Synthesis and testing of 2-deoxy-2,2-dihaloglycosides as mechanism-based inhibitors of alpha-glycosidases.
J Org Chem
; 73(8): 3070-7, 2008 Apr 18.
Article
en En
| MEDLINE
| ID: mdl-18345685
The synthesis of a series of 2-deoxy-2,2-dihaloglycosyl halides as potential alpha-glycosidase inactivators has been achieved via the halogenation of protected 2-fluoroglycal precursors. Direct chlorination of per-O-acetylated 2-fluoro-d-glucal and 2-fluoromaltal followed by basic deprotection yielded the corresponding 2-chloro-2-deoxy-2-fluoroglycosyl chlorides. Reaction of the per-O-acetylated 2-fluoroglycals with acetyl hypofluorite or Selectfluor yielded the 2-deoxy-2,2-difluoroglycosyl derivatives, which were converted to their alpha-chlorides using thionyl chloride and deprotected under basic conditions. Trinitrophenyl glycosides of the 2-deoxy-2,2-difluoro mono- and disaccharides were synthesized by arylation of the hemiacetals with picryl fluoride, then deprotected with HCl in methanol. All three monosaccharide derivatives caused active site-directed, time-dependent inactivation of yeast alpha-glucosidase via the trapping of covalent glycosyl-enzyme intermediates, and kinetic parameters for inactivation by each compound were determined. Surprisingly neither of the 2-deoxy-2,2-dihalomaltosyl chlorides caused time-dependent inactivation of human pancreatic alpha-amylase, despite the fact that the trinitrophenyl 2-deoxy-2,2-difluoromaltoside functioned in that mode. The trinitrophenyl glycosides appear to be approximately 1000-fold more reactive than the corresponding chlorides in the enzyme active sites.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Compuestos de Flúor
/
Compuestos de Cloro
/
Glicósido Hidrolasas
/
Glicósidos
Límite:
Humans
Idioma:
En
Revista:
J Org Chem
Año:
2008
Tipo del documento:
Article
Pais de publicación:
Estados Unidos