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

AbstractThe García‐González 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 α‐L‐fucosidase inhibitor (Ki=2–4 μM), whereas 4b (with a N‐benzylcarboxamide group) is a good β‐galactosidase inhibitor.