Open AccessNovel α‐L‐fucosidase inhibitors from the bark of Angylocalyx pynaertii (Leguminosae)
Author(s) -
Asano Naoki,
Yasuda Kayo,
Kizu Haruhisa,
Kato Atsushi,
Fan JianQiang,
Nash Robert J.,
Fleet George W. J.,
Molyneux Russell J.
Publication year - 2001
Publication title -
european journal of biochemistry
Language(s) - English
Resource type - Journals
eISSN - 1432-1033
pISSN - 0014-2956
DOI - 10.1046/j.1432-1327.2001.01837.x
Subject(s) - stereochemistry , piperidine , chemistry , fucosidase , anomer , hydroxymethyl , ring (chemistry) , glycoconjugate , fucose , biochemistry , galactose , organic chemistry
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 µ m ), 2,5‐imino‐1,2,5‐trideoxy‐ l ‐glucitol (0.49 µ m ), 2,5‐dideoxy‐2,5‐imino‐ d ‐fucitol (17 µ m ), 2,5‐imino‐1,2,5‐trideoxy‐ d ‐altritol (3.7 µ m ), DMJ (4.7 µ m ), N ‐methyl‐DMJ (30 µ m ), 6‐ O ‐α‐ l ‐rhamnopyranosyl‐DMJ (Rha‐DMJ, 0.06 µ m ), and β‐ l ‐homofuconojirimycin (β‐HFJ, 0.0053 µ m ). 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.