المؤلفون: Xavier Verdaguer, José M. García Fernández, Katsumi Higaki, Eiji Nanba, Alex de la Fuente, Antoni Riera, Carmen Ortiz Mellet, Rocío Rísquez-Cuadro

المساهمون: Universidad de Sevilla. Departamento de Química orgánica, Ministerio de Economía y Competitividad (MINECO). España, Junta de Andalucía, European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER), European Commission. Fondo Social Europeo (FSO), Universidad de Sevilla

المصدر: Digital.CSIC. Repositorio Institucional del CSIC
instname
idUS. Depósito de Investigación de la Universidad de Sevilla

مصطلحات موضوعية: Models, Molecular, 1-Deoxynojirimycin, Stereochemistry, Hexosaminidase inhibitors, Mutant, Molecular Conformation, Iminosugar, Chemistry Techniques, Synthetic, Tay-Sachs disease, 010402 general chemistry, 01 natural sciences, Drug Discovery, Humans, Hexosaminidase, Glycoside hydrolase, Enzyme Inhibitors, Pharmacology, chemistry.chemical_classification, Bicyclic molecule, 010405 organic chemistry, Organic Chemistry, Stereoselective synthesis, Stereoisomerism, General Medicine, Pharmacological chaperones, Imino Sugars, 0104 chemical sciences, Hexosaminidases, Kinetics, Enzyme, chemistry, Biochemistry, sp2-iminosugars, Stereoselectivity

الوصف: Due to their capacity to inhibit hexosaminidases, 2-acetamido-1,2-dideoxy-iminosugars have been widely studied as potential therapeutic agents for various diseases. An efficient stereoselective synthesis of 2-acetamido-1,2-dideoxyallonojirimycin (DAJNAc), the most potent inhibitor of human placenta b-Nacetylglucosaminidase (b-hexosaminidase) among the epimeric series, is here described. This novel procedure can be easily scaled up, providing enough material for structural modifications and further biological tests. Thus, two series of sp2-iminosugar conjugates derived from DAJNAc have been prepared, namely monocyclic DAJNAc-thioureas and bicyclic 2-iminothiazolidines, and their glycosidase inhibitory activity evaluated. The data evidence the utmost importance of developing diversity-oriented synthetic strategies allowing optimization of electrostatic and hydrophobic interactions to achieve high inhibitory potencies and selectivities among isoenzymes. Notably, strong differences in the inhibition potency of the compounds towards b-hexosaminidase from human placenta (mature) or cultured fibroblasts (precursor form) were encountered. The ensemble of data suggests that the ratio between them, and not the inhibition potency towards the placenta enzyme, is a good indication of the chaperoning potential of TaySachs disease-associated mutant hexosaminidase

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6c5cdb2c357f4536852ffe09288c201aTest
http://hdl.handle.net/10261/137497Test

المؤلفون: José M. García Fernández, Katsumi Higaki, Alda Lisa Concia, Pere Clapés, M. Isabel García-Moreno, Teresa Mena-Barragán, Carmen Ortiz Mellet, Eiji Nanba

المصدر: European journal of medicinal chemistry. 121

مصطلحات موضوعية: Glycoside Hydrolases, Stereochemistry, Iminosugar, 010402 general chemistry, 01 natural sciences, Pyrrolidine, chemistry.chemical_compound, Structure-Activity Relationship, Drug Discovery, medicine, Structure–activity relationship, Moiety, Humans, Enzyme Inhibitors, Pharmacology, Gaucher Disease, biology, Bicyclic molecule, 010405 organic chemistry, Organic Chemistry, General Medicine, Fibroblasts, 0104 chemical sciences, Imino Sugars, Pharmacological chaperone, chemistry, Biochemistry, Chaperone (protein), biology.protein, Triol, medicine.drug, Imino Pyranoses

الوصف: 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.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::25ff26fc321962d3a0dce4a4e17f3d25Test
https://pubmed.ncbi.nlm.nih.gov/26361824Test