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

Abstract

The extract of bark of Angylocalyx pynaertii (Leguminosae) was found to potently inhibit mammalian a-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 a-l-fucosidase and their K i values are as follows: 6-deoxy-DMDP (83 mm), 2,5-imino-1,2,5-trideoxy-l-glucitol (0.49 mm), 2,5-dideoxy-2,5-imino-d-fucitol (17 mm), 2,5-imino-1,2,5-trideoxy-d-altritol (3.7 mm), DMJ (4.7 mm), N-methyl-DMJ (30 mm), 6-O-a-l-rhamnopyranosyl-DMJ (Rha-DMJ, 0.06 mm), and b-l-homofuconojirimycin (b-HFJ, 0.0053 mm). We definitively deduced the structural requirements of inhibitors of a-l-fucosidase for the piperidine alkaloids (DMJ derivatives). The minimum structural feature of a-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 a-l-fucosidase. The replacement of the methyl group of b-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 a-l-fucosidase than DMJ. This implies that the lysosomal a-l-fucosidase may have subsites recognizing oligosaccharyl structures in natural substrates.

New Sugar-Mimic Alkaloids from the Pods of Angylocalyx pynaertii

“…4 The 50% aqueous EtOH extract of the pods was also similarly treated with ionexchange resins and tested for inhibitory activity of rat…”

Dihydroxyacetone Phosphate Aldolase Catalyzed Synthesis of Structurally Diverse Polyhydroxylated Pyrrolidine Derivatives and Evaluation of their Glycosidase Inhibitory Properties

“…[43,44] The activity of compound 6, not previously reported to the best of our knowledge, is amongst the highest reported for pyrrolidine and piperidine type iminosugars. [45][46][47][48][49] Other pyrrolidine derivatives with similar stereochemistry (i.e., 3S,4R,5S) have also been reported as strong inhibitors of al-fucosidase, [50][51][52] while some diastereomerically related isomers of 5 and 6 have shown much lower activities (e.g. K i = 165 mm for the 2R,3R,4R,5R isomer [46] ), suggesting a strong stereochemical demand of the a-l-fucosidase active site.…”

“…[45][46][47][48][49] Other pyrrolidine derivatives with similar stereochemistry (i.e., 3S,4R,5S) have also been reported as strong inhibitors of al-fucosidase, [50][51][52] while some diastereomerically related isomers of 5 and 6 have shown much lower activities (e.g. K i = 165 mm for the 2R,3R,4R,5R isomer [46] ), suggesting a strong stereochemical demand of the a-l-fucosidase active site. In this sense, looking at the compounds synthesized in this work, modification of the stereochemistry at C-5 from S to R, for example, compare 4 c versus 4 e, or at C-4 from R to S, for example, compare 4 b versus 4 a, 4 i versus 4 h, or 4 p versus 4 o, result in moderate to large decreases of the inhibitory activity (Table 3).…”

Recent Advances in the Total Synthesis of Piperidine Azasugars

“…[14] Recently, novel polyhydroxylated piperidine alkaloids with a longer alkyl substituent branched on the cyclic moiety have been isolated from Adenophorae radix, such as (+)-adenophorine (6), 1-deoxyadenophorine (16), or β-1-C-butyl DGJ (17). [7] Figure 4.…”