The antiviral activity of several nucleoside analogues is often limited by their rapid degradation by pyrimidine nucleoside phosphorylases. In an attempt to avoid this degradation, several modified nucleosides have been synthesized. A series of 4h-thio2h-deoxyuridines exhibits an anti-[herpes simplex virus (HSV)] activity significantly higher (20-600 times) than that shown by the corresponding 4h-oxy counterpart. We investigated the mode of action of these compounds and we found that : (i) several 4h-thio-2h-deoxyuridines are phosphorylated to the mono-and diphosphates by HSV-1 thymidine kinase (TK) more efficiently than their corresponding 4h-oxy counterpart ; (ii) both are inhibitors of cellular thymidylate synthase ; (iii) 4h-thio-2h-deoxyuridines are resistant to phosphorolysis by human thymidine phosphorylase ; (iv) both 4h-oxy-and 4h-thio-2h-deoxyuridines are phosphorylated to deoxyribonucleotide triphosphate in HSV-1-infected cells and are incorporated into viral DNA ; (v) 4h-thio-

(E)-5-(2-Bromovinyl)-2'-deoxy-4'-thiouridine (S-BVDU) is a potent antiherpesvirus agent and its use in gene therapy as an anticancer agent has recently been described. We here outline 2 efficient methods for the synthesis of S-BVDU. The decision as to which method is to be used depends upon the starting materials available but starting from BVU, an overall yield of beta-nucleoside of 35% can be expected. From 5-ethyl-2'-deoxy-4'-thiouridine, radical bromination using bromine will give a quantitative conversion to S-BVDU if unreacted starting material is recycled (50%) or using N-bromosuccinimide, a one step yield in excess of 80% can be obtained.

Efficient Syntheses of (E)-5-(2-Bromovinyl)-2'-deoxy-4'-thiouridine; a Nucleoside Analogue with Potent Biological Activity.-Two efficient, alternative routes to the synthesis of the title thiouridine [cf. protected precursors (VII) and (X)], one of the most potent and selective antiherpesvirus compounds known, are developed. -(BASNAK, I.; OTTER, G. P.; DUN-COMBE, R. J.; WESTWOOD, N. B.; PIETRARELLI, M.; HARDY, G. W.; MILLS, G.; RAHIM, S. G.; WALKER, R. T.; Nucleosides Nucleotides 17 (1998) 1-3, 29-38; Sch. Chem., Univ. Birmingham, Edgbaston, Birmingham B15 2TT, UK; EN)