title: Inhibitor versus chaperone behaviour of d-fagomine, DAB and LAB sp(2)-iminosugar conjugates against glycosidases: A structure-activity relationship study in Gaucher fibroblasts.
abstract: A library of sp(2)-iminosugar conjugates derived from the piperidine iminosugar d-fagomine and the enantiomeric pyrrolidine iminosugars DAB and LAB has been generated in only two steps involving direct coupling of the fully unprotected polyhydroxylated heterocycles with isothiocyanates, to give monocyclic thiourea adducts, and further intramolecular nucleophilic displacement of the δ-located primary hydroxyl group by the thiocarbonyl sulphur atom, affording bicyclic isothioureas. These transformations led to a dramatic shift in the inhibitory selectivity from α- to β-glucosidases, with inhibition potencies that depended strongly on the nature of the aglycone-type moiety in the conjugates. Some of the new derivatives behaved as potent inhibitors of human β-glucocerebrosidase (GCase), the lysosomal enzyme whose dysfunction is responsible for Gaucher disease. Moreover, GCase inhibition was 10-fold weaker at pH 5 as compared to pH 7, which is generally considered as a good property for pharmacological chaperones. Surprisingly, most of the compounds strongly inhibited GCase in wild type fibroblasts at rather low concentrations, showing an unfavourable chaperone/inhibitor balance on disease-associated GCase mutants in cellulo. A structure-activity relationship analysis points to the need for keeping a contiguous triol system in the glycone moiety of the conjugates to elicit a chaperone effect. In any case, the results reported here represent a proof of concept of the utmost importance of implementing diversity-oriented strategies for the identification and optimization of potent and specific glycosidase inhibitors and chaperones.
authors.affiliation: Department of Organic Chemistry, Faculty of Chemistry, University of Seville, C/ Profesor García González 1, 41012 Seville, Spain.
authors.forename: Teresa
authors.initials: T
authors.lastname: Mena-Barragán
authors.affiliation: Department of Organic Chemistry, Faculty of Chemistry, University of Seville, C/ Profesor García González 1, 41012 Seville, Spain.
authors.forename: M Isabel
authors.initials: MI
authors.lastname: García-Moreno
authors.affiliation: Division of Functional Genomics, Research Center for Bioscience and Technology, Tottori University, 86 Nishi-cho, Yonago 683-8503, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Nanba
authors.affiliation: Division of Functional Genomics, Research Center for Bioscience and Technology, Tottori University, 86 Nishi-cho, Yonago 683-8503, Japan. Electronic address: kh4060@med.tottori-u.ac.jp.
authors.forename: Katsumi
authors.initials: K
authors.lastname: Higaki
authors.affiliation: Instituto de Química Avanzada de Cataluña, IQAC-CSIC. Jordi Girona 18-26, 08034 Barcelona, Spain.
authors.forename: Alda Lisa
authors.initials: AL
authors.lastname: Concia
authors.affiliation: Instituto de Química Avanzada de Cataluña, IQAC-CSIC. Jordi Girona 18-26, 08034 Barcelona, Spain. Electronic address: pere.clapes@iqac.csic.es.
authors.forename: Pere
authors.initials: P
authors.lastname: Clapés
authors.affiliation: Instituto de Investigaciones Químicas (IIQ), CSIC - Universidad de Sevilla, C/ Américo Vespucio 49, Isla de la Cartuja, 41092 Seville, Spain.
authors.forename: José Manuel
authors.initials: JM
authors.lastname: García Fernández
authors.affiliation: Department of Organic Chemistry, Faculty of Chemistry, University of Seville, C/ Profesor García González 1, 41012 Seville, Spain. Electronic address: mellet@us.es.
authors.forename: Carmen
authors.initials: C
authors.lastname: Ortiz Mellet
mesh_terms: D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D005347:Fibroblasts / Q000187:drug effects*; D005776:Gaucher Disease / Q000473:pathology*; D006026:Glycoside Hydrolases / Q000037:antagonists & inhibitors*; D006801:Humans; D050112:Imino Pyranoses / Q000737:chemistry*; D050111:Imino Sugars / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D050112:Imino Pyranoses; D050111:Imino Sugars; C105643:fagomine; D006026:Glycoside Hydrolases
keywords: Gaucher disease; Glycosidase inhibitor; Iminosugar; Pharmacological chaperone; Pyrrolidine; d-Fagomine