9-(3,4-dihydroxybutyl)guanine, a new inhibitor of herpesvirus multiplication

Larsson, Anna‐Karin; Öberg, Bo; Alenius, Stefan; Hagberg, Carolina E.; Johansson, Nils‐Gunnar; Lindborg, B; Stening, G.

doi:10.1128/aac.23.5.664

Cited by 57 publications

(36 citation statements)

References 28 publications

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“…The compounds are poor substrates for cellular thymidine kinases. The antiviral effects of HBG and (RS)-DHBG coincide with a preferential inhibition of viral DNA synthesis in infected cells (11,13). The synthesis of DNA in noninfected cells is not affected at concentrations that cause antiviral effects.…”

mentioning

confidence: 92%

“…The compounds are poor substrates for cellular thymidine kinases. The antiviral effects of HBG and (RS)-DHBG coincide with a preferential inhibition of viral DNA synthesis in infected cells (11,13 (11)(12)(13)(14). The difference in phosphorylation rate is 7-fold for H4SV type 1 (HSV-1) thymidine kinase and 2.5-fold for HSV type 2 (HSV-2) thymidine kinase.…”

mentioning

confidence: 93%

“…1) are inhibitors of herpes simplex virus (HSV) replication in cell cultures (11,13,14). Their specificities are largely determined by selective phosphorylation to monophosphates by viral thymidine kinases.…”

mentioning

confidence: 99%

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Antiherpes effects and pharmacokinetic properties of 9-(4-hydroxybutyl) guanine and the (R) and (S) enantiomers of 9-(3,4-dihydroxybutyl)guanine

Ericson¹,

Larsson²,

Aoki³

et al. 1985

Antimicrob Agents Chemother

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Three acyclic guanosine analogs with similar structures, the (R) and (S) forms of 9-(3,4-dihydroxybutyl)guanine and 9-(4-hydroxybutyl)guanine, were compared for antiherpes activity in vivo and in vitro. The three guanosine analogs were viral thymidine kinase-dependent inhibitors of virus multiplication. In ceil cultures, (S)-9-(3,4-dihydroxybutyl)guanine was the least active of these three drugs against a variety of herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) strains. This was also the case for a certain HSV-1 or HSV-2 strain in different cell lines, In cell cultures, (R)-9-(3,4-dihydroxybutyl)guanine and 9-(4-hydroxybutyl)guanine had similar antiherpes activities. However, in vivo in cutaneous HSV-1 infections in guinea pigs treated topically and in systemic HSV-2 infections in mice treated orally or intraperitoneally, only (R)-9-(3,4-dihydroxybutyl)guanine had a therapeutic effect. The extremely short half-life in plasma and the high clearance of 9-(4-hydroxybutyl)guanine as compared with those of (R)-9-(3,4-dihydroxybutyl)guanine probably made 9-(4-hydroxybutyl)guanine inefficacious when given intraperitoneally or orally to mice infected with herpesvirus. On the other hand, no kinetic differences between (R)-9-(3,4-dihydroxybutyl)guanine and 9-(4-hydroxybutyl)guanine were observed in penetration through guinea pig skin ex vivo, and no preferential metabolism of 9-(4-hydroxybutyl)guanine in skin was noted. We deduced that high thyntidine levels in guinea pig skin preferentially antagonize the antiviral effect of 9-(4-hydroxybutyl)guanine in cutaneous HSV-1 infections.The acyclic guanosine analogs 9-(4-hydroxybutyl)guanine (HBG) and 9-(3,4-dihydroxybutyl)guanine [(RS)-DHBG] (Fig. 1) are inhibitors of herpes simplex virus (HSV) replication in cell cultures (11,13,14). Their specificities are largely determined by selective phosphorylation to monophosphates by viral thymidine kinases. The compounds are poor substrates for cellular thymidine kinases. The antiviral effects of HBG and (RS)-DHBG coincide with a preferential inhibition of viral DNA synthesis in infected cells (11,13 (11)(12)(13)(14). The difference in phosphorylation rate is 7-fold for H4SV type 1 (HSV-1) thymidine kinase and 2.5-fold for HSV type 2 (HSV-2) thymidine kinase. Nevertheless, in inhibiting HSV-1 or HSV-2 replication in infected Vero cells, HBG and (RS)-DHBG have similar activities.In this study, we present a more extensive comparison of the antiviral effects in vitro and in vivo of HBG and the two enantiomeric forms of DHBG, (R)-DHBG and (S)-DHBG (Fig. 1)

