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-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.
Tseng
C K
CK
Laboratory of Medicinal Chemistry, National Cancer Institute, Bethesda, Maryland 20892.
Marquez
V E
VE
Fuller
R W
RW
Goldstein
B M
BM
Haines
D R
DR
McPherson
H
H
Parsons
J L
JL
Shannon
W M
WM
Arnett
G
G
Hollingshead
M
M
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
D000998:Antiviral Agents; C048460:3-deazaneplanocin; D006867:Hydrolases; D043383:Adenosylhomocysteinase; D000241:Adenosine