(Z)- and (E)-[2-Fluoro-2-(hydroxymethyl)cyclopropylidene]methylpurines and -pyrimidines, a New Class of Methylenecyclopropane Analogues of Nucleosides: Synthesis and Antiviral Activity

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Abstract
The Z- and E-isomers of fluoromethylenecyclopropane analogues 1 1a−d and 1 2a−d were synthesized, and their antiviral activities were evaluated. The purine (Z,E)-methylenecyclopropane carboxylates 1 3 and 24 were selectively fluorinated using lithium diisopropylamide, LiCl, and N-fluorobenzenesulfonimide to give (Z,E)-fluoroesters 22 and 25. Reduction with LiBH4 or diisobutylaluminum hydride gave after chromatographic separation Z-isomers 11 a and 11e and E-isomers 1 2a and 1 2e. The O-demethylation of 11 e and 1 2e afforded guanine analogues 11 b and 1 2b. Fluorination of (Z,E)-cytosine and thymine esters 1 5 and 1 6 afforded (Z,E)-fluoroesters 26 and 27, which were resolved before the reduction to analogues 11c and 11d and 1 2c and 1 2d. Adenine Z-isomer 11 a was the most effective against Towne and AD169 strains of human cytomegalovirus (HCMV, EC50 3.6 and 6.0 μM, respectively), but it was less effective against murine virus (MCMV, EC50 69 μM). Thymine Z-isomer 11d was effective against HSV-1 in BSC-1 cells (ELISA, EC50 2.5 μM) but inactive against HSV-1 or HSV-2 in Vero or HFF cells. All of the analogues with the exception of 1 2d were effective at least in one of the assays against Epstein−Barr virus (EBV) in Daudi or H-1 cells in a micromolar or submicromolar range. Cytosine and thymine Z-isomers 11c and 11 d were active against varicella zoster virus (VZV) with EC50 0.62 μM. Adenine Z- and E-isomers 11 a and 1 2a were effective against HIV-1 in MT-2 or MT-4 cells with EC50 12−22 and 2.3−7.6 μM, respectively, whereas only 1 2a was effective against hepatitis B virus (HBV) with EC50 15 μM. Analogues 11a and 1 2a were weak substrates for adenosine deaminase.