Stereoselective synthesis of 2-acetamido-1,2-dideoxynojirimycin (DNJNAc) and ureido-DNJNAc derivatives as new hexosaminidase inhibitors

• Published in: Organic & biomolecular chemistry Vol. 13; no. 23; pp. 6500 - 6510
• Main Authors: De la Fuente, Alex, Mena-Barragan, Teresa, Farrar-Tobar, Ronald A., Verdaguer, Xavier, Garcia Fernandez, Jose M., Ortiz Mellet, Carmen, Riera, Antoni
• Format: Journal Article
• Language: English
• Published: CAMBRIDGE Royal Soc Chemistry 01.01.2015; Royal Society of Chemistry
• Subjects: 1-Deoxynojirimycin - analogs & derivatives; 1-Deoxynojirimycin - chemical synthesis; 1-Deoxynojirimycin - chemistry; 1-Deoxynojirimycin - pharmacology; Acetamides - chemical synthesis; Acetamides - chemistry; Animals; beta-N-Acetylhexosaminidases - antagonists & inhibitors; beta-N-Acetylhexosaminidases - isolation & purification; Cattle; Chemistry; Chemistry Techniques, Synthetic; Chemistry, Organic; Disseny de medicaments; Drug design; Drug Evaluation, Preclinical - methods; Enzyme inhibitors; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Humans; Inhibidors enzimàtics; Molecular Structure; Physical Sciences; Science & Technology; Stereoisomerism; Structure-Activity Relationship; ASYMMETRIC-SYNTHESIS; PHARMACOLOGICAL CHAPERONES; ALPHA-MANNOSIDASE; BIOLOGICAL EVALUATION; SELECTIVE INHIBITORS; BETA-GALACTOSIDASE; N-ACETYLHEXOSAMINIDASE INHIBITORS; GLYCOSIDASE INHIBITORS; CYCLIC SULFATES; GAUCHER-DISEASE
• ISSN: 1477-0520; 1477-0539
• DOI: 10.1039/c5ob00507h

2-Acetamido-1,2-dideoxyiminosugars are selective and potent inhibitors of hexosaminidases and therefore show high therapeutic potential for the treatment of various diseases, including several lysosomal storage disorders. A stereoselective synthesis of 2-acetamido-1,2-dideoxynojirimycin (DNJNAc), the iminosugar analog of N-acetylglucosamine, with a high overall yield is here described. This novel procedure further allowed accessing ureido-DNJNAc conjugates through derivatization of the endocyclic amine on a key pivotal intermediate. Remarkably, some of the ureido-DNJNAc representatives behaved as potent and selective inhibitors of beta-hexosaminidases, including the human enzyme, being the first examples of neutral sp(2)-iminosugar-type inhibitors reported for these enzymes. Moreover, the amphiphilic character of the new ureido-DNJNAc is expected to confer better drug-like properties.