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

The extract of bark of Angylocalyx pynaertii (Leguminosae) was found to pot ently inhibit mammalian alpha -L-fucosidases. A thorough examination of the extract resulted in the discovery of 15 polyhydroxylated alkaloids, includ ing the known alkaloids from seeds of this plant, 1,4-dideoxy-1,4-imino-D-a rabinitol (DAB), 1-deoxymannojirimycin (DMJ) and 2,5-imino-1,2,5-trideoxy-D -mannitol (6-deoxy-DMDP). Among them, eight sugar-mimic alkaloids showed th e 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 st ructural requirements of inhibitors of alpha -L-fucosidase for the piperidi ne alkaloids (DMJ derivatives). The minimum structural feature of alpha -L- fucosidase inhibitors is the correct configuration of the three hydroxyl gr oups on the piperidine ring corresponding to C2, C3 and C4 of L-fucose. Fur thermore, the addition of a methyl group in the correct configuration to th e ring carbon atom corresponding to C5 of L-fucose generates extremely powe rful inhibition of alpha -L-fucosidase. The replacement of the methyl group of beta -HFJ by a hydroxymethyl group reduced its inhibitory potential abo ut 80-fold. This suggests that there may be a hydrophobic region in or arou nd the active site. The existence or configuration of a substituent group o n the ring carbon atom corresponding to the anomeric position of L-fucose d oes not appear to be important for the inhibition. interestingly, Rha-DMJ w as a 70-fold more potent inhibitor of alpha -L-fucosidase than DMJ. This im plies that the lysosomal alpha -L-fucosidase may have subsites recognizing oligosaccharyl structures in natural substrates.