sorivudine and thymine-arabinoside

Introduction of a bulky lipophilic acyl entity at the 2'-OH position of both 1-beta-D-arabinofuranosylthymine (araT) and (E)-5-(2-bromovinyl)-1-beta-D-arabinofuranosyluracil (BVaraU), consistently resulted in a marked ( approximately 10-fold) increase in the inhibitory activity of these new arabinosyl nucleoside analogues for the mitochondrial thymidine kinase (TK-2)-catalysed conversion of 2 microM [methyl-(3)H]dThd to [methyl-(3)H]dTMP. The most potent derivatives were inhibitory to [methyl-(3)H]dThd phosphorylation by TK-2 within the lower micromolar concentration range. Substitution of the arabinosyl nucleoside derivatives with the acyl groups also dramatically increased the selectivity of these compounds. The inhibitory activity of araT and BVaraU to dThd phosphorylation by other related nucleoside kinases, including herpes simplex virus type 1 TK, varicella-zoster virus TK, and cytosolic TK-1, was completely annihilated upon 2'-O-acyl substitution (IC(50) > or = 1000 microM). Kinetic analysis revealed purely competitive inhibition of 2'-O-acyl-BVaraU against TK-2-catalysed thymidine phosphorylation (K(i)/K(m): 2.3). However, 2'-O-acyl-BVaraU was extremely poorly converted to the corresponding arabinosyl nucleoside 5'-monophosphate by TK-2 as revealed by [gamma-(32)P]phosphate transfer studies from [gamma-(32)P]ATP. Thus, the 2'-O-acyl derivatives of BVaraU did not behave as substrates, but rather as potent and highly selective inhibitors of TK-2. This is the first report on such a highly selective arabinosyl nucleoside inhibitor of mitochondrial TK-2, and opens perspectives for the rational design of selective mitochondrial TK-2 inhibitors.

Topics: Adenosine Triphosphate; Antineoplastic Agents; Antiviral Agents; Arabinofuranosyluracil; Arabinonucleosides; Binding, Competitive; Humans; Kinetics; Mitochondria; Phosphorus Radioisotopes; Phosphorylation; Thymidine; Thymidine Kinase; Tritium

Antiviral activities of five nucleoside analogs against the VR-3 and WT-34 strains of herpes simplex virus type 1 (HSV-1) were investigated in Vero and human embryo lung fibroblast (HEL) cells. In HEL cells, the compounds showed antiviral activities against both strains of HSV-1, but in Vero cells, the antiviral activities of the compounds were reduced in proportion to their antiviral indexes (the 50% inhibitory dose [ID50] for cell growth divided by the 50% plaque reduction dose for virus). The ratio of the ID50 in Vero cells to the ID50 in HEL cells was larger in VR-3-infected cells than in WT-34-infected cells. The following results were obtained. (i) Thymidine kinase (TK; EC 2.7.1.21) activity in the VR-3- or WT-34-infected Vero cells was about half that in VR-3- or WT-34-infected HEL cells. Induction of viral TK was especially low in the VR-3-infected Vero cells. (ii) The ID50 of the plaque reduction assay in hypoxanthine, aminopterin, and thymidine medium revealed that the activity of cellular thymidylate synthetase (EC 2.1.1.45) was important in viral replication in VR-3-infected Vero cells. (iii) The VR-3-infected cells required larger thymidine and thymidine phosphate pools for viral replication than the WT-34-infected cells did, although uptake of 1-beta-D-arabinofuranosyl-E-5-(2-bromovinyl) uracil into infected cells was equal for both strains. (iv) In the VR-3-infected Vero cells, the quantity of 1-beta-D-arabinofuranosyl-E-5-(2-bromovinyl)uracil triphosphate was smaller than that in VR-3-infected HEL cells and WT-34-infected Vero and HEL cells.

Topics: Acyclovir; Aminopterin; Animals; Antiviral Agents; Arabinofuranosyluracil; Arabinonucleosides; Dose-Response Relationship, Drug; Fibroblasts; Humans; Idoxuridine; Lung; Nucleosides; Simplexvirus; Thymidine; Vero Cells; Vidarabine

1-beta-D-Arabinofuranosylthymine (ara-T) and 1-beta-D-arabinofuranosyl-E-5-(2-bromovinyl)uracil (BV-ara-U) were shown to have antiviral activity in vitro and in vivo against simian varicella virus. Both compounds successfully prevented clinical disease caused by inoculation of African green monkeys with simian varicella virus, eliminating the development of rash and substantially suppressing viremia. Ara-T treatment was effective by either intraperitoneal or oral routes of administration and BV-ara-U was active by both oral and intramuscular routes. Ara-T, however, was associated with the appearance of marked signs of neurotoxicity. Histologic examination of brain tissue demonstrated chromatolysis and pyknosis of neurons and pyknotic nuclei in glial cells. The neurologic impairment persisted in affected monkeys. This observation of central nervous system toxicity in monkeys is in contrast to studies in mice and rats where high doses of ara-T by multiple routes of administration were nontoxic. No apparent toxicity was observed in monkeys treated with BV-ara-U.

Topics: Animals; Arabinofuranosyluracil; Arabinonucleosides; Chickenpox; Chlorocebus aethiops; Herpesviridae Infections; Nervous System; Neurons; Thymidine; Uridine