brivudine and 6-aminothymine

5-Iodo-2'-deoxyuridine (IUDR) is a potent topical antiviral agent in experimental animals but is less active in man for treating cutaneous viral infections. We have shown here that IUDR is 5 times less active in human keratinocytes infected in vitro with herpes simplex virus type 1 than in guinea pig embryo cells infected in culture. To account, in part, for this difference in activity of IUDR, we measured the capacity of these different cultures to catabolize and thus inactivate the drug. IUDR is catabolized by thymidine phosphorylase; activity of this enzyme was very high in human keratinocytes in vitro but was very low in guinea pig embryo cells. The antiviral activity of IUDR in human keratinocytes, however, was not increased by inhibiting thymidine phosphorylase; inhibiting thymidine phosphorylase apparently increased the availability of thymidine that would compete with IUDR and, indeed, the activity of IUDR in infected cells was reduced by addition of thymidine to the medium. These data indicate that the catabolism of IUDR and related analogs alters antiviral activity in human keratinocytes.

Topics: Animals; Antiviral Agents; Bromodeoxyuridine; Drug Interactions; Guinea Pigs; Herpes Simplex; Humans; Idoxuridine; Keratinocytes; Simplexvirus; Thymidine; Thymidine Phosphorylase; Thymine; Zidovudine

(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

Various 5-substituted-2'-deoxyuridines (dUrd), including 5-ethyl,5-propyl-, 5-trifluoromethyl-, 5-hydroxymethyl-, 5-formyl-, 5-vinyl-, (E)-5-(2-chlorovinyl)-, (E)-5-(2-bromovinyl)-, 5-fluoro-, 5-chloro-, 5-bromo-, 5-iodo-, 5-cyano-, 5-thiocyano-, 5-nitro- and 5-amino-dUrd, were shown to be effective substrates for the thymidine (dThd) phosphorylase isolated from human blood platelets. Some of dUrd analogs, i.e. the highly potent and selective antiherpes agent (E)-5-(2-bromovinyl)-dUrd, were degraded more rapidly than the natural substrates, dUrd and dThd. All dUrd analogs were also readily catabolised by intact human blood platelets. The potent inhibitors of thymidine phosphorylase, 6-amino-thymine and 6-amino-5-bromo-uracil, strongly inhibited the phosphorolysis of (E)-5-(2-bromovinyl)-dUrd by both purified enzyme and intact platelets.

Topics: Blood Platelets; Bromodeoxyuridine; Bromouracil; Chromatography, High Pressure Liquid; Deoxyuridine; Humans; In Vitro Techniques; Pentosyltransferases; Thymidine Phosphorylase; Thymine