Synthesis of 3-deazaneplanocin A, a powerful inhibitor of S-adenosylhomocysteine hydrolase with potent and selective in vitro and in vivo antiviral activities

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-deazaneplanoci...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1989-07, Vol.32 (7), p.1442-1446
Main Authors: Tseng, Christopher K. H, Marquez, Victor E, Fuller, Richard W, Goldstein, Barry M, Haines, David R, McPherson, Howard, Parsons, Jack L, Shannon, William M, Arnett, Gussie
Format: Article
Language:English
Subjects:
Adenosine - analogs & derivatives
Adenosine - chemical synthesis
Adenosine - pharmacology
Adenosylhomocysteinase
Animals
Antiviral Agents
Avian Sarcoma Viruses - drug effects
Carbohydrates. Nucleosides and nucleotides
Chemical Phenomena
Chemistry
Exact sciences and technology
Hydrolases - antagonists & inhibitors
Mice
Nucleosides, nucleotides and oligonucleotides
Organic chemistry
Parainfluenza Virus 3, Human - drug effects
Preparations and properties
Simplexvirus - drug effects
vaccinia virus
Vaccinia virus - drug effects
Vero Cells
Vesicular stomatitis Indiana virus - drug effects
vesicular stomatitis virus
yellow fever virus
Yellow fever virus - drug effects
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00127a007