Harnessing pyrrolidine iminosugars into dimeric structures for the rapid discovery of divalent glycosidase inhibitors

• DOI: 10.1016/j.ejmech.2018.04.008
• Publication Date: 2018-04-05T19:48:59Z
• Authors: Ana T. Carmona; Sebastián Carrión...; Valeria Pingitore; Elena Moreno-Clavijo; Inmaculada Robina; Antonio J. Moreno...
• Keywords: alpha-L-Fucosidase; Pyrrolidines; beta-Galactosidase; 01 natural sciences; Imino Sugars; 0104 chemical sciences; Structure-Activity Relationship; Drug Design; Animals; Humans; Cattle; Click Chemistry; Enzyme Inhibitors; Dimerization

The synthesis of three libraries (1a-l, 1a'-l' and 2a-l) of dimeric iminosugars through CuAAC reaction between three different alkynyl pyrrolidines and a set of diazides was carried out. The resulting crude dimers were screened in situ against two α-fucosidases (libraries 1a-l and 1a'-l') and one β-galactosidase (2a-l). This method is pioneer in the search of divalent glycosidase inhibitors. It has allowed the rapid identification of dimer 1i as the best inhibitor of α-fucosidases from bovine kidney (Ki = 0.15 nM) and Homo sapiens (Ki = 60 nM), and dimer 2e as the best inhibitor of β-galactosidase from bovine liver (Ki = 5.8 μM). In order to evaluate a possible divalent effect in the inhibition, the synthesis and biological analysis of the reference monomers were also performed. Divalent effect was only detected in the inhibition of bovine liver β-galactosidase by dimer 2e.