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confidence: 92%

“…The compounds are poor substrates for cellular thymidine kinases. The antiviral effects of HBG and (RS)-DHBG coincide with a preferential inhibition of viral DNA synthesis in infected cells (11,13 (11)(12)(13)(14). The difference in phosphorylation rate is 7-fold for H4SV type 1 (HSV-1) thymidine kinase and 2.5-fold for HSV type 2 (HSV-2) thymidine kinase.…”

mentioning

confidence: 93%

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Antiherpes effects and pharmacokinetic properties of 9-(4-hydroxybutyl) guanine and the (R) and (S) enantiomers of 9-(3,4-dihydroxybutyl)guanine

Ericson¹,

Larsson²,

Aoki³

et al. 1985

Antimicrob Agents Chemother

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“…itory than the (89). Its mode of action, like that of ACG, appears to involve phosphorylation, initially by the HSV kinase, and subsequent inhibition of viral DNA synthesis.…”

Section: Dihjdroyprpyladenine and 9-dihdroxybutylguaninementioning

confidence: 99%

Antiviral agents - some current developments

Shugar¹

1985

Pure and Applied Chemistry

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“…Subsequent members of this class include, amongst many others, 9-(1,3-dihydroxy-2-propoxymethyl)guanine (DHPG, 2'NDG), with in vitro antiviral activity superior to that of acyclovir (1 1-13), and others with lower activities, e.g. 9-(2,3-dihydroxypropy1)adenine (DHPA) (14), 9-(2,3-dihydroxy-1-propoxymethy1)guanine (DHPMG) (1 5, 16), and 9-(3,4-dihydroxybuty1)guanine (DHBG) (17).…”

Section: Introductionmentioning

confidence: 99%

Solid state and solution conformations of 1 -(β-D-2′,3′-secoribofuranosyl)-5,6-dichlorobenzimidazole, an acyclonucleoside analogue

Birnbaum¹,

Stolarski²,

Kazimierczuk³

et al. 1985

Can. J. Chem.

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The title compound crystallizes in the monoclinic space group P21, with two independent molecules in the asymmetric unit (Z = 4). The unit cell dimensions are a = 11.861(2), b = 7.897(1), c = 14.527(3) Å, β = 91.28(1)°. X-ray intensity data were measured on a diffractometer, and the crystal structure was determined by direct methods. Least-squares refinement converged at R = 0.036 for 2980 reflections. The glycosidic torsion angle [C(2)—N(1)—C(1′)—O(1′)] is 53.9° in molecule A and 129.8° in molecule B. In both molecules, the orientation of C(1′)—O(1′) to C(2′)—O(2′) is trans. The conformations about C(3′)—C(4′) and C(4′)—C(5′) are different in each of the two molecules. These features are compared with those of acyclonucleoside analogues with antiviral activity. The conformation in aqueous medium was examined with the aid of high-resolution 1H nmr spectroscopy, and the results are compared with those obtained from the X-ray analysis.

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9-(3,4-dihydroxybutyl)guanine, a new inhibitor of herpesvirus multiplication

Cited by 57 publications

References 28 publications

Antiherpes effects and pharmacokinetic properties of 9-(4-hydroxybutyl) guanine and the (R) and (S) enantiomers of 9-(3,4-dihydroxybutyl)guanine

Antiherpes effects and pharmacokinetic properties of 9-(4-hydroxybutyl) guanine and the (R) and (S) enantiomers of 9-(3,4-dihydroxybutyl)guanine

Antiviral agents - some current developments

Solid state and solution conformations of 1 -(β-D-2′,3′-secoribofuranosyl)-5,6-dichlorobenzimidazole, an acyclonucleoside analogue

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