A potent bicyclic inhibitor of a family 27 alpha-galactosidase.
Two isomeric bicyclo[4.1.0]heptane analogues of the glycosidase inhibitor galacto-validamine, (1R*,2S,3S,4S,5S,6S*)-5-amino-1-(hydroxymethyl)bicyclo[4.1.0]heptane-2,3,4-triol, have been synthesized in 13 steps from 2,3,4,6-tetra-O-benzyl-D-galactose. The inhibitory activities of the two conformationally restricted amines, and their corresponding acetamides, were measured against commercial alpha-galactosidase enzymes from coffee bean and E. coli. The activity of the glycosyl hydrolase family GH27 enzyme (coffee bean) was competitively inhibited by the 1R,6S-amine (7), a binding interaction that was characterized by a K(i) value of 0.541 microM. The GH36 E. coli alpha-galactosidase exhibited a much weaker binding interaction with the 1R,6S-amine (IC(50)= 80 microM). The diastereomeric 1S,6R-amine (9) bound weakly to both galactosidases, (coffee bean, IC(50)= 286 microM) and (E. coli, IC(50)= 2.46 mM).
Wang
Yi
Y
Department of Chemistry, Simon Fraser University, 8888 University Drive, Burnaby, V5A 1S6, British Columbia, Canada. bennet@sfu.ca.
Bennet
Andrew J
AJ
D003069:Coffee / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004926:Escherichia coli / Q000201:enzymology; D020128:Inhibitory Concentration 50; D019906:Nuclear Magnetic Resonance, Biomolecular; D000519:alpha-Galactosidase / Q000037:antagonists & inhibitors* / Q000145:classification*
D003069:Coffee; D004791:Enzyme Inhibitors; D000519:alpha-Galactosidase