2-Hydroxyethoxymethyl)guanine activity against viruses of the herpes group

Schaeffer, Howard J.; Beauchamp, Lilia M.; Miranda, Paulo de; Elion, Gertrude B.; Bauer, Dirk; Collins, Peter

doi:10.1038/272583a0

Cited by 1,106 publications

(420 citation statements)

References 9 publications

Supporting

Mentioning

408

Contrasting

Unclassified

Order By: Relevance

“…Of all the compounds tested (Table 2), (E)-5-(2-bromovinyl)-dUrd and (E)-5-(2-iodovinyl)-dUrd emerged as the most potent anti-herpes agents: in order of decreasing activity; (E)-5-(2-bromovinyl)-dUrd > (E)-5-(2-iodovinyl)-dUrd > acycloguanosine araC > 5-bromo-dCrd > 5-iodo-dUrd > araT > 5-trifluoromethyl-dUrd > 5-ethyl-dUrd > 5-propyl-dUrd > 5-propynyloxy-dUrd > araA > phosphonoacetate > AIDDU > EHNA. For some of these compounds a similar order of activity has been established in a previous study (12): acycloguanosine > araC > 5-iodo-dUrd > trifluoromethyl-dUrd > araA > phosphonoacetate.…”

Section: Antimetabolic Activitymentioning

confidence: 67%

“…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-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.…”

mentioning

confidence: 99%

See 1 more Smart Citation

(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.

437

198

View full text Add to dashboard Cite

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...

show abstract

Section: Antimetabolic Activitymentioning

confidence: 67%

mentioning

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.

437

198

View full text Add to dashboard Cite

show abstract

“…The ED50 for acyclovir is around 0.1 uM for HSV type 1 (Schaeffer et al, 1978). During the trial therapeutic acyclovir levels for HSV were obtained.…”

Section: Acyclovir Levelsmentioning

confidence: 99%

Oral acyclovir prophylaxis against herpes simplex virus in non-Hodgkin lymphoma and acute lymphoblastic leukaemia patients receiving remission induction chemotherapy. A randomised double blind, placebo controlled trial

Anderson¹,

Scarffe²,

Sutton³

et al. 1984

Br J Cancer

View full text Add to dashboard Cite

Summary Forty-one patients receiving remission induction chemotherapy with vincristine, adriamycin and prednisolone (VAP) for high grade lymphoma or acute lymphoblastic leukaemia were entered into a double blind, placebo controlled trial of oral acyclovir prophylaxis against herpes simplex virus (HSV) infection. The dose of acyclovir was 200mg four times daily for the duration of chemotherapy (six weeks). Of the 40 evaluable patients, 20 were randomised to each arm. Prophylactic oral acyclovir significantly reduced the incidence of clinical HSV infection from 60% on placebo to 5% acyclovir (P<0.001), and the incidence of viral isolates from 70% on placebo to 5% on acyclovir (P<0.001).Herpetic infections are common in immunosuppressed patients with malignant diseases (Aston et al., 1972;Casazza et al., 1966;Lam et al., 1981;Meyers et al., 1980;Muller et al., 1972), and may be life threatening. The oral ulceration and stomatitis caused by HSV may be associated with significant morbidity. In the past year eight of 25 (32%) patients with non-Hodgkin's lymphoma, admitted to our oncology ward with pyrexia when neutropenic, had virologically confirmed HSV infections. Intravenous acyclovir has been shown in randomised, placebo controlled trials to be effective in the treatment of HSV infection in immunocompromised patients (Chou et al., 1981;Mitchell et al., 1981;Wade et al., 1982), and in the prophylaxis of HSV infection (Hann et al., 1983;Saral et al. 1981). A report of oral acyclovir prophylaxis in bone marrow transplant patients has shown a reduced incidence of HSV in those patients treated with acyclovir compared with placebo, without significant toxicity (Gluckman et al. 1983). The aim of this trial was to evaluate the efficacy of prophylactic oral acyclovir against HSV infections in lymphoma and leukaemia patients receiving remission induction chemotherapy, in a double blind placebo controlled trial. Patients and methodsForty-one patients with high grade non-Hodgkin lymphoma or acute lymphoblastic leukaemia who were to receive chemotherapy using the VAP regimen (Blackledge et al., 1980) (Vincristine 2mg intravenously weekly for six weeks, Adriamycin 60 mgm-2 intravenously fortnightly for three doses, and oral prednisolone at 50 mg day-1 for six weeks)were eligible for the trial. After obtaining informed consent patients were randomised to receive acyclovir 200mg four times daily or placebo tablets of identical appearance. The tablets commenced on the first day of chemotherapy and were prescribed for six weeks.Patients with non-Hodgkin lymphoma attended the outpatient clinic for examination and treatment each week, and those with acute leukaemia were inpatients for the duration of therapy. Throat swabs and blood samples for haematology, biochemistry and acyclovir levels were taken weekly. Blood for viral serology was taken every three weeks. At each outpatient visit patients were asked about oral symptoms and coldsores. Lesions present at the time of consultation were swabbed for viral culture and if applicable sa...

