Glycosidase inhibition

The bioactivity of imino sugars is due to the fact that they inhibit glycosidases. Once protonated, the imino sugar mime the oxonium ion intermediate of the reaction catalysed by those enzymes (Fig. 32), and therefore binds the active site. 

In order to modify the anomeric reactivity, also the anomeric carbon as been replaced with a different atom. The most studied case is that of the so defined 1-azasugars, in which a nitrogen is located at the anomeric position.81 Such compounds, like imino sugars to which are strictly related, are able to inhibit glycosidases. Interestingly, the presence of the trivalent... 

C-Glycosidic linkages are present in various natural products and may inhibit glycosidases due to the structural analogy to their O-counterparts.42 Glycosyl phosphates 63 and 48 served successfully in the a-selective synthesis of aryl... 

H. Liu, X. Liang, H. Sohoel, A. Billow, and M. Bols, Noeuromycin, a glycosyl cation mimic that strongly inhibits glycosidases, J. Am. Chem. Soc., 123 (2001) 5116-5117. 

Nash RJ, Watson AA and Asano N (1996) Polyhy-droxylated alkaloids that inhibit glycosidases. Alkaloids, Chemical and Biological Perspectives (ed Pelletier SW) Vol 11. Elsevier, Amsterdam, pp 345-376. 

Compounds that inhibit oligosaccharide digestion not only impair herbivore nutrition but can also act as antifeedants. A variety of plant-derived secondary metabolites inhibit glycosidases (Table 13.1). Numerous plant protein glycosidase inhibitors have been isolated and some of these have dual functions as both a-amylase and trypsin inhibitors (Table 13.2). 

Aaptamine (103), which is a cytotoxic benzonaphthyridine alkaloid isolated from the sponge Aaptos aaptos, induces differentiation in chronic leukemia cells (33). Schulzeine A (104) is a novel dihydroquinoline alkaloids isolated from the sponge Penares schulzei that inhibits glycosidases (12). 

R.C. Griffiths. PhD Thesis, Polyhydroxylated Alkaloids and their Ability to Inhibit Glycosidases , 1998, University of Wales, U.K. 

A distinction will be made between the glycosidase-inhibiting alkaloids and the amino sugars, amino acids and other miscellaneous compounds which also inhibit glycosidases. These will be considered briefly in Section 1.9. 

Chapter 5, a related chapter by Robert J. Nash, Naoki Asano, and Alison A. Watson, reviews polyhydroxylated alkaloids that inhibit glycosidases. Topics covered include distribution, ecological significance and toxicity, isolation, synthesis, and biosynthesis. 

Fig. 11.1-11 Tunicamycin 10 is an inhibitor of N-glycan biosynthesis, while natural products such as 1-deoxymannojirimycin inhibit glycosidase function.

Polyhydroxylated piperidines from natural sources, which have structures and shapes resembling monosaccharides have been found as a -glycosidase inhibitors. They competitively inhibit glycosidases whose substrates they most closely resemble. 1-Deoxynojirimycin (moranoline) (98 1), was isolated from Mori Cortex (root bark of the mulberry tree, Morus bombycis (Moraceae)), leaves of Jacobinia suberecta (Acanthaceae)... 

Both alkaloids (castanospermine and swansonine) have the ability to inhibit glycosidase enzymes (GEs), the activity of which is necessary in glycoprotein biosynthesis. 

Indolizidine alkaloids [15] such as castanospermine and swainsonine are formed from pipecolic acid, an amino acid derived from lysine, which can be elongated by malonyl-CoA followed by ring closure. When protonated, these alkaloids are oxonium mimics strongly inhibiting glycosidases. 

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