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

The synthesis of three libraries (1a-l, 1a'-l' and 2a-l) of dimeric iminosugars through CuAAC reaction between three different allcynyl pyrrolidines and a set of diazides was carried out. The resulting crude dimers were screened in situ against two a-fucosidases (libraries 1a-l and 2a'-l')') and one fi-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 alpha-fucosidases from bovine kidney (K-i = 0.15 nM) and Homo sapiens (K-i = 60 nM), and dimer 2e as the best inhibitor of beta-galactosidase from bovine liver (K-i = 5.8 mu M). 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 beta-galactosidase by dimer 2e. (C) 2018 Elsevier Masson SAS. All rights reserved.