Artículo
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
Autor/es | Fuente, Alex de la
Rísquez Cuadro, Rocio Verdaguer, Xavier García Fernández, José Manuel Nanba, Eiji Higaki, Katsumi Ortiz Mellet, Carmen Riera, Antoni |
Departamento | Universidad de Sevilla. Departamento de Química orgánica |
Fecha de publicación | 2016 |
Fecha de depósito | 2022-06-06 |
Publicado en |
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Resumen | 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 ... 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 β-N-acetylglucosaminidase (β-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 β-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. |
Agencias financiadoras | 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 |
Identificador del proyecto | CTQ2011-23620
CTQ2014-56361-P SAF2013-44021R CTQ2010-15848 P08-FQM-03711 |
Cita | Fuente, A.d.l., Rísquez Cuadro, R., Verdaguer, X., García Fernández, J.M., Nanba, E., Higaki, K.,...,Riera, A. (2016). 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. European Journal of Medicinal Chemistry, 121, 926-938. |
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