Amphiphilic 1-Deoxynojirimycin Derivatives through Click Strategies for Chemical Chaperoning in N370S Gaucher Cells

In Gaucher disease (GD), mutant beta-glucocerebrosidases (beta-GCase) that are misfolded are recognized by the quality control machinery of the endoplasmic reticulum (ER) and degraded proteolytically. Hydrophobic iminosugars can be used as pharmacological chaperones to provide an improvement in the folding of the enzyme and promote trafficking from the ER. We have developed here an efficient click procedure to tether hydrophobic substituents to N-azidopropyl-1-deoxynojirimycin. A set of 14 original iminosugars was designed and evaluated for inhibition of commercially available glucosidases. Most of the compounds were micromolar inhibitors of those enzymes. In vitro inhibition assays with the N370S beta-GCase revealed that the sublibrary containing the derivatives with aromatic aglycons displayed the highest inhibitory potency. Chaperone activity of the whole set of synthetic compounds was also explored in mutant Gaucher cells. The most active compound gave a nearly 2-fold increase in enzyme activity at 20 mu M, a significantly higher value than the 1.33-fold recorded for the reference compound N-nonyl-1-deoxynojirimycin (N-nonyl-DNJ). As previously reported with bicyclic sp(2)-iminosugars (Luan, Z.; Higald, K.; Aguilar-Moncayo, M.; Ninomiya, H.; Ohno, K.; Garcia-Moreno, M. I.; Ortiz Mellet, C.; Garcia Fernandez, J. M.; Suzuki, Y. ChemBioChem 2009, 10, 2780), in vitro inhibition of beta-GCase measured for the compounds did not correlate with the cellular chaperone activity. The potency of new iminosugar chaperones is therefore not predictable from structure-activity relationships studies based on the in vitro beta-GCase inhibition.