Harnessing pyrrolidine iminosugars into dimeric structures for the rapid discovery of divalent glycosidase inhibitors.
Eur J Med Chem
; 151: 765-776, 2018 May 10.
Article
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| MEDLINE
| ID: mdl-29674295
ABSTRACT
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 ß-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 (Kiâ¯=â¯0.15â¯nM) and Homo sapiens (Kiâ¯=â¯60â¯nM), and dimer 2e as the best inhibitor of ß-galactosidase from bovine liver (Kiâ¯=â¯5.8⯵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 ß-galactosidase by dimer 2e.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Pirrolidinas
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Beta-Galactosidase
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Imino Açúcares
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Alfa-L-Fucosidase
Limite:
Animals
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Humans
Idioma:
En
Revista:
Eur J Med Chem
Ano de publicação:
2018
Tipo de documento:
Article