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

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 K _i 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 piperidinc 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.