title: Efficient stereoselective synthesis of 2-acetamido-1,2-dideoxyallonojirimycin (DAJNAc) and sp(2)-iminosugar conjugates: Novel hexosaminidase inhibitors with discrimination capabilities between the mature and precursor forms of the enzyme.
abstract: 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 sp(2)-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.
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac 10, 08028 Barcelona, Spain.
authors.forename: Alex
authors.initials: A
authors.lastname: de la Fuente
authors.affiliation: Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, Apartado 1203, E-41071 Sevilla, Spain.
authors.forename: Rocío
authors.initials: R
authors.lastname: Rísquez-Cuadro
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac 10, 08028 Barcelona, Spain; Departament de Química Orgànica, Universitat de Barcelona, Martí i Franquès, 1, E-08028 Barcelona, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Verdaguer
authors.affiliation: Instituto de Investigaciones Químicas (IIQ), CSIC and Universidad de Sevilla, Américo Vespucio 49, Isla de la Cartuja, E-41092 Sevilla, Spain.
authors.forename: José M
authors.initials: JM
authors.lastname: García Fernández
authors.affiliation: Division of Functional Genomics, Research Center for Bioscience and Technology, Tottori University, 86 Nishi-cho, Yonago 683-8503, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Nanba
authors.affiliation: Division of Functional Genomics, Research Center for Bioscience and Technology, Tottori University, 86 Nishi-cho, Yonago 683-8503, Japan. Electronic address: kh4060@med.tottori-u.ac.jp.
authors.forename: Katsumi
authors.initials: K
authors.lastname: Higaki
authors.affiliation: Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, Apartado 1203, E-41071 Sevilla, Spain. Electronic address: mellet@us.es.
authors.forename: Carmen
authors.initials: C
authors.lastname: Ortiz Mellet
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac 10, 08028 Barcelona, Spain; Departament de Química Orgànica, Universitat de Barcelona, Martí i Franquès, 1, E-08028 Barcelona, Spain. Electronic address: antoni.riera@irbbarcelona.org.
authors.forename: Antoni
authors.initials: A
authors.lastname: Riera
mesh_terms: D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D060326:Chemistry Techniques, Synthetic; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006596:Hexosaminidases / Q000037:antagonists & inhibitors*; D006801:Humans; D050111:Imino Sugars / Q000737:chemistry*; D007700:Kinetics; D008958:Models, Molecular; D008968:Molecular Conformation; D013237:Stereoisomerism
chemical_list: C586052:2-acetamido-1,2-dideoxyallonojirimycin; D004791:Enzyme Inhibitors; D050111:Imino Sugars; D017485:1-Deoxynojirimycin; D006596:Hexosaminidases
keywords: Hexosaminidase inhibitors; Pharmacological chaperones; Stereoselective synthesis; Tay-Sachs disease; sp(2)-iminosugars