Configurationally selective transition state analogue inhibitors of glycosidases. A study with nojiritetrazoles, a new class of glycosidase inhibitors

Abstract

“Mannonojiretetrazole” ( 7), a novel mannosidase inhibitor, has been synthesized in six steps from 2,3,4,6-tetra- O-benzyl- d-mannose oxime. The structure of 7 has been established by X-ray analysis. The solid state conformation of 7 is 6 H 7 (= 4 H 3, numbering based on carbohydrate nomenclature), and the conformation in CD 3OD is close to S 7 (sofa; = S 3, numbering based upon carbohydrate nomenclature), while the conformation of the previously synthesized analogue with the gluco configuration ( 6) is 6 H 7, both in the solid state and in solution in D 2O or CD 3OD. Both 6 and 7 have been tested as inhibitors of each of a series of five α- and β-glucosidases and -mannosidases as well as of a β-galactosidase, and inhibition constants have been determined. A good correlation (ϱ = 0.9) was found between log K i for each inhibitor—enzyme pair and log ( V m/ K m) for the corresponding substrate—enzyme pair, thereby providing the first such proof for any glycosidase inhibitor being a transition state analogue. This clearly demonstrates a case where true transition state analogue inhibitors of glycosidases are configurationally selective.