CONFIGURATIONALLY SELECTIVE TRANSITION-STATE ANALOG INHIBITORS OF GLYCOSIDASES - A STUDY WITH NOJIRITETRAZOLES, A NEW CLASS OF GLYCOSIDASE INHIBITORS

''Mannonojiritetrazole'' (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 H-6(7) (=H-4(3), numbering based on carbohydrate nomenclature), and the conformation in CD3OD 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 H-6(7), both in the solid state and in solution in D2O or CD3OD. Both 6 and 7 have been tested as inhibitors of each of a series of five alpha- and beta-glucosidases and -mannosidases as well as of a beta-galactosidase, and inhibition constants have been determined. A good correlation (p = 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.