Click chemistry approach to new N-substituted aminocyclitols as potential pharmacological chaperones for Gaucher disease.
New N-alkylaminocyclitols bearing a 1,2,3-triazole system at different positions of the alkyl chain have been prepared as potential GCase pharmacological chaperones using click chemistry approaches. Among them, compounds 1d and 1e, with the shorter spacer (n = 1) between the alkyltriazolyl system and the aminocyclitol core, were the most active ones as GCase inhibitors, revealing a determinant effect of the location of the triazole ring on the activity. Furthermore, SAR data and computational docking models indicate a correlation between lipophilicity and enzyme inhibition and suggest "extended" and "bent" potential binding modes for the compounds. In the "bent" mode, the most active compounds could establish a hydrogen-bond interaction between the triazole moiety and enzyme residue Q284. Such an interaction would be precluded in compounds with a longer spacer between the triazole and the aminocyclitol core.
Díaz
Lucía
L
Facultat de Farmacia, Unitat de Quimica Farmaceutica (Unitat Associada al CSIC), Universitat de Barcelona, Avda. Joan XXIII, s/n, 08028 Barcelona, Spain.
Bujons
Jordi
J
Casas
Josefina
J
Llebaria
Amadeu
A
Delgado
Antonio
A
D054812:Cyclitols / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005776:Gaucher Disease / Q000188:drug therapy / Q000201:enzymology; D005962:Glucosylceramidase / Q000037:antagonists & inhibitors*; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D054812:Cyclitols; D014230:Triazoles; D005962:Glucosylceramidase