Towards Selective Binding to the GLUT5 Transporter: Synthesis, Molecular Dynamics and In Vitro Evaluation of Novel C-3-Modified 2,5-Anhydro-D-mannitol Analogs.

Deregulation and changes in energy metabolism are emergent and important biomarkers of cancer cells. The uptake of hexoses in cancer cells is mediated by a family of facilitative hexose membrane-transporter proteins known as Glucose Transporters (GLUTs). In the clinic, numerous breast cancers do not show elevated glucose metabolism (which is mediated mainly through the GLUT1 transporter) and may use fructose as an alternative energy source. The principal fructose transporter in most cancer cells is GLUT5, and its mRNA was shown to be elevated in human breast cancer. This offers an alternative strategy for early detection using fructose analogs. In order to selectively scout GLUT5 binding-pocket requirements, we designed, synthesized and screened a new class of fructose mimics based upon the 2,5-anhydromannitol scaffold. Several of these compounds display low millimolar IC50 values against the known high-affinity 18F-labeled fructose-based probe 6-deoxy-6-fluoro-D-fructose (6-FDF) in murine EMT6 breast cancer cells. In addition, this work used molecular docking and molecular dynamics simulations (MD) with previously reported GLUT5 structures to gain better insight into hexose–GLUT interactions with selected ligands governing their preference for GLUT5 compared to other GLUTs. The improved inhibition of these compounds, and the refined model for their binding, set the stage for the development of high-affinity molecular imaging probes targeting cancers that express the GLUT5 biomarker.

去调控以及能量代谢的改变是癌细胞新兴且重要的生物标志物。癌细胞对己糖的摄取是由一个被称为葡萄糖转运蛋白（GLUTs）的易化己糖膜转运蛋白家族所介导的。在临床上，许多乳腺癌并不表现出葡萄糖代谢升高（葡萄糖代谢主要是通过GLUT1转运蛋白介导的），并且可能使用果糖作为替代能源。大多数癌细胞中主要的果糖转运蛋白是GLUT5，并且其信使核糖核酸（mRNA）在人类乳腺癌中被证明是升高的。这为使用果糖类似物进行早期检测提供了一种替代策略。为了选择性地探究GLUT5结合口袋的要求，我们基于2,5 - 脱水甘露醇支架设计、合成并筛选了一类新的果糖模拟物。在小鼠EMT6乳腺癌细胞中，这些化合物中的几种对已知的高亲和力的基于果糖的18F标记探针6 - 脱氧 - 6 - 氟 - D - 果糖（6 - FDF）显示出低微摩尔的半数抑制浓度（IC50）值。此外，这项工作使用了分子对接以及分子动力学模拟（MD），并结合先前报道的GLUT5结构，以便更好地了解己糖 - GLUT相互作用以及所选配体对GLUT5相对于其他GLUTs的偏好性。这些化合物抑制作用的改善以及它们结合模型的优化，为开发针对表达GLUT5生物标志物的癌症的高亲和力分子成像探针奠定了基础。