title: Synthesis of 3-deazaneplanocin A, a powerful inhibitor of S-adenosylhomocysteine hydrolase with potent and selective in vitro and in vivo antiviral activities.
abstract: The neplanocin A analogue 3-deazaneplanocin A (2b) has been synthesized. A direct SN2 displacement on the cyclopentenyl mesylate 3 by the sodium salt of 6-chloro-3-deazapurine afforded the desired regioisomer 4 as the major product. After deprotection, this material was converted to 3-deazaneplanocin A in two steps. X-ray crystallographic analysis confirmed the assigned structure. Consistent with its potent inhibition of S-adenosylhomocysteine hydrolase, 3-deazaneplanocin A displayed excellent antiviral activity in cell culture against vesicular stomatitis, parainfluenza type 3, yellow fever, and vaccinia viruses. Antiviral activity was also displayed in vivo against vaccinia virus by using a mouse tailpox assay. The significantly lower cytotoxicity of 3-deazaneplanocin A, relative to its parent compound neplanocin A, may be due to its lack of conversion to 5'-triphosphate and S-adenosylmethionine metabolites.
authors.affiliation: Laboratory of Medicinal Chemistry, National Cancer Institute, Bethesda, Maryland 20892.
authors.forename: C K
authors.initials: CK
authors.lastname: Tseng
authors.forename: V E
authors.initials: VE
authors.lastname: Marquez
authors.forename: R W
authors.initials: RW
authors.lastname: Fuller
authors.forename: B M
authors.initials: BM
authors.lastname: Goldstein
authors.forename: D R
authors.initials: DR
authors.lastname: Haines
authors.forename: H
authors.initials: H
authors.lastname: McPherson
authors.forename: J L
authors.initials: JL
authors.lastname: Parsons
authors.forename: W M
authors.initials: WM
authors.lastname: Shannon
authors.forename: G
authors.initials: G
authors.lastname: Arnett
authors.forename: M
authors.initials: M
authors.lastname: Hollingshead
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D043383:Adenosylhomocysteinase; D000818:Animals; D000998:Antiviral Agents; D001358:Avian Sarcoma Viruses / Q000187:drug effects; D055598:Chemical Phenomena; D002621:Chemistry; D006867:Hydrolases / Q000037:antagonists & inhibitors*; D051379:Mice; D010224:Parainfluenza Virus 3, Human / Q000187:drug effects; D018139:Simplexvirus / Q000187:drug effects; D014616:Vaccinia virus / Q000187:drug effects; D014709:Vero Cells; D014721:Vesicular stomatitis Indiana virus / Q000187:drug effects; D015005:Yellow fever virus / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; C048460:3-deazaneplanocin; D006867:Hydrolases; D043383:Adenosylhomocysteinase; D000241:Adenosine