A. S. Jones

The synthesis of the potent anti-herpes virus agent, E-5(2-bromovinyl)-2′-deoxyuridine and related compounds

Abstract The synthesis of E -5(2-bromovinyl)-2′-deoxyuridine in good yield from deoxyuridine via an intermediate organopalladium derivative is described. The corresponding chloro and iodo compounds have also been made as have the corresponding bromo and iodo 2′-deoxycytidines.

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.

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.

Sister chromatid exchange induced by anti-herpes drugs.

The rate of sister chromatid exchange induced by several anti-herpes agents was measured to assess their potential mutagenicity. The agents--5-iodo-deoxyuridine (IDU), 5-trifluoromethyl-deoxyuridine (TFT), and [E]-5-(2-bromovinyl)-deoxyuridine (BVDU)--were incubated at various concentrations with human lymphocytes and fibroblasts, and that rate of sister chromatid exchanges was measured. In lymphocytes and fibroblasts BVDU and IDU did not induce exchange except at concentrations of 50 mg/l, while TFT increased the rate of exchange at a concentration of 0.5 mg/l. The rate of sister chromatid exchange is a sensitive index of chromosomal damage, and these findings provide information on the safety of some of the antiherpes agents tested. TFT increased the rate of exchange at a concentration that coincides with its minimal antiviral concentration, but BVDU did not induce exchange at therapeutic concentrations.