Inhibition of Herpes simplex virus thymidine kinases by 2-Phenylamino-6-oxopurines and related compounds: Structure-Activity Relationships and antiherpetic activity in vivo. (Articolo in rivista)

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  • Inhibition of Herpes simplex virus thymidine kinases by 2-Phenylamino-6-oxopurines and related compounds: Structure-Activity Relationships and antiherpetic activity in vivo. (Articolo in rivista) (literal)
Anno
  • 2005-01-01T00:00:00+01:00 (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#doi
  • 10.1021/jm049059x (literal)
Alternative label
  • Manikowski A; Verri A; Lossani A; Gebhardt BM; Gambino J; Focher F; Spadari S; Wright GE (2005)
    Inhibition of Herpes simplex virus thymidine kinases by 2-Phenylamino-6-oxopurines and related compounds: Structure-Activity Relationships and antiherpetic activity in vivo.
    in Journal of medicinal chemistry
    (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#autori
  • Manikowski A; Verri A; Lossani A; Gebhardt BM; Gambino J; Focher F; Spadari S; Wright GE (literal)
Pagina inizio
  • 3919 (literal)
Pagina fine
  • 3929 (literal)
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  • 48 (literal)
Rivista
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#note
  • Impact Factor = 5.076 (literal)
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  • 11 (literal)
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  • articolo scientifico (literal)
Note
  • ISI Web of Science (WOS) (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#affiliazioni
  • GLSynthesis Inc., One Innovation Drive, Worcester, Massachusetts 01605, Istituto di Genetica Molecolare, Consiglio Nazionale delle Ricerche, Pavia, Italy 27100, and LSU Eye Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112 (literal)
Titolo
  • Inhibition of Herpes simplex virus thymidine kinases by 2-Phenylamino-6-oxopurines and related compounds: Structure-Activity Relationships and antiherpetic activity in vivo. (literal)
Abstract
  • Derivatives of the herpes simplex thymidine kinase inhibitor HBPG [2-phenylamino-9-(4-hydroxybutyl)-6-oxopurine] have been synthesized and tested for inhibitory activity against recombinant enzymes (TK) from herpes simplex types 1 and 2 (HSV-1, HSV-2). The compounds inhibited phosphorylation of [3H]thymidine by both enzymes, but potencies differed quantitatively from those of HBPG and were generally greater for HSV-2 than HSV-1 TKs. Changes in inhibitory potency were generally consistent with the inhibitor/substrate binding site structure based on published X-ray structures of HSV-1 TK. In particular, several 9-(4-aminobutyl) analogues with bulky tertiary amino substituents were among the most potent inhibitors. Variable substrate assays showed that the most potent compound, 2-phenylamino-9-[4-(1-decahydroquinolyl)butyl]-6-oxopurine, was a competitive inhibitor, with Ki values of 0.03 and 0.005 microM against HSV-1 and HSV-2 TKs, respectively. The parent compound HBPG was uniquely active in viral infection models in mice, both against ocular HSV-2 reactivation and against HSV-1 and HSV-2 encephalitis. In assays lacking [3H]thymidine, HBPG was found to be an efficient substrate for the enzymes. The ability of the TKs to phosphorylate HBPG may relate to its antiherpetic activity in vivo. (literal)
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