Synthesis and Testing of 2-Deoxy-2,2-Dihaloglycosides as Mechanism-Based Inhibitors of -Glycosidases
详细信息 查看全文
- 作者：Ran Zhang ; John D. McCarter ; Curtis Braun ; Wai Yeung ; Gary D. Brayer ; Stephen G. Withers
- 刊名：Journal of Organic Chemistry
- 出版年：2008
- 出版时间：April 18, 2008
- 年：2008
- 卷：73
- 期：8
- 页码：3070 - 3077
- 全文大小：148K
- 年卷期：v.73,no.8(April 18, 2008)
- ISSN：1520-6904
文摘
The synthesis of a series of 2-deoxy-2,2-dihaloglycosyl halides as potential 
-glycosidase inactivatorshas been achieved via the halogenation of protected 2-fluoroglycal precursors. Direct chlorination ofper-O-acetylated 2-fluoro-D-glucal and 2-fluoromaltal followed by basic deprotection yielded thecorresponding 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, whichwere converted to their -chlorides using thionyl chloride and deprotected under basic conditions.Trinitrophenyl glycosides of the 2-deoxy-2,2-difluoro mono- and disaccharides were synthesized byarylation of the hemiacetals with picryl fluoride, then deprotected with HCl in methanol. All threemonosaccharide derivatives caused active site-directed, time-dependent inactivation of yeast -glucosidasevia the trapping of covalent glycosyl-enzyme intermediates, and kinetic parameters for inactivation byeach compound were determined. Surprisingly neither of the 2-deoxy-2,2-dihalomaltosyl chlorides causedtime-dependent inactivation of human pancreatic -amylase, despite the fact that the trinitrophenyl 2-deoxy-2,2-difluoromaltoside functioned in that mode. The trinitrophenyl glycosides appear to be approximately1000-fold more reactive than the corresponding chlorides in the enzyme active sites.
-glycosidase inactivatorshas been achieved via the halogenation of protected 2-fluoroglycal precursors. Direct chlorination ofper-O-acetylated 2-fluoro-D-glucal and 2-fluoromaltal followed by basic deprotection yielded thecorresponding 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, whichwere converted to their -chlorides using thionyl chloride and deprotected under basic conditions.Trinitrophenyl glycosides of the 2-deoxy-2,2-difluoro mono- and disaccharides were synthesized byarylation of the hemiacetals with picryl fluoride, then deprotected with HCl in methanol. All threemonosaccharide derivatives caused active site-directed, time-dependent inactivation of yeast -glucosidasevia the trapping of covalent glycosyl-enzyme intermediates, and kinetic parameters for inactivation byeach compound were determined. Surprisingly neither of the 2-deoxy-2,2-dihalomaltosyl chlorides causedtime-dependent inactivation of human pancreatic -amylase, despite the fact that the trinitrophenyl 2-deoxy-2,2-difluoromaltoside functioned in that mode. The trinitrophenyl glycosides appear to be approximately1000-fold more reactive than the corresponding chlorides in the enzyme active sites.