Fluorescent-tagged sp2-iminosugars with potent β-glucosidase inhibitory activity

Probing the Inhibitor versus Chaperone Properties of sp2-Iminosugars towards Human β-Glucocerebrosidase: A Picomolar Chaperone for Gaucher Disease

“…The conversion of the amine-type endocyclic nitrogen of iminosugars into a pseudoamide-type functionality, with high sp 2 -hybridation character (sp 2 -iminosugars) [ 21 , 22 ], has demonstrated to be a very promising strategy to improve both parameters, with several sp 2 -iminosugar representatives under investigational or preclinical development for the LSDs Gaucher [ 23 , 24 , 25 , 26 , 27 ], Fabry [ 28 ], G M1 -gangliosidosis [ 29 , 30 ], and Tay-Sachs diseases [ 31 ]. The glycosidase inhibitory and chaperoning abilities of sp 2 -iminosugars have been found to be strongly dependent on the mono- [ 32 , 33 , 34 , 35 , 36 ] or bicyclic structure of the sugar glycone-like skeleton [ 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 ], the configurational pattern [ 45 , 46 , 47 , 48 ], and the nature of nonglycone-type substituents [ 49 , 50 , 51 ]. Differently from classical iminosugars, for which the lability of aminal functionalities prevents the installation of anomeric substituents (except in the case of pseudo- C -glycosides) [ 52 , 53 , 54 , 55 ], sp 2 -iminosugars can bear O -, S -, N -, or C -anomeric aglycone groups while keeping full chemical and configurational stability [ 56 , 57 , 58 , 59 , 60 , ...…”

Conformationally-Locked N-Glycosides with Selective β-Glucosidase Inhibitory Activity: Identification of a New Non-Iminosugar-Type Pharmacological Chaperone for Gaucher Disease

“…Implementing molecular diversity-oriented strategies in conformationally locked bicyclic glycomimetics is particularly attractive toward these channels. Several polyhydroxylated bicyclic cores armed with anchoring functionalities compatible with library generation schemes have been proposed, among which the so-called sp 2 iminosugars have proven particularly useful (Figure ). − This family of sugar mimics incorporates a pseudoamide group in the structure that facilitates the installation of substituents either at the pseudoanomeric position (e.g., in the carbamate-type bicyclic nojirimycin derivative 1 ) , or at an exocyclic nitrogen (e.g., in the isourea-type bicyclic nojirimycin derivative 2 ). , Total discrimination between α- and β-glucosidase enzymes and even between closely related α-glucosidase isoenzymes could be achieved in this manner, which translated into interesting lead compounds in view of developing drug candidates for the treatment of breast cancer and Gaucher disease, the LSD with the highest prevalence. , In the first case, the biological activity was ascribed to selective inhibition of the neutral α-glucosidases at the endoplasmic reticulum (ER). In the second case, binding of the glycomimetic to the active site of mutant β-glucocerebrosidase (GCase) in the ER restored trafficking to the lysosome, acting as pharmacological chaperone.…”

Mechanistic Insights into the Chaperoning of Human Lysosomal-Galactosidase Activity: Highly Functionalized Aminocyclopentanes and C-5a-Substituted Derivatives of 4-epi-Isofagomine

“…Notably, despite indisputable biochemical evidence based on quite a few inhibitors probed [41,46,47,55,[61][62][63][64], the frequently observed synergistic inhibitory effect of the terminal dansyl amide could not be correlated to additional specific binding events of this moiety to the protein as was implied by the lack of electron density for this substituent in the bacterial model enzyme-inhibitor complexes examined.…”