Structural glycosidase inhibitor

Preparation of polyhydroxylated 6-oxanortropane glycomimetics (e.g. 32), structurally related to the glycosidase inhibitor family of the calystegines, was reported. The synthetic strategy involves the furanose/piperidine... 

FIG. 2. Polyhydroxylated azepanes 9-13 that have been assayed as glycosidase inhibitors. These structures were inspired by the natural-product glycosidase inhibitors nojirimycin (14) and fagomine (15). 

Many glycosidase inhibitors are structurally related to natural substrates, closely resembling carbohydrates. However, several exceptions to this generalization are known. These include such diverse structures as the diterpene andrographolide and its analogues (38, Scheme 12),134 3,21-di-O-acetylcichoridiol (39, a triterpenoid),135 acridone alkaloids, and oriciacridone (40).136... 

A. Varrot, M. Schiilein, M. Pipelier, A. Vasella, and G. J. Davies, Lateral protonation of a glycosidase inhibitor. Structure of the Bacillus agaradhaerens Cel5A in complex with cellobiose-derived imidazole at 0.97 A resolution,./. Am. Chem. Soc., 121 (1999) 2621—2622. 

T. M. Gloster, S. Roberts, G. Perugino, M. Rossi, M. Moracci, N. Panday, M. Terinek, A. Vasella, and G. J. Davies, Structural, kinetic and thermodynamic analysis of glucoimidazole-derived glycosidase inhibitors, Biochemistry, 45 (2006) 11879—11884. 

V. Notenboom, S. J. Williams, R. Hoos, S. G. Withers, and D. R. Rose, Detailed structural analysis of glycosidase/inhibitor interactions Complexes of Cex from Cellulomonas fimi with xylobiose-derived aza-sugars, Biochemistry, 39 (2000) 11553—11563. 

L. G. Dickson, E. Leroy, and J.-L. Reymond, Structure-activity relationships in aminocyclopentitol glycosidase inhibitors, Org. Biomol. Chem., 2 (2004) 1217-1226. 

The simple piperidine pelletierine from Punica granatum (pomegranate) (Punicaceae) and Duboisia myoporoides (Solanaceae) is an anthelmintic. The simple piperidine derivatives deoxy-mannojirimycin (DMJ) and deoxynojirimycin (DNJ) from Lonchocarpus species (Fabaceae) are glycosidase inhibitors because they are structurally similar to the pyranose (six-membered ring) sugar moieties of the glycosidase disaccharide substrates. 

The rational design of potent glycosidase inhibitors may be based on the transition state structures of the enzymatic reaction because this is the point of greatest stabilization by the enzyme — in the case of glycosidases with K s up to However, the true catalytic... 

Herein, I will describe a variety of synthetic strategies directed to total syntheses and chemical modifications of these glycosidase inhibitors and the structure and activity relationships of their derivatives. Also, the methodologies of carbasugar formation from sugars wiU be described. 

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