Efficient stereoselective synthesis of 2-acetamido-1,2- dideoxyallonojirimycin (DAJNAc) and sp2-iminosugar conjugates: Novel hexosaminidase inhibitors with discrimination capabilities between the mature and precursor forms of the enzyme
| العنوان: | Efficient stereoselective synthesis of 2-acetamido-1,2- dideoxyallonojirimycin (DAJNAc) and sp2-iminosugar conjugates: Novel hexosaminidase inhibitors with discrimination capabilities between the mature and precursor forms of the enzyme |
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| 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 |
| بيانات النشر: | Elsevier, 2016. |
| سنة النشر: | 2016 |
| 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 |
| اللغة: | English |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6c5cdb2c357f4536852ffe09288c201aTest http://hdl.handle.net/10261/137497Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....6c5cdb2c357f4536852ffe09288c201a |
| قاعدة البيانات: | OpenAIRE |
| الوصف غير متاح. |