Thiosugars: beta-N-acetylhexosaminidase inhibitors and 2-thio-S-acetyl glycosylation donors.

摘要

The catalytic mechanism by which a glycosyl hydrolase (β-N-acetylhexosaminidase, a retaining enzyme) processes N-acetylglucosamines has been investigated. By two stable thiazoline based analogues, namely NAG-thiazoline 1–13 and allosamizoline analogue 1–32, it was determined that the catalytic mechanism for this class of enzymes likely is in agreement with the mechanism proposed by Sinnott, involving cyclized intermediate 1–7 (see Figure 1, Chapter 1). NAG-thiazoline 1–13 was found to be a potent, competitive inhibitor of jack bean N-acetylglucosaminidase with a Ki = 280 nM, while the allosamizoline analogue 1–32 had a Ki = 160 mM against the same enzyme. A crystal structure by Mark et al. of NAG-thiazoline 1–13 complexed with a bacterial (β-N-acetylhexosaminidase also provides support for Sinnott's mechanism.; A stereoselective glycosylation method using a 2-thioacetyl-based donor 2–173 has been developed. The thioacetyl group of 2–173 was found to be effective in providing anchimeric assistance. Three β-linked disaccharides were synthesized through use of this donor. Two of these disaccharides (2–183 and 2–184) were desulfurized with Raney-nickel to afford the corresponding β-2′-deoxy glycosides (2–186 and 2–187). It was also shown that 2–173 could be selectively S-deacetylated to afford the 2-mercapto analogue 2–198, which could be used in making thioconjugates.