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Publication details

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 - Centro de Química e Bioquímica 
Miguel Machuqueiro (Author)
Dep. Química e Bioquímica
CQB - Centro de Química e Bioquímica 
Ana P. Marques (Author)
Timothy M. Dore (Author)
Amélia P. Rauter (Author)
Dep. Química e Bioquímica
CQB - Centro de Química e Bioquímica 

Scope
International

Refereeing
Yes

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)

Volume
60
Number
2

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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APA
Ana R. Jesus, Diogo Vila-Viçosa, Miguel Machuqueiro, Ana P. Marques, Timothy M. Dore, Amélia P. Rauter, (2017). Targeting Type 2 Diabetes with C-Glucosyl Dihydrochalcones as Selective Sodium Glucose Co-Transporter 2 (SGLT2) Inhibitors: Synthesis and Biological Evaluation. Journal of Medicinal Chemistry, 60, 568-579. ISSN 0022-2623. eISSN . http://dx.doi.org/10.1021/acs.jmedchem.6b01134

IEEE
Ana R. Jesus, Diogo Vila-Viçosa, Miguel Machuqueiro, Ana P. Marques, Timothy M. Dore, Amélia P. Rauter, "Targeting Type 2 Diabetes with C-Glucosyl Dihydrochalcones as Selective Sodium Glucose Co-Transporter 2 (SGLT2) Inhibitors: Synthesis and Biological Evaluation" in Journal of Medicinal Chemistry, vol. 60, pp. 568-579, 2017. 10.1021/acs.jmedchem.6b01134

BIBTEX
@article{36944, author = {Ana R. Jesus and Diogo Vila-Viçosa and Miguel Machuqueiro and Ana P. Marques and Timothy M. Dore and Amélia P. Rauter}, title = {Targeting Type 2 Diabetes with C-Glucosyl Dihydrochalcones as Selective Sodium Glucose Co-Transporter 2 (SGLT2) Inhibitors: Synthesis and Biological Evaluation}, journal = {Journal of Medicinal Chemistry}, year = 2017, pages = {568-579}, volume = 60 }