P. J. Barr

Pharmacokinetics of E-5-(2-Bromovinyl)-2′-Deoxyuridine in Mice

The pharmacokinetics of the newly developed anti-herpes agent, E-5-(2-bromovinyl)-2′-deoxyuridine, was compared with that of the standard anti-herpes drug 5-iodo-2′-deoxyuridine. Both compounds were administered to mice at 100 mg/kg by either the intraperitoneal, subcutaneous, or oral route. The active blood drug levels achieved by E-5-(2-bromovinyl)-2′-deoxyuridine were considerably higher than those attained by 5-iodo-2′-deoxyuridine (serum peak concentrations: 40 to 100 and 4 to 10 μg/ml, respectively). Active blood drug levels could still be found 320 min after oral administration of E-5-(2-bromovinyl)-2′-deoxyuridine.

Synthesis of some 5-halogenovinyl derivatives of uracil and their conversion into 2′-deoxyribonucleosides

Treatment of 5-formyluracil with malonic acid in the presence of piperidine gave (E)-5-(2-carboxyvinyl)uracil which, upon reaction with the appropriate N-halogenosuccinimide, gave (E)-5-(2-bromovinyl)uracil, (E)-5-(2-chlorovinyl)uracil, and (E)-5-(2-iodovinyl)uracil. The last mentioned compound was also obtained by the action of iodine chloride on 5-vinyluracil. 5-(1-Chlorovinyl)uracil upon treatment with bromine gave 5(2-bromo-1-chlorovinyl)uracil which reacted with sodium methoxide to give 5-bromoethynyluracil. (E)-5-(2-Bromovinyl)-uracil was converted into into its trimethylsilyl derivative which was condensed with 2-deoxy-3,5-di-O-(p-toluoyl)-α-D-erythro-pentofuranosyl chloride to give the α- and β-anomers of the blocked deoxyribonucleoside. Removal of the p-toluoyl blocking groups with sodium methoxide afforded (E)-5-(2-bromovinyl)-1-(2-deoxy-α-D-erythro-pentofuranosyl)uracil and (E)-5-(2-bromovinyl)-2′-deoxyuridine. A similar series of reactions gave (E)-5-(2-iodovinyl)-2′-deoxyuridine and 5-(2-bromo-1-chlorovinyl)-2′-deoxyuridine. 5-(1-Chlorovinyl)uracil could be condensed similarly with the blocked sugar derivative to give the α- and β-anomers of the blocked deoxyribonucleoside. Attempted removal of the groups with sodium methoxide gave 2′-deoxy-5-ethynyluridine and mild treatment with methanolic ammonia gave the same product and some 2′-deoxy-5-ethynyl-5′-O-(p-toluoyl)-uridine. 5-(1-Chlorovinyl)-2′-deoxyuridine was obtained by the addition of HCl to 2′-deoxy-5-ethynyluridine. Aspects of the elimination reactions of 5-(halogenovinyl)uracil derivatives are discussed.

COMPARATIVE STUDY OF THE POTENCY AND SELECTIVITY OF ANTI-HERPES COMPOUNDS

Several anti-herpes compounds, including phosphonoacetic acid, 9-(2-hydroxyethoxymethyl) guanine, 9-β-D-arabinofuranosyladenine, 1-β-D-arabinofuranosylthymine, 5-iodo-5′-amino-2;5′-dideoxyuridine, 5-iodo-2′-deoxyuridine, 5-bromo-2′-deoxycytidine and various other 5-substituted 2′-deoxyuridines and 2′-deoxycytidines were compared in vitro (primary rabbit kidney cells) for both antiviral activity (based on the ID50 required to inhibit the cytopathogenicity of the KOS strain of type 1 herpes simplex virus) and antimetabolic activity (based on the ID50 required to inhibit the incorporation of 2′-deoxyuridine into host cell DNA). Of the whole set of compounds tested, E-5-(2-bromovinyl)- and E-5-(2-iodovinyl)-2′-deoxyuridine emerged as both the most potent and the most selective anti-herpes agents.

The synthesis of nucleosides derived from 5-ethynyluracil and 5-ethynylcytosine

5-Ethynyluridine and 2′-deoxy-5-ethynyluridine have been synthesised by condensation of the trimethylsilyl derivative of 5-ethynyluracil with the appropriate blocked sugar derivatives and removal of the blocking groups. The α-anomer of 2′-deoxy-5-ethynyluridine was also obtained. 2,4-Dichloro-5-(1-chlorovinyl)pyrimidine upon treatment with ammonia gave a mixture of 2-amino-4-chloro-5-(1-chlorovinyl)pyrimidine and 4-amino-2-chloro-5-(1-chlorovinyl)pyrimidine. The latter upon treatment with potassium hydroxide in aqueous dioxan gave 5-ethynylcytosine. Condensation of the trimethylsilyl derivative of 5-ethynylcytosine with appropriate protected sugar derivatives and removal of the protecting groups gave 5-ethynylcytidine, 2′-deoxy-5-ethynylcytidine, and its α-anomer.