Fluorocarbocyclic nucleosides : synthesis and antiviral activity of 2'- and 6'-fluorocarbocyclic 2'-deoxy guanosines

• Published in: Journal of medicinal chemistry Vol. 34; no. 3; pp. 907 - 914
• Main Authors: BORTHWICK, A. D, KIRK, B. E, BIGGADIKE, K, EXALL, A. M, BUTT, S, ROBERTS, S. M, KNIGHT, D. J, COATES, J. A. V, RYAN, D. M
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 01-03-1991
• Subjects: Antiviral Agents - chemical synthesis; Antiviral Agents - chemistry; Antiviral Agents - therapeutic use; Carbohydrates. Nucleosides and nucleotides; Chemical Phenomena; Chemistry; Deoxyguanosine - analogs & derivatives; Deoxyguanosine - chemical synthesis; Deoxyguanosine - chemistry; Deoxyguanosine - pharmacology; Deoxyguanosine - therapeutic use; Exact sciences and technology; Herpes Simplex - drug therapy; Magnetic Resonance Spectroscopy; Molecular Structure; Nucleosides, nucleotides and oligonucleotides; Organic chemistry; Preparations and properties; Simplexvirus - physiology; Structure-Activity Relationship; Virus Replication - drug effects; Purine nucleoside; Herpesviridae; Alphaherpesvirinae; Rodentia; In vitro; Biological activity; Virus; In vivo; Vertebrata; Mammalia; Cyclitol; Mouse; Analog; Animal; Antiviral; Herpesvirus hominis; Fluorine Organic compounds
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00107a006

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.