Structural requirements of olefinic 5-substituted deoxyuridines for antiherpes activity

Goodchild, John; Porter, Roderick A.; Raper, Robert H.; Sim, Iain S.; Upton, R. M.; Viney, Julie; Wadsworth, Harry J.

doi:10.1021/jm00363a009

Cited by 66 publications

(37 citation statements)

References 1 publication

(1 reference statement)

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“…In compounds 5 and 7, where the 2'-deoxyuridine and bromo substituents are cis, C-1 is deshielded 6 3.4-4.3, C-2 is shielded 64. [4][5].0, and C-3 is shielded6 3.3-3.6 relative to the corresponding carbon atoms in the trans compounds 6 and 8. These differences in 13C chemical shifts provide a rapid method to distinguish the cis (1S,2S, 1R,2R) from the trans (1S,2R, 1R,2S) stereoisomers.…”

Section: Resultsmentioning

confidence: 99%

“…bolic>lly ;rapped within infected cells, but not in uninfected host cells (2,3). Structure-activity correlations for olefinic 5-substituted-2'-deoxyuridines indicated optimum inhibition of HSV-1 occurred when the C-5 substituent was unsaturated and conjugated with the pyrimidine ring, was not longer than four carbon atoms in length, had the E stereochemistry, and included a hydrophobic electronegative atom (4). It was anticipated that 2'-deoxyuridine possessing a 5-(2,2-dibromocyclopropyl) or 5-(2-bromocyclopropy1) substituent could serve as a biological isostere of the (E)-5-(2-bromovinyl) substituent present in BVDU.…”

Section: (E)-~-(2-bromovin~~)-2'-deoxyuridine (Bvdu) Is a Potentmentioning

confidence: 99%

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Synthesis, separation, and absolute configuration of the two 5-(2,2-dibromocyclopropyl) and four 5-(2-bromocyclopropyl) diastereomers of 2′-deoxyuridine

Tandon¹,

Wiebe²,

Knaus³

1989

Can. J. Chem.

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Section: Resultsmentioning

confidence: 99%

Section: (E)-~-(2-bromovin~~)-2'-deoxyuridine (Bvdu) Is a Potentmentioning

confidence: 99%

Synthesis, separation, and absolute configuration of the two 5-(2,2-dibromocyclopropyl) and four 5-(2-bromocyclopropyl) diastereomers of 2′-deoxyuridine

Tandon¹,

Wiebe²,

Knaus³

1989

Can. J. Chem.

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“…Currently, more effective and selective antiherpes drugs are being sought. One possible strategy is the exploitation of differences between virus-specific enzymes and the corresponding host cell enzymes [3]. Thus, the objectives of this study are twofold:…”

Section: Introductionmentioning

confidence: 99%

A pseudoreceptor modelling study of the varicella-zoster virus and human thymidine kinase binding sites

Greenidge

Merz

Folkers

1995

J Computer-Aided Mol Des

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A representative range of pyrimidine nucleoside analogues that are known to inhibit herpes simplex virus (HSV) replication have been used to construct receptor binding site models for the varicella-zoster virus (VZV) thymidine kinase (TK) and human TK1. Given a set of interacting ligands, superimposed in such a manner as to define a pharmacophore, the pseudoreceptor modelling technique Yak provides a means of building binding site models of macromolecules for which no three-dimensional experimental structures are available. Once the models have been evaluated by their ability to reproduce experimental binding data [Vedani et al., J. Am. Chem. Soc., 117 (1995) 4987], they can be used for predictive purposes. Calculated and experimental values of relative binding affinity are compared. Our models suggest that the substitution of one residue may be sufficient to determine ligand subtype affinity.

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“…eknaus@pharmacy.ualberta.ca has the (E) stererochemisty, and possesses a hydrophobic electronegative atom (3).…”

mentioning

confidence: 99%

Synthesis of 5-(1-azidovinyl) and 5-[2-(1-azirinyl)] analogs of 2′-deoxyuridine

Kumar¹,

Wiebe²,

Knaus³

1996

Can. J. Chem.

