856669-38-0Relevant articles and documents
Inhibition of herpes simplex virus thymidine kinases by 2-phenylamino-6-oxopurines and related compounds: Structure-activity relationships and antiherpetic activity in vivo
Manikowski, Andrzej,Verri, Annalisa,Lossani, Andrea,Gebhardt, Bryan M.,Gambino, Joseph,Focher, Federico,Spadari, Silvio,Wright, George E.
, p. 3919 - 3929 (2007/10/03)
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 μM 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.
