title: (R)-(-)- and (S)-(+)-Synadenol: synthesis, absolute configuration, and enantioselectivity of antiviral effect.
abstract: Synthesis of (R)-(-)- and (S)-(+)-synadenol (1a and 2a, 95-96% ee) is described. Racemic synadenol (1a + 2a) was deaminated with adenosine deaminase to give (R)-(-)-synadenol (1a) and (S)-(+)-hypoxanthine derivative 5. Acetylation of the latter compound gave acetate 6. Reaction with N, N-dimethylchloromethyleneammonium chloride led to 6-chloropurine derivative 7. Ammonolysis furnished (S)-(+)-synadenol (2a). Absolute configuration of 1a was established by two methods: (i) synthesis from (R)-methylenecyclopropanecarboxylic acid (8) and (ii) X-ray diffraction of a single crystal of (-)-synadenol hydrochloride. Racemic methylenecyclopropanecarboxylic acid (10) was resolved by a modification of the described procedure. The R-enantiomer 8 was converted to ethyl ester 13 which was brominated to give vicinal dibromides 14. Reduction with diisobutylaluminum hydride then furnished alcohol 15 which was acetylated to the corresponding acetate 16. Alkylation-elimination procedure of adenine with 16 yielded acetates 17 and 18. Deprotection with ammonia afforded a mixture of Z- and E-isomers 1a and 19 of the R-configuration. Comparison with products 1a and 2a by chiral HPLC established the R-configuration of (-)-synadenol (1a). These results were confirmed by X-ray diffraction of a single crystal of (-)-synadenol hydrochloride. The latter forms a pseudosymmetric dimer with adenine-adenine base pairing in the lattice with the nucleobase in an anti-like conformation. Enantiomers 1a and 2a exhibit varied enantioselectivity toward different viruses. Both enantiomers are equipotent against human cytomegalovirus (HCMV) and varicella zoster virus (VZV). The S-enantiomer 2a is somewhat more effective than R-enantiomer 1a in herpes simplex virus 1 and 2 (HSV-1 and HSV-2) assays. By contrast, enantioselectivity of antiviral effect is reversed in Epstein-Barr virus (EBV) and human immunodeficiency virus type 1 (HIV-1) assays where the R-enantiomer 1a is preferred. In these assays, the S-enantiomer 2a is less effective (EBV) or devoid of activity (HIV-1).
authors.affiliation: Department of Chemistry, Experimental and Clinical Chemotherapy Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan 48201-1379, USA.
authors.forename: Y L
authors.initials: YL
authors.lastname: Qiu
authors.forename: A
authors.initials: A
authors.lastname: Hempel
authors.forename: N
authors.initials: N
authors.lastname: Camerman
authors.forename: A
authors.initials: A
authors.lastname: Camerman
authors.forename: F
authors.initials: F
authors.lastname: Geiser
authors.forename: R G
authors.initials: RG
authors.lastname: Ptak
authors.forename: J M
authors.initials: JM
authors.lastname: Breitenbach
authors.forename: T
authors.initials: T
authors.lastname: Kira
authors.forename: L
authors.initials: L
authors.lastname: Li
authors.forename: E
authors.initials: E
authors.lastname: Gullen
authors.forename: Y C
authors.initials: YC
authors.lastname: Cheng
authors.forename: J C
authors.initials: JC
authors.lastname: Drach
authors.forename: J
authors.initials: J
authors.lastname: Zemlicka
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D002851:Chromatography, High Pressure Liquid; D002942:Circular Dichroism; D018360:Crystallography, X-Ray; D003521:Cyclopropanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003587:Cytomegalovirus / Q000187:drug effects / Q000254:growth & development; D005347:Fibroblasts; D015497:HIV-1 / Q000187:drug effects / Q000254:growth & development; D006515:Hepatitis B virus / Q000187:drug effects / Q000254:growth & development; D014645:Herpesvirus 3, Human / Q000187:drug effects / Q000254:growth & development; D004854:Herpesvirus 4, Human / Q000187:drug effects / Q000254:growth & development; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008968:Molecular Conformation; D018139:Simplexvirus / Q000187:drug effects / Q000254:growth & development; D013237:Stereoisomerism; D014709:Vero Cells; D010948:Viral Plaque Assay
chemical_list: D000998:Antiviral Agents; D003521:Cyclopropanes; C116544:synadenol; D000225:Adenine