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 Dore, Amélia P. Rauter

Research output: Contribution to journalArticle

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

Fingerprint

Sodium-Glucose Transporter 2
Symporters
Sodium-Glucose Transport Proteins
Type 2 Diabetes Mellitus
Inhibitory Concentration 50
Chalcone
Glucose
Facilitative Glucose Transport Proteins
Poisons
Libraries
Cultured Cells
Fluorescence
Sodium
Kidney
Membranes
dihydrochalcone

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Targeting type 2 diabetes with c-glucosyl dihydrochalcones as selective sodium glucose co-transporter 2 (sglt2) inhibitors : Synthesis and biological evaluation. / Jesus, Ana R.; Vila-Viçosa, Diogo; Machuqueiro, Miguel; Marques, Ana P.; Dore, Timothy; Rauter, Amélia P.

In: Journal of Medicinal Chemistry, Vol. 60, No. 2, 26.01.2017, p. 568-579.

Research output: Contribution to journalArticle

Jesus, Ana R. ; Vila-Viçosa, Diogo ; Machuqueiro, Miguel ; Marques, Ana P. ; Dore, Timothy ; Rauter, Amélia P. / 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. 2017 ; Vol. 60, No. 2. pp. 568-579.
@article{a99a8e66b90547d6a7e13a82699f168a,
title = "Targeting type 2 diabetes with c-glucosyl dihydrochalcones as selective sodium glucose co-transporter 2 (sglt2) inhibitors: Synthesis and biological evaluation",
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.",
author = "Jesus, {Ana R.} and Diogo Vila-Vi{\cc}osa and Miguel Machuqueiro and Marques, {Ana P.} and Timothy Dore and Rauter, {Am{\'e}lia P.}",
year = "2017",
month = "1",
day = "26",
doi = "10.1021/acs.jmedchem.6b01134",
language = "English (US)",
volume = "60",
pages = "568--579",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "2",

}

TY - JOUR

T1 - Targeting type 2 diabetes with c-glucosyl dihydrochalcones as selective sodium glucose co-transporter 2 (sglt2) inhibitors

T2 - Synthesis and biological evaluation

AU - Jesus, Ana R.

AU - Vila-Viçosa, Diogo

AU - Machuqueiro, Miguel

AU - Marques, Ana P.

AU - Dore, Timothy

AU - Rauter, Amélia P.

PY - 2017/1/26

Y1 - 2017/1/26

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85010644658&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85010644658&partnerID=8YFLogxK

U2 - 10.1021/acs.jmedchem.6b01134

DO - 10.1021/acs.jmedchem.6b01134

M3 - Article

VL - 60

SP - 568

EP - 579

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 2

ER -