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 alpha -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 alpha -L-fucosidase and their K-i values are as follows: 6-deoxy-DMDP (83 muM), 2,5-imino-1,2,5-trideoxy-L-glucitol (0.49 muM), 2,5-dideoxy- 2,5-imino-D-fucitol (17 muM) 2,5-imino-1,2,5-trideoxy-D-altritol (3.7 muM), DMJ (4.7 muM), N-methyl-DMJ (30 muM), 6-O-alpha -L-rhamnopyranosyl-DMJ (Rha-DMJ, 0.06 muM), and beta -L-homofuconojirimycin (beta -HFJ, 0.0053 muM) We definitively deduced the structural requirements of inhibitors of alpha -L-fucosidase for the piperidine alkaloids (DMJ derivatives). The minimum structural feature of alpha -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 alpha -L-fucosidase. The replacement of the methyl group of beta -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 alpha -L-fucosidase than DMJ. This implies that the lysosomal alpha -L-fucosidase may have subsites recognizing oligosaccharyl structures in natural substrates.