Novel alpha-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 Ki values are as follows: 6-deoxy-DMDP (83 microM), 2,5-imino-1,2,5-trideoxy-L-glucitol (0.49 microM), 2,5-dideoxy-2,5-imino-D-fucitol (17 microM), 2,5-imino-1,2,5-trideoxy-D-altritol (3.7 microM), DMJ (4.7 microM), N-methyl-DMJ (30 microM), 6-O-alpha-L-rhamnopyranosyl-DMJ (Rha-DMJ, 0.06 microM), and beta-L-homofuconojirimycin (beta-HFJ, 0.0053 microM). 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.
Asano
N
N
Faculty of Pharmaceutical Sciences, Hokuriku University, Kanagawa-machi, Kanazawa, Japan. naoki22@po.incl.ne.jp
Yasuda
K
K
Kizu
H
H
Kato
A
A
Fan
J Q
JQ
Nash
R J
RJ
Fleet
G W
GW
Molyneux
R J
RJ
D017485:1-Deoxynojirimycin / Q000737:chemistry / Q000494:pharmacology; D000470:Alkaloids / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D002417:Cattle; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D007887:Fabaceae / Q000737:chemistry*; D006801:Humans; D018547:Plant Stems / Q000737:chemistry; D010946:Plants, Medicinal; D013329:Structure-Activity Relationship; D005644:alpha-L-Fucosidase / Q000037:antagonists & inhibitors*
D000470:Alkaloids; D004791:Enzyme Inhibitors; D017485:1-Deoxynojirimycin; D005644:alpha-L-Fucosidase