Synthesis and antiviral activity of 1-cyclobutyl-5-(2-bromovinyl)uracil nucleoside analogues and related compounds.
A series of racemic (1 alpha (E), 2 beta, 3 alpha)-1-[2,3-bis(hydroxymethyl)cyclobutyl]-5-(2-halovinyl)uracils was synthesized and evaluated in cell culture. The bromovinyl, iodovinyl, and chlorovinyl analogues, 13, 15, and 16, respectively, are all potent inhibitors of varicella zoster virus (VZV), but are less inhibitory to the replication of human cytomegalovirus (HCMV) and herpes simplex viruses 1 and 2 (HSV-1, HSV-2). The excellent anti-VZV activities of 13, 15, and 16 coupled with their virtual inability to inhibit WI-38 cell growth indicate high in vitro therapeutic indices. VZV thymidine kinase readily converts these compounds to their respective monophosphates but not to their corresponding diphosphates. Compound 13a, the (1'R) enantiomer of the bromovinyl analogue 13, was also synthesized, and its potency is comparable to that of the racemate. A lower homologue 14, (1 alpha (E),2 beta, 3 alpha)-1-[2-hydroxy-3-(hydroxymethyl)cyclobutyl]-5- (2-bromovinyl)uracil, was found to be inactive against VZV, HCMV, HSV-1, and HSV-2.
Slusarchyk
W A
WA
Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000.
Bisacchi
G S
GS
Field
A K
AK
Hockstein
D R
DR
Jacobs
G A
GA
McGeever-Rubin
B
B
Tino
J A
JA
Tuomari
A V
AV
Yamanaka
G A
GA
Young
M G
MG
D000998:Antiviral Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D002478:Cells, Cultured; D003503:Cyclobutanes / Q000138:chemical synthesis / Q000494:pharmacology*; D003587:Cytomegalovirus / Q000187:drug effects / Q000502:physiology; D014645:Herpesvirus 3, Human / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D010766:Phosphorylation; D018139:Simplexvirus / Q000187:drug effects / Q000502:physiology; D013937:Thymidine Kinase / Q000378:metabolism; D014498:Uracil / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D003503:Cyclobutanes; D014498:Uracil; D013937:Thymidine Kinase