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: C K Tseng, V E Marquez, R W Fuller, B M Goldstein, D R Haines, H McPherson, J L Parsons, W M Shannon, G Arnett, M Hollingshead
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 32 Issue 7 Pg. 1442-6 (Jul 1989) ISSN: 0022-2623 [Print] United States
• PMID: 2544721 (Publication Type: Journal Article)

Chemical References

• Antiviral Agents
• 3-deazaneplanocin
• Hydrolases
• Adenosylhomocysteinase
• Adenosine

Topics

• Adenosine (analogs & derivatives, chemical synthesis, pharmacology)
• Adenosylhomocysteinase
• Animals
• Antiviral Agents
• Avian Sarcoma Viruses (drug effects)
• Chemical Phenomena
• Chemistry
• Hydrolases (antagonists & inhibitors)
• Mice
• Parainfluenza Virus 3, Human (drug effects)
• Simplexvirus (drug effects)
• Vaccinia virus (drug effects)
• Vero Cells
• Vesicular stomatitis Indiana virus (drug effects)
• Yellow fever virus (drug effects)