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The regiospecific addition of bromine azide to the vinyl substituent of 5-vinyl-3',5'-di-0-acetyl-(or tertbutyldimethylsily1)-2'-deoxyuridines (2) yielded the corresponding 5-(1-azido-2-bromoethyl)-3',5'-di-O-protected-2'-deoxyuridines (3). Treatment of the 5-(1 -azido-2-bromoethyl) compounds 3 with t-BuOK, to effect the base-catalyzed elimination of HBr, afforded the corresponding 5-(I-azidoviny1)-2'-deoxyuridines (4,7). Thermal decomposition of 5-(1-azidoviny1)-2'-deoxyuridine (7) at 1 10°C in dioxane yielded 5-[2-( 1 -azirinyl)]-2'-deoxyuridine (9). 5-( 1 -Azidoviny 1)-2'-deoxyuridine (7) exhibited appreciable in vitro antiviral activities againist herpes simplex virus type 1 (HSV-1) and varizella zoster virus (VZV). Athough 7 increased the length of survival of HSV-1 brain-infected mice, it did not decrease the mortality rate relative to placebo. 5-[2-(1-Azirinyl)]-2'-deoxyuridine (9) was an inactive antiviral agent.Key words: azidovinyl, azirinyl, 2'-deoxyuridine, antiviral activity.RCsumC : L'addition rCgiospCcifique de l'azoture de brome sur le substituant vinylique des 5-vinyl-3'-di-0-acCtyl-(ou tertbutyldimCthylsilyl)-2'-dCsoxyuridines (2) conduit aux 5-(1-azido-2-bromoCthyl)-3',5'-protCgC-2'-dCs0xyuridines (3). Le traitement des composCs 3 par le t-BuOK provoque une Climination basocatalysCe de HBr qui conduit aux 5-(1-azidoviny1)-2'-dCsoxyuridines (4,7). La dCcomposition thermique de la 5-(azidoviny1)-2'-dCsoxyuridine (7), j. 1 10°C, dans le dioxane, foumit de la 5-12-(1-azirinyl)]-2'-dCsoxyuridine (9). La 5-(1-azidoviny1)-2'-dCsoxyuridine (7) prCsente des activitCs antiviral in vitro apprCciables contre le virus de l'herpks simplex de type I (HSV-1) et le virus zoster varizella (VZV). M&me si le composC 7 augmente le temps de survie des souris dont le cerveau a CtC infect6 au HSV-I, il ne diminue pas le taux de mortalit6 par rapport au placebo. Le 5-[2-(1-azirinyl)]-2'-dCsoxyuridine (9) n'est pas actif comme agent antiviral. The development of new methods for the synthesis of 2'-deoxyuridines that possess novel vinyl moieties at the C-5 position and exhibit potent antiviral activity represents an important area of drug design. 5-Vinyl-2'-deoxyuridine ( l a ) has been shown to exhibit potent antiviral activity against herpes simplex virus type-1 (HSV-l), type-2 (HSV-2), and vaccinia virus (1). Among the many 5-substituted pyrimidine nucleosides that have been studied, (E)-5-(2-halovinyl)-2'-deoxyuridines (lb; X = I (IVDU); X = Br (BVDU); X = C1 (CVDU)) are among the most active and selective in their action against HSV-1 (2). Incorporation of a methyl substituent at the l-position of the 5-(2-bromovinyl) moiety of BVDU (lc) (3), or a chloro substituent at the 1-position of the 5-vinyl moiety of VDU (16) (4), reduced activity against HSV-1. Structureactivity correlations for a group of 5-substituted-2'-deoxyuridines indicated that optimum antiviral activity against HSV-1 occurs when the C-5 substituent is unsaturated and conjugated with the uracil ring, is not larger than four atoms in length...

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Structural requirements of olefinic 5-substituted deoxyuridines for antiherpes activity

Cited by 66 publications

References 1 publication

Synthesis, separation, and absolute configuration of the two 5-(2,2-dibromocyclopropyl) and four 5-(2-bromocyclopropyl) diastereomers of 2′-deoxyuridine

Synthesis, separation, and absolute configuration of the two 5-(2,2-dibromocyclopropyl) and four 5-(2-bromocyclopropyl) diastereomers of 2′-deoxyuridine

A pseudoreceptor modelling study of the varicella-zoster virus and human thymidine kinase binding sites

Synthesis of 5-(1-azidovinyl) and 5-[2-(1-azirinyl)] analogs of 2′-deoxyuridine

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