Document type
Journal articles
Document subtype
Full paper
Title
Targeting Type 2 Diabetes with C-Glucosyl Dihydrochalcones as Selective Sodium Glucose Co-Transporter 2 (SGLT2) Inhibitors: Synthesis and Biological Evaluation
Participants in the publication
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
Summary
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
Date of Submisson/Request
2016-07-29
Date of Acceptance
2016-11-28
Date of Publication
2017-01-18
Institution
FACULDADE DE CIÊNCIAS DA UNIVERSIDADE DE LISBOA
Where published
Journal of Medicinal Chemistry
Publication Identifiers
ISSN - 0022-2623
Publisher
American Chemical Society (ACS)
Number of pages
11
Starting page
568
Last page
579
Document Identifiers
DOI -
https://doi.org/10.1021/acs.jmedchem.6b01134
URL -
http://dx.doi.org/10.1021/acs.jmedchem.6b01134
Awards
This journal is ranked in the TOP 5% of Medicinal Chemistry
This Journal is ranked in the TOP 4% of Drug Discovery
Rankings
SCIMAGO Q1 (2017) - 2.567 - Drug Discovery
Web Of Science Q1 (2017) - 6.253 - Chemistry, Medicinal SCIE
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