A potent bicyclic inhibitor of a family 27 α-galactosidase

Wang, Yi; Bennet, Andrew J.

doi:10.1039/b704509c

Cited by 25 publications

(28 citation statements)

References 33 publications

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“…22 More recently, activated forms of these compounds have been used as covalent inhibitors. 23 In these cases the conformational restriction limits the accessible conformations to “off-pathway” 3 H 2 and 2 H 3 half-chairs 23 (or perhaps their related 1,4 boats) recently elegantly revealed by X-ray crystallography.…”

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confidence: 99%

Carba-cyclophellitols Are Neutral Retaining-Glucosidase Inhibitors

Beenakker¹,

Wander²,

Offen

et al. 2017

J. Am. Chem. Soc.

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The conformational analysis of glycosidases affords a route to their specific inhibition through transition-state mimicry. Inspired by the rapid reaction rates of cyclophellitol and cyclophellitol aziridine—both covalent retaining β-glucosidase inhibitors—we postulated that the corresponding carba “cyclopropyl” analogue would be a potent retaining β-glucosidase inhibitor for those enzymes reacting through the 4H3 transition-state conformation. Ab initio metadynamics simulations of the conformational free energy landscape for the cyclopropyl inhibitors show a strong bias for the 4H3 conformation, and carba-cyclophellitol, with an N-(4-azidobutyl)carboxamide moiety, proved to be a potent inhibitor (Ki = 8.2 nM) of the Thermotoga maritimaTmGH1 β-glucosidase. 3-D structural analysis and comparison with unreacted epoxides show that this compound indeed binds in the 4H3 conformation, suggesting that conformational strain induced through a cyclopropyl unit may add to the armory of tight-binding inhibitor designs.

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mentioning

confidence: 99%

Carba-cyclophellitols Are Neutral Retaining-Glucosidase Inhibitors

Beenakker¹,

Wander²,

Offen

et al. 2017

J. Am. Chem. Soc.

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“…1b), compounds that could generate the desired carbocationic intermediate (Fig. 1c), improving on a previous route 28 to obtain the known alcohol 6 from commercially available 2,3,4,6-tetra-O-benzyl-D-galactopyranose (7) in 15.0% overall yield (Supplementary Methods and Supplementary Figs 1-5). We next achieved diastereoselective cyclopropanation of alkene 6 to obtain either 8 or 9 by including B2 equivalents of trifluoroacetic acid in the reaction mixture 29 and by judicious choice of the reaction solvent.…”

Section: Synthesis Of Glycosidase Inactivatorsmentioning

confidence: 99%

“…We also found that the rate of inactivation decreased in the presence of the competitive inhibitor 5 (ref. 28), indicating that inactivation is driven by action occurring at the enzymatic active site (Fig. 3b).…”

Section: Synthesis Of Glycosidase Inactivatorsmentioning

confidence: 99%

A mechanism-based inactivator of glycoside hydrolases involving formation of a transient non-classical carbocation

et al. 2014

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The design of mechanism-based enzyme inactivators to generate chemical probes for biological research is an important challenge in carbohydrate chemistry. Here we describe the synthesis and biological evaluation of a novel carbocyclic mechanism-based inactivator of galactosidases (glycoside hydrolase families 27 and 36). Upon catalysis of this unnatural substrate, a transient non-classical carbocation forms within the enzyme active site. We show that the inactivation event, which proceeds via a bicyclobutonium ion intermediate, leads to a single alkylation event that occurs on the enzymatic nucleophile, an aspartic acid residue in this case. We also show that the catalytic proficiencies for enzymatic hydrolysis of substrates and inactivation by our bicyclo[4.1.0]heptyl analogue of galactose differ by only a factor of 20. This inactivator has the potential for further development as a useful biological research tool for both basic research and biotechnological applications.

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“…On the other hand, the spiroaziridines and spirodiaziridines 160 and 161 were prepared and evaluated as glycosidase inhibitors against -glucosidases from almonds, -glucosidase from Caldocellum saccharolyticum, andglucosidase from yeast with poor results compared with cyclopentylamine 162 (Figure 27) Two isomeric bicyclo[4.1.0]heptane 163 and 164 ( Figure 27) have been synthesized and evaluated against -galactosidase enzymes from coffee bean and E. coli [335]. The activity of the glycosyl hydrolase family GH27 enzyme (coffee bean) was competitively inhibited by the 1R,6S-amine with a value of 0.541 M. The E. coli -galactosidase exhibited a much weaker binding interaction with the 1R,6S-amine (IC 50 = 80 M).…”

Section: International Journal Of Carbohydrate Chemistrymentioning

confidence: 99%

Biosynthesis and Biological Activity of Carbasugars

Roscales

Plumet

2016

International Journal of Carbohydrate Chemistry

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The first synthesis of carbasugars, compounds in which the ring oxygen of a monosaccharide had been replaced by a methylene moiety, was described in 1966 by Professor G. E. McCasland's group. Seven years later, the first true natural carbasugar (5a-carba-R-D-galactopyranose) was isolated from a fermentation broth of Streptomyces sp. MA-4145. In the following decades, the chemistry and biology of carbasugars have been extensively studied. Most of these compounds show interesting biological properties, especially enzymatic inhibitory activities, and, in consequence, an important number of analogues have also been prepared in the search for improved biological activities. The aim of this review is to give coverage on the progress made in two important aspects of these compounds: the elucidation of their biosynthesis and the consideration of their biological properties, including the extensively studied carbapyranoses as well as the much less studied carbafuranoses.

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A potent bicyclic inhibitor of a family 27 α-galactosidase

Cited by 25 publications

References 33 publications

Carba-cyclophellitols Are Neutral Retaining-Glucosidase Inhibitors

Carba-cyclophellitols Are Neutral Retaining-Glucosidase Inhibitors

A mechanism-based inactivator of glycoside hydrolases involving formation of a transient non-classical carbocation

Biosynthesis and Biological Activity of Carbasugars

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