)-2-((HYDROXYMETHYL)CYCLOPROPYLIDENE)METHYLADENINE AND )-2-((HYDROXYMETHYL)CYCLOPROPYLIDENE)METHYLGUANINE AND )-2-((HYDROXYMETHYL)CYCLOPROPYLIDENE)METHYLADENINE AND )-2-((HYDROXYMETHYL)CYCLOPROPYLIDENE)METHYLGUANINE - NEW NUCLEOSIDE ANALOGS WITH A BROAD-SPECTRUM ANTIVIRAL ACTIVITY

New nucleoside analogues 14-17 based on a methylenecyclopropane struct ure were synthesized and evaluated for antiviral activity. Reaction of 2,3-dibromopropene (19) with adenine (18) led to bromoalkene 20, whic h was benzoylated to give N-6,N-6-dibenzoyl derivative 23. Attempts to convert 20 or 23 to bromocyclopropanes 21 and 22 by reaction with eth yl diazoacetate catalyzed by Rh-2(OAc)(4) were futile. By contrast, 2, 3-dibromopropene (19) afforded smoothly (E)- and (Z)-dibromocyclopropa ne carboxylic esters 24 + 25. Alkylation of adenine (18) with 24 + 25 gave (E)- and (Z)-bromo derivatives 21 + 22. Base-catalyzed eliminatio n of HBr resulted in the formation of (Z)- and (E)-methylenecyclopropa necarboxylic esters 26 + 27. More convenient one-pot alkylation-elimin ation of adenine (18) or 2-amino-6-chloropurine (30) with 24 + 25 affo rded (Z)- and (E)-methylenecyclopropane derivatives 26 + 27 and 31 + 3 2. The Z-isomers were always predominant in these mixtures (Z/E simila r to 2/1). Reduction of 26 + 27 and 31 + 32 with DIBALH afforded (Z)- and (E)-methylenecyclopropane alcohols 14 + 16 and 33 + 34. The latter were resolved directly by chromatography. Compounds 14 + 16 were conv erted to N-6-(dimethylamino)methylene derivatives 28 and 29 which were separated and deprotected to give 14 and 16. Reaction of 33 and 34 wi th HCO2H led to guanine analogues 15 and 17. The H-1 NMR spectra of th e Z-analogues 14 and 15 are consistent with an anti-like conformation of the nucleobases. By contrast, H-1 NMR and IR spectra of bromo ester 21 are indicative of syn-conformation of adenine. Several Z-(hydroxym ethyl)methylenecyclopropanes exhibited in vitro antiviral activity in micromolar or submicromolar range against human and murine cytomegalov irus (HCMV and MCMV), Epstein-Barr virus (EBV), human herpes virus 6 ( HHV-6), varicella tester virus (VZV), and hepatitis B virus (HBV). Ana logues 14, 15, and 33 were the most effective agents against HCMV (IC5 0 1-2.1, 0.04-2.1, and 0.8-5.6 mu M), MCMV (IC50 2.1, 0.3, and 0.3 mu M) and EBV in H-1 (IC50 0.2, 0.3, and 0.7 mu M) and Daudi cells (IC50 3.2, 5.6, and 1.2 mu M). Adenine analogue 14 was active against HBV (I C50 2 mu M), VZV (IC50 2.5 mu M), and HHV-6 (IC50 14 mu M). Synadenol (14) and the E-isomer (16) were substrates of moderate efficiency for adenosine deaminase from calf intestine. The E-isomer 16 was more reac tive than Z-isomer 14. The deamination of 14 effectively stopped at 50 % conversion. Synadenol (14) was also deaminated by AMP deaminase from aspergillus sp.