SYNTHESIS AND EVALUATION OF INDOLIZINE-TYPE INHIBITORS OF N-ACETYL-BETA-D-GLUCOSAMINIDASES

To check if the strong inhibition of N-acetyl-beta-D-glucosaminidase b y the tetrazole 8 and the imidazoles 9 and 10 correlates with the pres ence of a heteroatom corresponding to the glycosidic O-atom, we prepar ed the GlcNAc-derived pyrroles (tetrahydroindolizines) 18, 19, 27, 28, 34, and 35, lacking such a heteroatom. For this, the glucose-derived pyrroles 11-13 were treated with a Lewis acid in the presence of trime thylsilyl azide. Conditions of kinetic control favored the formation o f the gluco-azides 14, 23, and 30, while thermodynamic control favoure d the manno-azides 20, 29, and 36. Reduction of the azides 14, 20, 23, 30, and 36 by Pd/C-catalyzed hydrogenolysis or, better, with propaned ithiol and Et3N, followed by acetylation or trifluoroacetylation and h ydrogenolytic debenzylation, gave the deprotected acetamido- and trifl uoroacetamido-pyrroles 18, 19, 22, 27, 28, 34, 35, 40, and 41. As comp ared to the tetrazole 8 and the imidazole 9, the pyrroles 18, 19, 27, 28, 34, and 35 are only modest inhibitors of N-acetyl-beta-D-glucosami nidase from bovine kidney (K-i values between 10 and 75 mu M), indicat ing the necessity of a heteroatom at the glycosidic position. K-i Valu es between 100 and 160 mu M for the inhibition of N-acetyl-beta-D-gluc osaminidase from jack beans were determined for the pyrroles 19, 34, a nd 35. The trifluoracetamides inhibited both enzymes about twice as st rongly as the corresponding acetamides.