Tipo
Artigos em Revista
Tipo de Documento
Artigo Completo
Título
Targeting Type 2 Diabetes with C-Glucosyl Dihydrochalcones as Selective Sodium Glucose Co-Transporter 2 (SGLT2) Inhibitors: Synthesis and Biological Evaluation
Participantes na publicação
Ana R. Jesus (Author)
Diogo Vila-Viçosa (Author)
CQB
Miguel Machuqueiro (Author)
Dep. Química e Bioquímica
CQB
Ana P. Marques (Author)
Timothy M. Dore (Author)
Amélia P. Rauter (Author)
Dep. Química e Bioquímica
CQB
Resumo
Inhibiting glucose reabsorption by sodium glucose co-transporter proteins (SGLTs) in the kidneys is a relatively new strategy for treating type 2 diabetes. Selective inhibition of SGLT2 over SGLT1 is critical for minimizing adverse side effects associated with SGLT1 inhibition. A library of C-glucosyl dihydrochalcones and their dihydrochalcone and chalcone precursors was synthesized and tested as SGLT1/SGLT2 inhibitors using a cell-based fluorescence assay of glucose uptake. The most potent inhibitors of SGLT2 (IC50 = 9–23 nM) were considerably weaker inhibitors of SGLT1 (IC50 = 10–19 μM). They showed no effect on the sodium independent GLUT family of glucose transporters, and the most potent ones were not acutely toxic to cultured cells. The interaction of a C-glucosyl dihydrochalcone with a POPC membrane was modeled computationally, providing evidence that it is not a pan-assay interference compound. These results point toward the discovery of structures that are potent and highly selective inhibitors of SGLT2.\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\n\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\n\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\n
Data de Submissão/Pedido
2016-07-29
Data de Aceitação
2016-11-28
Data de Publicação
2017-01-18
Instituição
FACULDADE DE CIÊNCIAS DA UNIVERSIDADE DE LISBOA
Suporte
Journal of Medicinal Chemistry
Identificadores da Publicação
ISSN - 0022-2623
Editora
American Chemical Society (ACS)
Número de Páginas
11
Página Inicial
568
Página Final
579
Identificadores do Documento
DOI -
https://doi.org/10.1021/acs.jmedchem.6b01134
URL -
http://dx.doi.org/10.1021/acs.jmedchem.6b01134
Distinções
This journal is ranked in the TOP 5% of Medicinal Chemistry
This Journal is ranked in the TOP 4% of Drug Discovery
Identificadores de Qualidade
SCIMAGO Q1 (2017) - 2.567 - Drug Discovery
Web Of Science Q1 (2017) - 6.253 - Chemistry, Medicinal SCIE
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