Phosphorus Dendrimers for Metal‐Free Ligation: Design of Multivalent Pharmacological Chaperones against Gaucher Disease - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Chemistry - A European Journal Année : 2023

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

Résumé

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 β-glucocerebrosidase and acid α-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, final dodecavalent compound proved to be one of the best β-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 β-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.
Fichier principal
Vignette du fichier
Tran, Phosphorus dendrimers for metal-free, 2023.pdf (3.83 Mo) Télécharger le fichier
Origine : Publication financée par une institution
Licence : CC BY NC ND - Paternité - Pas d'utilisation commerciale - Pas de modification

Dates et versions

hal-04175496 , version 1 (02-10-2023)

Licence

Paternité - Pas d'utilisation commerciale - Pas de modification

Identifiants

Citer

My Lan Tran, Marc Borie-Guichot, Virginie Garcia, Abdelouahd Oukhrib, Yves Génisson, et al.. Phosphorus Dendrimers for Metal‐Free Ligation: Design of Multivalent Pharmacological Chaperones against Gaucher Disease. Chemistry - A European Journal, 2023, 29 (53), pp.e202301210. ⟨10.1002/chem.202301210⟩. ⟨hal-04175496⟩
40 Consultations
7 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More