Comparative Study of the Potency and Selectivity of Anti-Herpes Compounds

Clercq, E. De; Descamps, J.; Barr, Philip J.; Jones, A. S.; Serafinowski, P.; Walker, Richard; Huang, Guang-Fu; Torrence, Paul F.; Schmidt, Charles L.; Mertes, Mathias P.; Kulikowski, Tadeusz; Shugar, David

doi:10.1016/b978-0-08-024384-9.50026-9

Cited by 31 publications

(28 citation statements)

References 33 publications

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“…The results (Table 1) showed that propenyl-dU and 1-butenyl-dU were the most inhibitory of the compounds tested (MIC, 0.5 ,ug/ml), whereas the nonconjugated isomers of these compounds, allyl-dU and 2-butenyl-dU, were significantly less active (MICs, 100 and 10 pLg/ml, respectively). The saturated, hydrocarbon-substituted deoxyuridine butyl-dU (MIC, 10 ,ug/ml) had the same activity as 2-butenyl-dU. The anti-HSV-1 activity of a pair of isomers, allyl-dU and propenyldU, was examined in more detail in a virus yield reduction assay.…”

Section: Resultsmentioning

confidence: 99%

Possible molecular basis for antiviral activity of certain 5-substituted deoxyuridines

Sim¹,

Goodchild²,

Meredith³

et al. 1983

Antimicrob Agents Chemother

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The antiviral activity of five structurally related pyrimidine nucleosides, E-5-propenyl-2'-deoxyuridine, 5-allyl-2'-deoxyuridine, E-5-(1-butenyl)-2'-deoxyuridine, 54(2-butenyl)-2'-deoxyuridine, and 5-butyl-2'-deoxyuridine, in cell culture against herpes simplex virus type 1 was examined. Analogs in which the C-C double bond of the 5-substituent was in conjugation with the pyrimidine ring were more potent antiviral drugs than were the corresponding nonconjugated and alkylsubstituted analogs. Differences in antiviral activity similar to those observed in cell-culture occurred in virus-infected mice. The molecular basis for the greater antiviral activity of the conjugated isomers was investigated. It was observed that the c6njugated isomer E-5-propenyl-2'-deoxyuridine had a greater affinity for virus thymidine kinase and, as the 5'-triphosphate, for virus DNA polymerase than did the nonconjugated isomer 5-allyl-2'-deoxyuridine. The results are discussed in relation to other data in the literature.Since the discovery of the antiviral activity of 5-iodo-2'-deoxyuridine against herpes simplex virus type 1 (HSV-1), a number of 5-substituted deoxyuridines that inhibit HSV-1 replication have been described. The moieties introduced at C-5 of the pyrimidine ring to confer antiviral activity are diverse (for a review, see reference 9), but of particular interest are the saturated hydrocarbons propyl (5, 12) and ethyl (5, 14), the unsaturated hydrocarbons vinyl (5), allyl (5), and propenyl (8,28), and the halogen-substituted unsaturated hydrocarbons bromovinyl (11) and trifluoropropenyl (8). These compounds differ widely in their ability to inhibit HSV-1, but the reasons for these differences are not clear.Indeed, the development of such compounds has been largely empirical, and their mechanism of action is not fully understood.E-5-(2-Bromovinyl)-2'-deoxyuridine is the most active anti-HSV-1 compound of this type described to date. It can competitively inhibit thymidine phosphorylation (7) by acting as a substrate for HSV-1 thymidine/thymidylate kinase (6, 17). Its 5'-triphosphate has been shown by high-pressure liquid chromatographic analysis to be the most abundant phosphorylated species in the HSV-1-infected cell (27) and to competitively inhibit the utilization of dTTP by virus-induced DNA polymerase (1,25). If other 5-substituted deoxyuridines act by a similar mechanism, differences in antiviral activity in cell culture assays may be related to their respective inhibition constants for thymidine kinase and DNA polymerase. However, the possibility cannot be excluded that other enzymes may be the metabolic target, the inhibition of which results in reduced virus growth.Here we describe the antiherpes activity of two pairs of isomers in which the C-C double bond of the olefinic 5-substituent was conjugated to the double bond of the pyrimidine ring in one of each pair [E-5-propenyl-2'-deoxyuridine (propenyl-dU) and E-5-(1-butenyl)-2'-deoxyuridine (1-butenyl[dU)] and was uncorjugated in the second of each pair of [5-allyl-2...

