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.
J Med Chem. 2017 Jan 26;60(2):568-579. doi: 10.1021/acs.jmedchem.6b01134. Epub 2017 Jan 18.
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 (IC = 9-23 nM) were considerably weaker inhibitors of SGLT1 (IC = 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.
抑制肾脏中的钠-葡萄糖协同转运蛋白（SGLTs）对葡萄糖的重吸收是治疗 2 型糖尿病的一种相对较新的策略。选择性抑制 SGLT2 而不是 SGLT1 对于最小化与 SGLT1 抑制相关的不良反应至关重要。我们合成了一个 C-葡萄糖基二氢查耳酮及其二氢查耳酮和查尔酮前体库，并使用基于细胞的葡萄糖摄取荧光测定法测试其作为 SGLT1/SGLT2 抑制剂的活性。对 SGLT2 抑制作用最强的化合物（IC = 9-23 nM）对 SGLT1 的抑制作用要弱得多（IC = 10-19 μM）。它们对钠非依赖性 GLUT 家族葡萄糖转运体没有影响，而作用最强的化合物对培养细胞也没有急性毒性。通过计算建模研究了 C-葡萄糖基二氢查耳酮与 POPC 膜的相互作用，为其不是泛分析干扰化合物提供了证据。这些结果表明，我们发现了对 SGLT2 具有强大和高度选择性抑制作用的结构。
