Fluoro carbocyclic nucleosides: synthesis and antiviral activity of 2'- and 6'-fluoro carbocyclic pyrimidine nucleosides including carbocyclic 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-5-methyluracil and carbocyclic 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-5-iodouracil.
The racemic carbocyclic 2'-fluoroarabinosyl pyrimidine nucleosides 8, 9 (C-FIAU), 12, and 13 (C-FMAU) and the 2'-fluororibosyl pyrimidine nucleosides 17, 20, and 21 were prepared from their respective protected 2'-fluoro amino diols 5 and 14. The carbocyclic 2'-2'-difluorothymidine analogue 27 was obtained from the protected difluoro amino diol 24 which was prepared from the ketone 23 and (diethylamino)sulfur trifluoride (DAST). The chiral carbocyclic 2'-deoxy-6'-fluorouridines 33, 34, 38, and 39 were synthesized from the protected 6'-fluoro amino diols 30 and 36, which were prepared by reduction of the azides 28 and 35. C-FMAU (13) and C-FIAU (9) were active in vitro against HSV-1 with ID50 values of 4.4 and 11 micrograms/mL, respectively, but they were inactive against HSV-2. The cytidine analogues 12 and 20 displayed modest activity in vitro against HSV-1 and HSV-2 but were inactive against human influenza A virus.
Borthwick
A D
AD
Department of Microbiological Chemistry, Glaxo Group Research, Greenford, Middlesex, U.K.
Evans
D N
DN
Kirk
B E
BE
Biggadike
K
K
Exall
A M
AM
Youds
P
P
Roberts
S M
SM
Knight
D J
DJ
Coates
J A
JA
D000818:Animals; D000998:Antiviral Agents; D002460:Cell Line; D055598:Chemical Phenomena; D002621:Chemistry; D003461:Crystallography; D009980:Influenza A virus / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D015394:Molecular Structure; D011741:Pyrimidine Nucleosides / Q000138:chemical synthesis / Q000494:pharmacology*; D018139:Simplexvirus / Q000187:drug effects*; D014709:Vero Cells; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D011741:Pyrimidine Nucleosides; C062440:1-((1,2,3,4)-2-fluoro-3-hydroxy-4-(hydroxymethyl)cyclopentyl)-5-methyl-2,4-(1H,3H)-pyrimidinedione; C062441:1-((1,2,3,4)-2-fluoro-3-hydroxy-4-( hydroxymethyl)cyclopentyl)-5-iodo-2,4(1H,3H)-pyrimidinedione