(Z)- and (E)-2-((Hydroxymethyl)cyclopropylidene)methyladenine and -guanine. New Nucleoside Analogues with a Broad-Spectrum Antiviral Activity

Abstract

New nucleoside analogues 14-17 based on a methylenecyclopropane structure were synthesized and evaluated for antiviral activity. Reaction of 2,3-dibromopropene (19) with adenine (18) led to bromoalkene 20, which was benzoylated to give N6,N6-dibenzoyl derivative 23. Attempts to convert 20 or 23 to bromocyclopropanes 21 and 22 by reaction with ethyl diazoacetate catalyzed by Rh2(OAc)4 were futile. By contrast, 2,3-dibromopropene (19) afforded smoothly (E)- and (Z)-dibromocyclopropane carboxylic esters 24 + 25. Alkylation of adenine (18) with 24 + 25 gave (E)- and (Z)-bromo derivatives 21 + 22. Base-catalyzed elimination of HBr resulted in the formation of (Z)- and (E)-methylenecyclopropanecarboxylic esters 26 + 27. More convenient one-pot alkylation-elimination of adenine (18) or 2-amino-6-chloropurine (30) with 24 + 25 afforded (Z)- and (E)-methylenecyclopropane derivatives 26 + 27 and 31 + 32. The Z-isomers were always predominant in these mixtures (Z/E approximately 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 converted to N6-(dimethylamino)methylene derivatives 28 and 29 which were separated and deprotected to give 14 and 16. Reaction of 33 and 34 with HCO2H led to guanine analogues 15 and 17. The 1H NMR spectra of the Z-analogues 14 and 15 are consistent with an anti-like conformation of the nucleobases. By contrast, 1H NMR and IR spectra of bromo ester 21 are indicative of syn-conformation of adenine. Several Z-(hydroxymethyl)methylenecyclopropanes exhibited in vitro antiviral activity in micromolar or submicromolar range against human and murine cytomegalovirus (HCMV and MCMV), Epstein-Barr virus (EBV), human herpes virus 6 (HHV-6), varicella zoster virus (VZV), and hepatitis B virus (HBV). Analogues 14, 15, and 33 were the most effective agents against HCMV (IC50 1-2.1, 0.04-2.1, and 0.8-5.6 microM), MCMV (IC50 2.1, 0.3, and 0.3 microM) and EBV in H-1 (IC50 0.2, 0.3, and 0.7 microM) and Daudi cells (IC50 3.2, 5.6, and 1.2 microM). Adenine analogue 14 was active against HBV (IC50 2 microM), VZV (IC50 2.5 microM), and HHV-6 (IC50 14 microM). Synadenol (14) and the E-isomer (16) were substrates of moderate efficiency for adenosine deaminase from calf intestine. The E-isomer 16 was more reactive than Z-isomer 14. The deamination of 14 effectively stopped at 50% conversion. Synadenol (14) was also deaminated by AMP deaminase from aspergillus sp.

Synthesis and Enantioselectivity of the Antiviral Effects of (R,Z)-,(S,Z)-methylenecyclopropane Analogues of Purine Nucleosides and Phosphoralaninate Prodrugs: Influence of Heterocyclic Base, Type of Virus and Host Cells

“…The procedure used for racemic compound (Qiu et al, 1998b) was followed. A solution of compound 5c (180 mg, 0.72 mmol) in formic acid (80%, 15 ml) was heated at 80°C for 3.5 h. The volatile components were evaporated in vacuo, the residue was dissolved in DMF (20 ml), AcO (a) Qiu et al, 1998a;(b) ,4.80;N,29.80.…”

“…The procedure described for the corresponding racemic compound (Qiu et al, 1998b) was performed with compound 5c as a starting material. A mixture of 5c (400 mg, 1.59 mmol) and NH 3 in methanol (saturated at 0°C, 80 ml) was heated in a stainless steel bomb at 95°C (bath temperature) for 16 h. After evaporation, the residue was chromatographed on a silica gel column using CH 2 Cl 2 -MeOH (4:1) to give the title product 5d (343 mg, 93%), mp.…”

“…All enantiomers were devoid of significant cytotoxicity in CEM cells. Against HIV-1, the (R,S)-synadenol 1 was active, whereas the racemic 2-aminopurine analogues were much less potent (Qiu et al, 1998b;Qiu et al, 1998c;Uchida et al, 1999). Previously, we found that the R enantiomer 5a was effective whereas S enantiomer 6a was devoid of activity (Qiu et al, 1998a).…”

Synthesis of methylenecyclopropane analogues of antiviral nucleoside phosphonates

“…The reproduction of the synthetic sequence on the scale of 0.27 mol was problem-free although little details were originally provided. 14 The commercially available diisopropyl methylphosphonate (9) and allyl bromide (10) were transformed to unsaturated phosphonate 11 in 70% yield (Scheme 1). Compound 11 was transformed to oxirane 12 (91%) and, finally, by an Scheme 1 intramolecular opening of the oxirane ring to cyclopropane 8 in 80% yield.…”

Σύνθεση Μιας Νέας Τάξης Φθορο - Θειο - Νουκλεοζιτών Με Πιθανή Αντιϊκή Και Αντικαρκινική Δράση

“…Qiu et al [113] have described the synthesis and the biological action of Z-and E-nucleoside analogues 91 (Fig. 42).…”