Synthesis and Glycosidase Inhibitory Activities of 5‐(1′,4′‐Dideoxy‐1′,4′‐imino‐D‐erythrosyl)‐2‐methyl‐3‐furoic Acid (=5‐[(3S,4R)‐3,4‐Dihydroxypyrrolidin‐2‐yl]‐2‐methylfuran‐3‐carboxylic Acid) Derivatives: New Leads as Selective α‐L‐Fucosidase and β‐Galactosidase Inhibitors

Abstract

The GarcÌa-Gonza¬lez reaction of d-glucose and ethyl acetoacetate generated ethyl 5-[(1'S)-d-erythrosyl]-2-methyl-3-furoate (5), which was converted to ethyl 5-[(1'R)-1',4'-dideoxy-1',4'-imino-d-erythrosyl]-2-methyl-3-furoate (3c) and to ethyl 5-[(1'S)-1',4'-dideoxy-1',4'-imino-d-erythrosyl]-2-methyl-3-furoate (4c). Similar methods were developed to generate other carboxylic acid derivatives such as methyl (see 3e and 4e), isopropyl (see 3f), and butyl esters (see 3g), S-phenyl (see 3a) and S-ethyl thioesters (see 3m), N-benzylcarboxamides 3b and 4b, glycine-derived amide 3h, and N-phenyl (see 3i), N-isopropyl (see 3j and 4j), N,N-diethyl-(see 3k and 4k), and N-ethyl-carboxamides (see 3l). All the new 5-(1',4'-dideoxy-1',4'-imino-d-erythrosyl)-3-furoic acid ( 5-[(3S,4R)-3,4-dihydroxypyrrolidin-2-yl)furan-3-carboxylic acid) derivatives 3 and 4 were assayed for inhibitory activity towards 25 commercially available glycosidases. Derivative 3a with a S-phenyl thioester group is a good and selective a-l-fucosidase inhibitor (K i 2 ± 4 mm), whereas 4b (with a N-benzylcarboxamide group) is a good b-galactosidase inhibitor.Introduction. ± Derivatives of pyrrolidine-3,4-diols ( 1,4-dideoxy-1,4-iminoalditols) constitute an important class of glycosidase inhibitors [1] although, in some cases, there is a lack of selectivity due to the higher conformational flexibility compared to 1,5-dideoxy-1,5-iminoalditols and other imino-bicyclic structures. For instance, simple meso-pyrrolidine-3,4-diol (1) is a weak and nonselective inhibitor [2] that presents activity towards several glycosidases.

Rapid discovery of potent α-fucosidase inhibitors by in situ screening of a library of (pyrrolidin-2-yl)triazoles

“…The LSI was performed using thioglycerol as the matrix. NMR and mass spectra were registered in CITIUS (University of Seville (3R,4S,5S)-5-Hydroxymethyl-3,4-O-isopropylidene-2-methyl-1-pyrroline-3,4-diol (7). To a solution of 6 (3.6 g, 8.5 mmol) in THF (20 mL), TBAF (1 M in THF, 8.5 mL, 8.5 mmol) was added.…”

“…In recent years, we have been actively working on the development of new iminocyclitols with inhibitory activity towards α-fucosidases. [6][7][8][9] We have shown that the presence of an additional aromatic or heteroaromatic binding component close to the five membered iminocyclitol increases notably their inhibitory activity (1 10 vs. 2, 8 Fig. 1).…”

“…[6][7][8][9] We have shown that the presence of an additional aromatic or heteroaromatic binding component close to the five membered iminocyclitol increases notably their inhibitory activity (1 10 vs. 2, 8 Fig. 1).…”

3,4-Dihydroxypyrrolidine as Glycosidase Inhibitor

“…The inhibitory activity of 64 towardsgalactosidase and -mannosidase is quite similar to that of A powerful inhibitior 85 against -fucosidase is similar to that of compound 63 [77,104]. Compounds with (2R,3R,4S)-configuration (86)(87)(88)(89)(90)(91)(92)(93)(94)(95)(96)(97) showed moderate inhibitory activities against -mannosidase [89], and those with a (2R,3S,4R)-configuration (98)(99)(100)(101)(102)(103)(104)(105)(106)(107)(108)(109) tend to inhibitglucosidase and -galactosidase [88,89,93,109,110]. The specificity of these compounds was explained based on the similarity with substrate structures of individual enzymes where it was considered that a flexible pyrrolidine structure could adopt a 4 E conformation and 2-and 3-OH groups might mimic the hydroxyl groups of glucopyranosyl cation species (Fig.…”

Exploring a Multivalent Approach to α‐L‐Fucosidase Inhibition

“…N , N′ , N″ ‐(1,3,5‐Phenylenetris(methylene))tris‐[5‐((2 R ,3 S ,4 R )‐3,4‐dihydroxypyrrolidin‐2‐yl)‐2‐methylfuran‐3‐carboxamide](3b): Acid 19 34b (88.9 mg, 0.246 mmol) was dissolved in DMF and 1,3,5‐tris(aminomethyl)benzene35 (11.5 mg, 0.07 mmol), DIPEA (43 μL, 0.246 mmol) and PyBOP (143.6 mg, 0.27 mmol) were added. The mixture was stirred overnight at room temp.…”