5-(2-bromovinyl)uracil and brivudine

The susceptibility of the bicyclic nucleoside analogs (BCNAs), highly potent and selective inhibitors of varicella-zoster virus (VZV), to the enzymes involved in nucleoside/nucleobase catabolism has been investigated in comparison with the established anti-VZV agent (E)-5-(2-bromovinyl)-2'-deoxyuridine [BVDU; brivudine (Zostex)]. Whereas human and bacterial thymidine phosphorylases (TPases) efficiently converted BVDU to its antivirally inactive free base (E)-5-(2-bromovinyl)uracil (BVU), BCNAs showed no evidence of conversion to the free base in the presence of these enzymes. The lack of substrate affinity of TPase for the BCNAs could be rationalized by computer-assisted molecular modeling of the BCNAs in the TPase active site. Moreover, in contrast with BVU, which is a potent and selective inhibitor of dihydropyrimidine dehydrogenase (DPD) (50% inhibitory concentration; 10 microM in the presence of a 25 microM concentration of the natural substrate thymine), the free base (Cf 1381; 6-octyl-2,3-dihydrofuro[2,3-d]pyrimidin-2-one) of BCNA (Cf 1368; 3-(2'-deoxy-beta-D-ribofuranosyl)-6-octyl-2,3-dihydrofuro[2,3-d]pyrimidin-2-one) and the free base Cf 2200 [6-(4-n-pentylphenyl)-2,3-dihydrofuro[2,3-d]pyrimidin-2-one] of BCNA (Cf 1743; 3-(2'-deoxy-beta-D-ribofuranosyl)-6-(4-n-pentylphenyl)-2,3-dihydrofuro[2,3-d]pyrimidin-2-one) did not inhibit the DPD-catalyzed catabolic reaction of pyrimidine bases (i.e., thymine) and pyrimidine base analogs [i.e., 5-fluorouracil (FU)] at a concentration of 250 microM. Consequently, whereas BVU caused a dramatic rise of FU levels in FU-treated mice, the BCNAs did not affect FU levels in such mice. From our data it is evident that BCNAs represent highly stable anti-VZV compounds that are not susceptible to breakdown by nucleoside/nucleobase catabolic enzymes and are not expected to interfere with cellular catabolic processes such as those involved in FU catabolism.

Topics: Animals; Antiviral Agents; Binding Sites; Bromodeoxyuridine; Bromouracil; Dihydrouracil Dehydrogenase (NADP); Drug Interactions; Escherichia coli; Fluorouracil; Herpesvirus 3, Human; Heterocyclic Compounds, 2-Ring; Humans; Mice; Models, Molecular; Nucleosides; Oxidoreductases; Substrate Specificity; Thymidine Phosphorylase

(E)-5-(2-Bromovinyl)uracil (BVU) and (E)-5-(2-bromovinyl)uridine (BVRU) were synthesized starting from 5-formyluracil via (E)-5-(2-carboxyvinyl)uracil or starting from 5-iodouridine via (E)-5-(2-carbomethoxyvinyl)uridine and (E)-5-(2-carboxyvinyl)uridine, respectively. Depending on the choice of the cell system, BVU and BVRU exhibited a marked activity against herpes simplex virus type 1 (HSV-1) in vitro. Although BVU and BVRU were less potent than the reference compound (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU), their antiviral activity spectrum was remarkably similar to that of BVDU. The latter findings suggest that BVU and BVRU are metabolically converted to BVDU or a phosphorylated product thereof. In vivo, BVU protected mice against a lethal disseminated HSV-1 infection.

Topics: Animals; Antiviral Agents; Bromodeoxyuridine; Bromouracil; Deoxyuridine; Herpes Simplex; Mice; Mice, Inbred BALB C; Rabbits; Simplexvirus; Thymine; Uridine; Virus Replication

In the rat, the highly potent anti-herpes drug (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVdUrd) is rapidly converted to its base (E)-5-(2-bromovinyl)uracil (BVUra) through the action of pyrimidine nucleoside phosphorylases. However, BVdUrd can be regenerated or even generated de novo from BVUra by a pentosyl transfer reaction upon the administration of 2'-deoxythymidine (dThd), 2'-deoxyuridine (dUrd) or 5-ethyl-2'-deoxyuridine (EtdUrd). The antiherpetic drugs EtdUrd and 5-(2-chloroethyl)-2'-deoxyuridine (ClEtdUrd) can also be regenerated or generated de novo from their respective bases 5-ethyluracil (EtUra) and 5-(2-chloroethyl)uracil (ClEtUra), by a pentosyl transfer mediated by the administration of dThd or dUrd as deoxyribosyl donor. The generation or regeneration of BVdUrd, EtdUrd and ClEtdUrd from their bases (BVUra, EtUra and ClEtUra, respectively) is readily achieved because the latter have long half-lifes. Thus, the active anti-herpes drugs can be (re)generated repeatedly after a single administration of these nucleosides or their bases, followed by repeated administrations of dUrd.

Topics: Animals; Antiviral Agents; Bromodeoxyuridine; Bromouracil; Deoxyuridine; Half-Life; Humans; Male; Rabbits; Rats; Rats, Inbred Strains; Simplexvirus; Uracil

(E)-5-(2-bromovinyl)-2'-deoxyuridine (BDVU), one of the most potent and selective anti-herpes agents described to date, and its close congeners (E)-5-(2-bromovinyl)-1-beta-D-arabinofuranosyluracil (BVaraU) and (E)-5-(2-bromovinyl)uracil (BVU), as well as the reference compounds 5-iodo-2'-deoxyuridine (IDU) and 5-trifluoro-2'-deoxythymidine (TFT) were examined for their genotoxic potential. With the exception of a weak activity of TFT in the newly developed strain TA 102, none of the compounds was active in a bacterial cell mutagenesis (Salmonella/microsome) assay. Nor did they induce DNA repair (unscheduled DNA synthesis) in primary rat hepatocytes. In a mammalian cell mutagenesis assay using V79 Chinese hamster cells, the reference compounds IDU and TFT proved highly cytotoxic and mutagenic, whereas BVDU, BVaraU and BVU were neither cytotoxic nor mutagenic.

Topics: Animals; Antiviral Agents; Bromodeoxyuridine; Bromouracil; Cells, Cultured; Cricetinae; Cricetulus; DNA Repair; Liver; Male; Mutagens; Rats; Rats, Inbred Strains; Salmonella typhimurium

Topics: Animals; Antiviral Agents; Bromodeoxyuridine; Bromouracil; Chromatography, High Pressure Liquid; Dogs; Humans; Rats; Reference Standards; Species Specificity