Synthesis and antiviral properties of (E)-5-(2-bromovinyl)-2'-deoxycytidine-related compounds

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Abstract
Treatment of 3'',5''-di-O-acetyl-(E)-5-(2-bromovinyl)-2''-deoxyuridine (2) with p-chlorophenyl phosphorodichloridate and 1,2,4-triazole gave 1-(3,5-di-O-acetyl-2-deoxy-.beta.-D-erythro-pentofuranosyl)-(E)-5-(2-bromovinyl)-4-(1,2,4-triazol-1-yl)pyrimidine-2(1H)-one (3). Reaction of 3 with ammonia gave (E)-5-(2-bromovinyl)-2''-deoxycytidine (1), the overall yield from 2 being 60%. A similar 4-(1,2,4-triazol-1-yl) derivative (4) was obtained from 3'',5''-di-O-acetylthymidine by the use of phosphoryl chloride as the condensing agent. Treatment of thymidine with trimethylsilylchloride and then with phosphoryl chloride and 1,2,4-triazole gave upon workup 1-(2-deoxy-.beta.-D-erythro-pentofuranosyl)-5-methyl-4(1,2,4-triazol-1-yl)pyrimidin-2(1H)-one (5). (E)-5-(2-Bromovinyl)-2''-deoxyuridine (BVDU) when similarly treated gave the corresponding (E)-5-(2-bromovinyl) compound 7. A minor product formed in both cases was a 4-(1,2,4-triazol-1-yl) derivative in which the nucleoside 5''-hydroxyl group had been replaced by chlorine (6 and 8). Whereas compounds 4-6 and 8 did not exhibit a selective antiviral effect, compounds 1-3 and 7 proved almost as active as the reference compound BVDU. In particular, compound 7, the 4-triazolyl derivative of BVDU, would seem worth pursuing for its potential as an inhibitor of herpes simplex virus type 1 and varicella-zoster virus.

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