Phosphorus Dendrimers for Metal-Free Ligation: Design of Multivalent Pharmacological Chaperones against Gaucher Disease

The first phosphorus dendrimers built on a cyclotriphosphazene core and decorated with six or twelve monofluorocyclooctyne units were prepared. A simple stirring allowed the grafting of N-hexyl deoxynojirimycin inhitopes onto their surface by copper-free strain promoted alkyne-azide cycloaddition click reaction. The synthesized iminosugars clusters were tested as multivalent inhibitors of the biologically relevant enzymes & beta;-glucocerebrosidase and acid & alpha;-glucosidase, involved in Gaucher and Pompe lysosomal storage diseases, respectively. For both enzymes, all the multivalent compounds were more potent than the reference N-hexyl deoxynojirimycin. Remarkably, the final dodecavalent compound proved to be one of the best & beta;-glucocerebrosidase inhibitors described to date. These cyclotriphosphazene-based deoxynojirimycin dendrimers were then evaluated as pharmacological chaperones against Gaucher disease. Not only did these multivalent constructs cross the cell membranes but they were also able to increase & beta;-glucocerebrosidase activity in Gaucher cells. Notably, dodecavalent compound allowed a 1.4-fold enzyme activity enhancement at a concentration as low as 100 nM. These new monofluorocyclooctyne-presenting dendrimers may further find numerous applications in the synthesis of multivalent objects for biological and pharmacological purposes.

Automated summary

The researchers synthesized phosphorus dendrimers with a cyclotriphosphazene core and decorated with monofluorocyclooctyne units. They grafted N-hexyl deoxynojirimycin inhibitors onto the surface of dendrimers. These synthesized iminosugars were tested as multivalent inhibitors of enzymes associated with Gaucher and Pompe lysosomal storage diseases, showing higher potency than the reference inhibitor. These dendrimers were also evaluated as pharmacological chaperones against Gaucher disease, exhibiting increased enzyme activity in Gaucher cells.