Synthesis of 5-amino-5-deoxy-D-mannopyranose and 1,5-dideoxy-1,5-imino-D-mannitol, and inhibition of alpha- and beta-D-mannosidases

The title compounds and the corresponding L-gulo derivatives were synthesised in 6 steps from benzyl 2,3:5,6-di-O-isopropylidene-alpha-D-mannofuranoside. The Ki values, determined from inhibition studies with alpha-D-mannosidases from jack beans, almonds, and calf liver, and beta-D-mannosidase from Aspergillus wentii, ranged from 70 to 400 microM for the mannitol derivative and from 1.2 to 20 microM for 5-amino-5-deoxy-D-mannopyranose, i.e., inhibition is 10(2)-10(4)-fold stronger than with D-mannose. Marked enhancement of inhibition with increasing pH is ascribed to the ionisation of a carboxyl group at the active site, forming an ion pair with the protonated inhibitor. The inhibition equilibrium between the jack-bean enzyme and the mannose derivative was approached slowly with kapp 2.0 X 10(5) M-1 X min-1. The mannose-derived inhibitor was also inhibitory against beta-D-glucosidases from almonds and Asp. wentii, with Ki values only 20-150-times larger than those for the inhibition of these enzymes by 5-amino-5-deoxy-D-glucopyranose. This moderate discrimination in binding of D-gluco and D-manno derivatives is in marked contrast to the high specificity shown by the glucosidase in catalysing the hydrolysis of mannosidases. A similar low specificity with respect to binding, combined with highly specific catalysis, was also seen with the mannosidases acting on inhibitors and substrates with the D-gluco configuration.