Carba-cyclophellitols Are Neutral Retaining-Glucosidase Inhibitors.

Autor: Beenakker TJM, Wander DPA, Offen WA; Department of Chemistry, University of York , Heslington, York, YO10 5DD, U.K., Artola M, Raich L; Departament de Quı́mica Inorgànica i Orgànica (Secció de Química Orgànica) & Institut de Quimica Teòrica i Computacional (IQTCUB), Universitat de Barcelona , Martí i Franquès 1, 08028 Barcelona, Spain., Ferraz MJ, Li KY, Houben JHPM, van Rijssel ER, Hansen T, van der Marel GA, Codée JDC, Aerts JMFG, Rovira C; Departament de Quı́mica Inorgànica i Orgànica (Secció de Química Orgànica) & Institut de Quimica Teòrica i Computacional (IQTCUB), Universitat de Barcelona , Martí i Franquès 1, 08028 Barcelona, Spain.; Institució Catalana de Recerca i Estudis Avançats (ICREA) , 08020 Barcelona, Spain., Davies GJ; Department of Chemistry, University of York , Heslington, York, YO10 5DD, U.K., Overkleeft HS
Jazyk: angličtina
Zdroj: Journal of the American Chemical Society [J Am Chem Soc] 2017 May 17; Vol. 139 (19), pp. 6534-6537. Date of Electronic Publication: 2017 May 05.
DOI: 10.1021/jacs.7b01773
Abstrakt: 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 4 H 3 transition-state conformation. Ab initio metadynamics simulations of the conformational free energy landscape for the cyclopropyl inhibitors show a strong bias for the 4 H 3 conformation, and carba-cyclophellitol, with an N-(4-azidobutyl)carboxamide moiety, proved to be a potent inhibitor (K i = 8.2 nM) of the Thermotoga maritima TmGH1 β-glucosidase. 3-D structural analysis and comparison with unreacted epoxides show that this compound indeed binds in the 4 H 3 conformation, suggesting that conformational strain induced through a cyclopropyl unit may add to the armory of tight-binding inhibitor designs.
Databáze: MEDLINE
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