Novel alpha-L-fucosidase inhibitors from the bark of Angylocalyx pynaertii (Leguminosae)

Abstract

The extract of bark of Angylocalyx pynaertii (Leguminosae) was found to potently inhibit mammalian α- l-fucosidases. A thorough examination of the extract resulted in the discovery of 15 polyhydroxylated alkaloids, including the known alkaloids from seeds of this plant, 1,4-dideoxy-1,4-imino- d-arabinitol (DAB), 1-deoxymannojirimycin (DMJ) and 2,5-imino-1,2,5-trideoxy- d-mannitol (6-deoxy-DMDP). Among them, eight sugar-mimic alkaloids showed the potent inhibitory activity towards bovine epididymis α- l-fucosidase and their Ki values are as follows: 6-deoxy-DMDP (83 µm), 2,5-imino-1,2,5-trideoxy- l-glucitol (0.49 µm), 2,5-dideoxy-2,5-imino- d-fucitol (17 µm), 2,5-imino-1,2,5-trideoxy- d-altritol (3.7 µm), DMJ (4.7 µm), N-methyl-DMJ (30 µm), 6-O-α- l-rhamnopyranosyl-DMJ (Rha-DMJ, 0.06 µm), and β- l-homofuconojirimycin (β-HFJ, 0.0053 µm). We definitively deduced the structural requirements of inhibitors of α- l-fucosidase for the piperidine alkaloids (DMJ derivatives). The minimum structural feature of α- l-fucosidase inhibitors is the correct configuration of the three hydroxyl groups on the piperidine ring corresponding to C2, C3 and C4 of l-fucose. Furthermore, the addition of a methyl group in the correct configuration to the ring carbon atom corresponding to C5 of l-fucose generates extremely powerful inhibition of α- l-fucosidase. The replacement of the methyl group of β-HFJ by a hydroxymethyl group reduced its inhibitory potential about 80-fold. This suggests that there may be a hydrophobic region in or around the active site. The existence or configuration of a substituent group on the ring carbon atom corresponding to the anomeric position of l-fucose does not appear to be important for the inhibition. Interestingly, Rha-DMJ was a 70-fold more potent inhibitor of α- l-fucosidase than DMJ. This implies that the lysosomal α- l-fucosidase may have subsites recognizing oligosaccharyl structures in natural substrates.