New Class of Glycoside Hydrolase Mechanism-Based Covalent Inhibitors: Glycosylation Transition State Conformations

Abstract

The design of covalent inhibitors in glycoscience research is important for the development of chemical biology probes. Here we report the synthesis of a new carbocyclic mechanism-based covalent inhibitor of an α-glucosidase. The enzyme efficiently catalyzes its alkylation via either an allylic cation or a cationic transition state. We show this allylic covalent inhibitor has different catalytic proficiencies for pseudoglycosylation and deglycosylation. Such inhibitors have the potential to be useful chemical biology tools.

High‐Throughput Approaches in Carbohydrate‐Active Enzymology: Glycosidase and Glycosyl Transferase Inhibitors, Evolution, and Discovery

“…In particular, increasing throughput and expanding the chemical space accessible drives initial hits to ever-higher affinities and selectivities.F or screening approaches,w hether applied to discovery of inhibitors,e volution of existing enzymes,o r discovery of new enzymes,c reative approaches such as coupled assays and product trapping continue to be reported for reliably coupling only the desired activity to aconvenient read-out, in ever-higher sensitivity,t hroughput, and discrimination. [94]). Thef uture of high-throughput approaches lies in ever-higher throughput and also in clever chemistry and molecular biology to generate meaningful questions to answer and useful collections to investigate, often yielding answers that would never be considered in arational approach.…”

“…[91], [92]), and C) allylic and cyclopropyl cations for yeast a-glucosidase inactivation( Ref. [94]). Carbocyclic sugar analoguesc ontaining sp 2 centers or fused rings shown as chair structures for simplicity.…”

“…[88] Approaches include 2-fluoro [89] or 5-fluoro sugars, [90] cyclophellitol epoxide [91,92] and aziridine derivatives, [93] or more recently described compounds that generate allylic and cyclopropyl cations [94] (Figure 4). [88] Approaches include 2-fluoro [89] or 5-fluoro sugars, [90] cyclophellitol epoxide [91,92] and aziridine derivatives, [93] or more recently described compounds that generate allylic and cyclopropyl cations [94] (Figure 4).…”

Rearrangement and nucleophilic trapping of bicyclo[4.1.0]hept-2-yl derived nonclassical bicyclobutenium ions

“…[7][8][9] These bicyclo[4.1.0]heptyl based mimics of galactopyranosides covalently label an α-galactosidase from a retaining glycoside hydrolase family (GH36) on its catalytic nucleophile (aspartate-327), 7,8 a process that presumably involves formation of a non-classical bicyclobutenium ion 2. 10,11 As a result, we are 12 SCHEME 2.…”

Gram-scale carbasugar synthesis via intramolecular seleno-Michael/aldol reaction

“…The advantage of carbasugar containing compounds is the lack of a glycosidic linkage resulting in the increased stability toward enzymatic degradation. 5,6 For example, synthetic nucleotide analogues containing thiosugar or carbasugars have been reported to be glycosyltransferase inhibitors. [7][8][9] The mechanism of glycosidase inhibition has been studied and several carba-analogues, such as Sergliozin-A 10 or SL0101, 11 have been introduced (Fig.…”