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

Article abstract of 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'β-fluoro isomer 2-amino-1,9-dihydro-9-[(1α,2α,3β,4α)-2-fluoro-3-hydroxy-4- (hydroxymethyl)cyclopentyl]-6H-purin-6-one (11a, C-AFG) and its 2'α-fluoro epimer 11b plus the chiral 6'β-fluoro isomer 2-amino-1,9-dihydro-9-[[1S-(1α,2α,3α,4β)]-2-fluoro-4- hydroxy-3-(hydroxymethyl)cyclopentyl]-6H-purin-6-one (11c) and its 6'α-fluoro epimer 11d were prepared from their respective fluoro amino diol hydrochlorides (6a,d). For comparison, the furanosyl compound 9-(2'-deoxy-2'-fluoro-β-D-arabinofuranosyl)guanine (17, AFG) was prepared by coupling 2-amino-6-chloropurine with 2-deoxy-2-fluoro-3,5-di-O- benzoyl-α-D-arabinofuranosyl bromide followed by base hydrolysis. The 6'α-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 >30-fold more active than ACV against HSV-1 and HSV-2 in vivo in the mouse systemic model. The 2'β-fluoro derivative (11a, C-AFG) was extremely potent in vitro against HSV-1 and HSV-2 (ID₅₀ 0.006 and 0.005 μg/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'α-fluoro 11b and 6'β-fluoro 11c isomers were much less active.