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

• Published in: Journal of medicinal chemistry Vol. 41; no. 1; pp. 10 - 23
• Main Authors: Qiu, Yao-Ling, Ksebati, Mohamad B, Ptak, Roger G, Fan, Boreas Y, Breitenbach, Julie M, Lin, Ju-Sheng, Cheng, Yung-Chi, Kern, Earl R, Drach, John C, Zemlicka, Jiri
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 01.01.1998; Amer Chemical Soc
• Subjects: Adenosine - analogs & derivatives; Adenosine - chemical synthesis; Adenosine - chemistry; Adenosine - pharmacology; AIDS/HIV; Animals; Anti-HIV Agents - chemical synthesis; Anti-HIV Agents - chemistry; Anti-HIV Agents - pharmacology; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Antiviral Agents - chemical synthesis; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Biological and medical sciences; Cell Line; Cell Survival - drug effects; Cercopithecus aethiops; Chemistry, Medicinal; Cyclopropanes - chemical synthesis; Cyclopropanes - chemistry; Cyclopropanes - pharmacology; Guanosine - analogs & derivatives; Guanosine - chemical synthesis; Guanosine - chemistry; Guanosine - pharmacology; Hepatitis B virus - drug effects; Hepatitis B virus - physiology; Herpesvirus 1, Human - drug effects; Herpesvirus 1, Human - physiology; Herpesvirus 2, Human - drug effects; Herpesvirus 2, Human - physiology; HIV-1 - drug effects; HIV-1 - physiology; Humans; Life Sciences & Biomedicine; Medical sciences; Mice; Microbial Sensitivity Tests; Molecular Structure; Nuclear Magnetic Resonance, Biomolecular; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Science & Technology; Spectrophotometry, Infrared; Vero Cells; Virus Replication - drug effects; HUMAN IMMUNODEFICIENCY VIRUS; OXETANOCIN; CARBOCYCLIC NUCLEOSIDES; HERPES-SIMPLEX VIRUS; BIOLOGICAL-ACTIVITY; Stereoisomer; Purine nucleoside; Cyclopropane derivatives; Structure activity relation; Antiviral; Chemical synthesis; In vitro; Homoallylic compound; Primary alcohol
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm9705723

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 N 6,N 6-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 ∼ 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 N 6-(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 μM), MCMV (IC50 2.1, 0.3, and 0.3 μM) and EBV in H-1 (IC50 0.2, 0.3, and 0.7 μM) and Daudi cells (IC50 3.2, 5.6, and 1.2 μM). Adenine analogue 14 was active against HBV (IC50 2 μM), VZV (IC50 2.5 μM), and HHV-6 (IC50 14 μM). 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.