Fluorocarbocyclic nucleosides: synthesis and antiviral activity of 2'- and 6'-fluorocarbocyclic 2'-deoxy guanosines.
A series of four isomeric 2'- and 6'-fluorocarbocyclic guanosine analogues have been prepared and evaluated as potential anti-herpes agents. The racemic 2' beta-fluoro isomer 2-amino-1,9-dihydro- 9-[(1 alpha, 2 alpha, 3 beta, 4 alpha)-2-fluoro-3-hydroxy-4- (hydroxymethyl)cyclopentyl]-6H-purin-6-one (11a, C-AFG) and its 2' alpha-fluoro epimer 11b plus the chiral 6' beta-fluoro isomer 2-amino-1,9-dihydro-9-[[1S-(1 alpha, 2 alpha, 3 alpha, 4 beta)]- 2-fluoro-4-hydroxy-3-(hydroxymethyl)cyclopentyl]-6H-purine-6-one (11c) and its 6' alpha-fluoro epimer 11d were prepared from their respective fluoro amino diol hydrochlorides (6a,d). For comparison, the furanosyl compound 9-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)guanine (17, AFG) was prepared by coupling 2-amino-6-chloropurine with 2-deoxy-2-fluoro-3,5-di-O-benzoyl-alpha- D-arabinofuranosyl bromide followed by base hydrolysis. The 6' alpha-fluoro derivative 11d exhibited comparable activity to that of acyclovir (ACV) against herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) in vitro but was greater than 30-fold more active than ACV against HSV-1 and HSV-2 in vivo in the mouse systemic model. The 2' beta-fluoro derivative (11a, C-AFG) was extremely potent in vitro against HSV-1 and HSV-2 (ID50 0.006 and 0.05 micrograms/mL) and in vivo it was greater than 2 orders of magnitude more potent than ACV against HSV-1 and 70-fold more potent against HSV-2. The 2' alpha-fluoro 11b and 6' beta-fluoro 11c isomers were much less active.
Borthwick
A D
AD
Glaxo Group Research, Greenford Middlesex, U.K.
Kirk
B E
BE
Biggadike
K
K
Exall
A M
AM
Butt
S
S
Roberts
S M
SM
Knight
D J
DJ
Coates
J A
JA
Ryan
D M
DM
D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D055598:Chemical Phenomena; D002621:Chemistry; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D006561:Herpes Simplex / Q000188:drug therapy*; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D018139:Simplexvirus / Q000502:physiology*; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; C067813:2-amino-1,9-dihydro-9-(2-fluoro-3-hydroxy-4-(hydroxymethyl)cyclopentyl)-6H-purin-6-one; C067812:2-amino-1,9-dihydro-9-(2-fluoro-4-hydroxy-3-(hydroxymethyl)cyclopentyl)-6H-purin-6-one; D003849:Deoxyguanosine