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Section: Resultsmentioning

confidence: 99%

Possible molecular basis for antiviral activity of certain 5-substituted deoxyuridines

Sim¹,

Goodchild²,

Meredith³

et al. 1983

Antimicrob Agents Chemother

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“…The methods for evaluating the cytostatic activity of the test compounds against the different FM3A cells were reported previously [16].…”

Section: Inhibition Of Cell Proliferation By Anti-herpetic Drugsmentioning

confidence: 99%

The cytostatic activity of 5‐(1‐azidovinyl)‐2′‐deoxyuridine (AzVDU) against herpes simplex virus thymidine kinase gene‐transfected FM3A cells is due to inhibition of thymidylate synthase and enhanced by UV light (λ = 254 nm) exposure

et al. 1995

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“…Even when applied as a 2.5% ointment, BVDU did not produce any toxicity to the eye, whereas both 2.5 and 0.1% BVDU ointments were found to be equally effective as a 0.5% BVDU ointment in treating herpetic keratitis (data not shown). BVDU does not affect the growth or metabolism of cultured cells, unless concentrations are employed that are 5,000-to 10,000-fold greater than those required to inhibit virus multiplication (1,2). This implies that BVDU is very selective in its antiherpes action.…”

mentioning

confidence: 95%

“…BVDU [(E)-5-(2-bromovinyl)-2'-deoxyuridine], a newly synthesized thymidine analog (12), has been evaluated by De Clercq et al (1,2) for its potency and selectivity as an antiherpes agent in primary rabbit kidney and human skin fibroblast cell cultures. In these cell cultures BVDU was about 20 times more active against the replication of herpes simplex virus (HSV) type 1 (strain KOS) and 60 times less toxic than IDU as judged by inhibition of deoxyuridine incorporation into host cell deoxyribonucleic acid.…”

mentioning

confidence: 99%

(E)-5-(2-bromovinyl)-2'-Deoxyuridine in the treatment of experimental herpes simplex keratitis

Maudgal¹,

Clercq²,

Descamps³

et al. 1980

Antimicrob Agents Chemother

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IDU (5-iodo-2'-deoxyuridine), BVDU [(E)-5-(2-bromovinyl)-2'-deoxyuridine] and placebo ointments were studied for their effects on experimental herpes simplex (type 1) keratoconjuncitivitis in rabbits. When treatment was begun 65 h after virus inoculation, both BVDU and IDU prevented development of keratitis. Both BVDU and IDU were also effective in suppressing the severity of conjunctivitis, and in this respect, BVDU proved significantly better than IDU. When treatment was started 110 h after virus inoculation, BVDU proved significantly better than IDU in promoting healing of established keratitis.

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Comparative Study of the Potency and Selectivity of Anti-Herpes Compounds

Cited by 31 publications

References 33 publications

Possible molecular basis for antiviral activity of certain 5-substituted deoxyuridines

Possible molecular basis for antiviral activity of certain 5-substituted deoxyuridines

The cytostatic activity of 5‐(1‐azidovinyl)‐2′‐deoxyuridine (AzVDU) against herpes simplex virus thymidine kinase gene‐transfected FM3A cells is due to inhibition of thymidylate synthase and enhanced by UV light (λ = 254 nm) exposure

(E)-5-(2-bromovinyl)-2'-Deoxyuridine in the treatment of experimental herpes simplex keratitis

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