Synthesis of 5-amino-5-deoxy-D-galactopyranose and 1,5-dideoxy-1,5-imino-D-galactitol, and their inhibition of alpha- and beta-D-galactosidases.
A 12-step route is presented starting from 1,2:5,6-di-O-isopropylidene-alpha-D-glucofuranose for the preparation of the title compounds and their L-altro analogues. Their synthesis is based on the reduction with Raney nickel of a protected 5-hydroxyimino derivative of L-arabino-hexofuranos-5-ulose, with the following improvements for the preparation of a D-galactofuranose derivative: oxidation at C-3 with pyridinium dichromate-acetic anhydride, stereospecific reduction of a 3-O-acetyl-hex-3-enofuranose intermediate to the D-gulo derivative, and inversion at C-3 of its 3-tosylate with tetrabutylammonium acetate in chlorobenzene. alpha-D-Galactosidase from coffee beans and from Escherichia coli and beta-D-galactosidase from E. coli and Aspergillus wentii were inhibited with Ki values that ranged from 0.0007 to 8.2 microM. Formation of the enzyme-inhibitor complexes with the D-galactose analogue was on the time-scale of minutes, whereas the D-galactitol analogue showed a slow approach to the inhibition only with alpha-D-galactosidase from coffee beans and beta-D-galactosidase from A. wentii. N-Alkylation of the D-galactitol analogue was detrimental to the inhibition except for beta-D-galactosidase from E. coli and beta-D-glucosidase from almonds, but, even with these enzymes, the observed affinity enhancements were 10(2) to 10(3)-times smaller than those of N-alkylated D-galactosylamine and D-glucosylamine.
D001230:Aspergillus / Q000201:enzymology; D004926:Escherichia coli / Q000201:enzymology; D005688:Galactosamine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D005696:Galactosidases / Q000037:antagonists & inhibitors*; D050112:Imino Pyranoses; D007202:Indicators and Reagents; D007700:Kinetics; D010944:Plants / Q000201:enzymology; D000519:alpha-Galactosidase / Q000037:antagonists & inhibitors*; D001616:beta-Galactosidase / Q000037:antagonists & inhibitors*
D050112:Imino Pyranoses; D007202:Indicators and Reagents; C051195:5-amino-5-deoxygalactopyranose; C051196:1,5-dideoxy-1,5-iminogalactitol; D005688:Galactosamine; D005696:Galactosidases; D000519:alpha-Galactosidase; D001616:beta-Galactosidase