Targeting type 2 diabetes with c-glucosyl dihydrochalcones as selective sodium glucose co-transporter 2 (sglt2) inhibitors: Synthesis and biological evaluation

Ana R. Jesus, Diogo Vila-Viçosa, Miguel Machuqueiro, Ana P. Marques, Timothy M. Dore, Amélia P. Rauter

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)568-579
Number of pages12
JournalJournal of Medicinal Chemistry
Volume60
Issue number2
DOIs
StatePublished - Jan 26 2017

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Fingerprint Dive into the research topics of 'Targeting type 2 diabetes with c-glucosyl dihydrochalcones as selective sodium glucose co-transporter 2 (sglt2) inhibitors: Synthesis and biological evaluation'. Together they form a unique fingerprint.

Cite this