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

• Published in: European journal of medicinal chemistry Vol. 121; pp. 926 - 938
• Main Authors: de la Fuente, Alex, Rísquez-Cuadro, Rocío, Verdaguer, Xavier, García Fernández, José M., Nanba, Eiji, Higaki, Katsumi, Ortiz Mellet, Carmen, Riera, Antoni
• Format: Journal Article
• Language: English
• Published: PARIS Elsevier Masson SAS 04.10.2016; Elsevier
• Subjects: Chemistry, Medicinal; Hexosaminidase inhibitors; Life Sciences & Biomedicine; Pharmacological chaperones; Pharmacology & Pharmacy; Science & Technology; sp2-iminosugars; Stereoselective synthesis; Tay-Sachs disease; sp2-iminosugars; Tay-Sachs disease; Hexosaminidase inhibitors; Pharmacological chaperones; Stereoselective synthesis; IMINOSUGAR C-GLYCOSIDES; CRYSTAL-STRUCTURE; BETA-N-ACETYLHEXOSAMINIDASE; FABRY DISEASE; SANDHOFF-DISEASE; GAUCHER-DISEASE; GM GANGLIOSIDOSIS; sp-iminosugars; DIRECTED DIHYDROXYLATION REACTION; TAY-SACHS
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2015.10.038

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. [Display omitted] •Stereoselective synthesis of 2-acetamido-1,2-dideoxyallonojirimycin.•Stereoselective synthesis of sp2-iminosugar conjugates.•Novel glycosidase inhibitors.•Monocyclic DAJNAc-thioureas as hexosaminidase inhibitors.•Bicyclic 2-iminothiazolidines as hexosaminidase inhibitors.