title: Conformationally-locked C-glycosides: tuning aglycone interactions for optimal chaperone behaviour in Gaucher fibroblasts.
abstract: A series of conformationally locked C-glycosides based on the 3-aminopyrano[3,2-b]pyrrol-2(1H)-one (APP) scaffold has been synthesized. The key step involved a totally stereocontrolled C-Michael addition of a serine-equivalent C-nucleophile to tri-O-benzyl-2-nitro-D-galactal, previously published by the authors. Stereoselective transformations of the Michael adduct allowed us the synthesis of compounds with mono- or diantennated aglycone moieties and different topologies. In vitro screening showed highly selective inhibition of bovine liver β-glucosidase/β-galactosidase and specific inhibition of human β-glucocerebrosidase among lysosomal glycosidases for compounds bearing palmitoyl chains in the aglycone, with a marked dependence of the inhibition potency upon their number and location. Molecular dynamics simulations highlighted the paramount importance of an optimal orientation of the hydrophobic substituent to warrant efficient non-glycone interactions, which are critical for the binding affinity. The results provide a rationale for the strong decrease of the inhibition potency of APP compounds on going from neutral to acidic pH. The best candidate was found to behave as pharmacological chaperone in Gaucher fibroblasts with homozygous N370S and F213I mutations, with enzyme activity enhancements similar to those encountered for the reference compound Ambroxol.
authors.affiliation: Departamento de Química and Centro de Investigación en Síntesis Química, Universidad de La Rioja, c/Madre de Dios, 53, 26006 Logroño, Spain. jesusmanuel.peregrina@unirioja.es.
authors.forename: C D
authors.initials: CD
authors.lastname: Navo
authors.forename: F
authors.initials: F
authors.lastname: Corzana
authors.forename: E M
authors.initials: EM
authors.lastname: Sánchez-Fernández
authors.forename: J H
authors.initials: JH
authors.lastname: Busto
authors.forename: A
authors.initials: A
authors.lastname: Avenoza
authors.forename: M M
authors.initials: MM
authors.lastname: Zurbano
authors.forename: E
authors.initials: E
authors.lastname: Nanba
authors.forename: K
authors.initials: K
authors.lastname: Higaki
authors.forename: C
authors.initials: C
authors.lastname: Ortiz Mellet
authors.forename: J M
authors.initials: JM
authors.lastname: García Fernández
authors.forename: J M
authors.initials: JM
authors.lastname: Peregrina
mesh_terms: D000818:Animals; D002417:Cattle; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D005347:Fibroblasts / Q000187:drug effects*; D005776:Gaucher Disease / Q000473:pathology*; D005962:Glucosylceramidase / Q000037:antagonists & inhibitors; D006027:Glycosides; D006801:Humans; D008099:Liver / Q000201:enzymology; D008958:Models, Molecular; D018832:Molecular Chaperones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D009005:Monosaccharides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D001616:beta-Galactosidase / Q000037:antagonists & inhibitors; D001617:beta-Glucosidase / Q000037:antagonists & inhibitors
chemical_list: C438934:C-glycoside; D004791:Enzyme Inhibitors; D006027:Glycosides; D018832:Molecular Chaperones; D009005:Monosaccharides; D001617:beta-Glucosidase; D001616:beta-Galactosidase; D005962:Glucosylceramidase