show abstract

“…The replication of this virus can be inhibited by a number of DNA synthesis inhibitors including cytosine arabinoside, bromodeoxyuridine and hydroxyurea (Kelly & Lescott, 1976. In this paper, we report the sensitivity of T. ni MNPV to other inhibitors of DNA virus replication, such as phosphonoformate, phosphonoacetate, 9-(2-hydroxyethoxymethyl)guanine (Acyclovir), and [E]-5-(2-bromovinyl)-2'-deoxyuridine (bromovinyldeoxyuridine; BVdU) (Mao et al, 1975;De Clercq et al, 1979;Helgstand et al, 1978 ;Schaeffer et al, 1978). All four drugs act by inhibiting virus-specified DNA polymerase, although both Acyclovir and BVdU must first be phosphorylated to their triphosphates by the successive action of virus-induced deoxythymidine (deoxycytidine) kinase or cellular kinases before they can interact with DNA polymerase.…”

Section: Introductionmentioning

confidence: 99%

Baculovirus Replication: Inhibition of Trichoplusia ni Multiple Nuclear Polyhedrosis Virus by [E]-5-(2-Bromovinyl)-2'-deoxyuridine

Wang

Lescott

Clercq

et al. 1983

Journal of General Virology

View full text Add to dashboard Cite

SUMMARY[E]-5-(2-bromovinyl)-2'-deoxyuridine (BVdU) inhibits the replication of the baculovirus Trichoplusia ni multiple nucleocapsid nuclear polyhedrosis virus in Spodoptera frugiperda cells. Virus-specific DNA synthesis and late protein synthesis are suppressed by the drug. BVdU is phosphorylated by deoxythymidine (deoxycytidine) kinase present in both uninfected and virus-infected cells, and in its 5'-triphosphate form it inhibits DNA polymerase activity in virus-infected cells. The effect of the BVdU is not completely reversible. Phosphonoacetic acid, phosphonoformic acid and Acyclovir have no effect on baculovirus replication. Acyclovir fails to compete with deoxycytidine and thymidine as substrates for pyrimidine deoxynucleoside kinase in virus-infected and uninfected cells.

show abstract

9-(2-Hydroxyethoxymethyl)guanine activity against viruses of the herpes group

Abstract: Of a series of nucleoside analogues synthesised, 9-(2-hydroxyethoxymethyl) guanine was found to have marked antiviral activity in animal models of herpes virus infections, associated with very low toxicity.

Cited by 1,106 publications

References 9 publications

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

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

Oral acyclovir prophylaxis against herpes simplex virus in non-Hodgkin lymphoma and acute lymphoblastic leukaemia patients receiving remission induction chemotherapy. A randomised double blind, placebo controlled trial

Baculovirus Replication: Inhibition of Trichoplusia ni Multiple Nuclear Polyhedrosis Virus by [E]-5-(2-Bromovinyl)-2'-deoxyuridine

Contact Info

Product

Resources

About