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.
authors.affiliation: Centro de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa , Ed C8, Piso 5, Campo Grande, 1749-016 Lisboa, Portugal.|New York University Abu Dhabi , P.O. Box 129188, Abu Dhabi, United Arab Emirates.
authors.forename: Ana R
authors.initials: AR
authors.lastname: Jesus
authors.affiliation: Centro de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa , Ed C8, Piso 5, Campo Grande, 1749-016 Lisboa, Portugal.
authors.forename: Diogo
authors.initials: D
authors.lastname: Vila-Viçosa
authors.affiliation: Centro de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa , Ed C8, Piso 5, Campo Grande, 1749-016 Lisboa, Portugal.
authors.forename: Miguel
authors.initials: M
authors.lastname: Machuqueiro
authors.affiliation: Centro de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa , Ed C8, Piso 5, Campo Grande, 1749-016 Lisboa, Portugal.
authors.forename: Ana P
authors.initials: AP
authors.lastname: Marques
authors.affiliation: New York University Abu Dhabi , P.O. Box 129188, Abu Dhabi, United Arab Emirates.
authors.forename: Timothy M
authors.identifier: 0000-0002-3876-5012
authors.initials: TM
authors.lastname: Dore
authors.affiliation: Centro de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa , Ed C8, Piso 5, Campo Grande, 1749-016 Lisboa, Portugal.
authors.forename: Amélia P
authors.identifier: 0000-0003-3790-7952
authors.initials: AP
authors.lastname: Rauter
mesh_terms: D047188:Chalcones / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D005960:Glucosides / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D057809:HEK293 Cells; D006801:Humans; D008567:Membranes, Artificial; D062105:Molecular Docking Simulation; D010713:Phosphatidylcholines / Q000737:chemistry; D051269:Sodium-Glucose Transporter 1 / Q000037:antagonists & inhibitors; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors
chemical_list: D047188:Chalcones; D005960:Glucosides; D008567:Membranes, Artificial; D010713:Phosphatidylcholines; C495674:SLC5A1 protein, human; C089180:SLC5A2 protein, human; D051269:Sodium-Glucose Transporter 1; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; C028694:1-palmitoyl-2-oleoylphosphatidylcholine