Synthesis and antiviral properties of (E)-5-(2-bromovinyl)-2'-deoxycytidine-related compounds.
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-br o movinyl)- 4-(1,2,4-triazol-1-yl)pyrimidin-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-acetyl-thymidine by the use of phosphoryl chloride as the condensing agent. Treatment of thymidine with trimethylsilyl chloride 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product formed in both cases was a 4-(1,2,4-triazol-1-yl) derivative in which the nucleoside 5'-hydroxyl group had been replaced by chlorine (6 and 8).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.
Jones
A S
AS
Chemistry Department, University of Birmingham, Great Britain.
Sayers
J R
JR
Walker
R T
RT
De Clercq
E
E
D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis*; D001972:Bromodeoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D001973:Bromodeoxyuridine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D002478:Cells, Cultured; D003841:Deoxycytidine / Q000031:analogs & derivatives*; D007202:Indicators and Reagents; D007668:Kidney; D011817:Rabbits; D018139:Simplexvirus / Q000187:drug effects*; D013329:Structure-Activity Relationship; D014721:Vesicular stomatitis Indiana virus / Q000187:drug effects*
D000998:Antiviral Agents; D007202:Indicators and Reagents; D003841:Deoxycytidine; D001972:Bromodeoxycytidine; C045536:5-(2-bromovinyl)-2'-deoxycytidine; D001973:Bromodeoxyuridine