Small Molecules Targeting Fructose Transport

Fructose, a simple sugar abundantly present in fruits, vegetables, and sweetened beverages, plays a crucial role in various metabolic pathways and has been implicated in the development of metabolic disorders such as obesity, diabetes, and cancer. Like glucose, fructose is transported across cell membranes by specialized transport proteins known as GLUTs. Notably, mounting evidence links fructose-specific GLUT5 and other non-specific fructose transporters, like GLUT2 and GLUT12, to cancer, making them attractive targets for therapeutic intervention. Consequently, significant efforts have been dedicated to identifying and developing small molecules capable of selectively modulating fructose transport. A specific GLUT5-targeting compound, 2,5-anhydro-D-mannitol (2,5-AM), has paved the way for the development of numerous fructose-mimicking probes with diverse properties, including inhibitory, radioactive imaging, fluorescent, photoactive, and drug delivery capabilities. In the present work, we utilized fluorescent conjugates of 2,5-AM as chemical tools to discern the two major fructose transporters, GLUT5 and GLUT2, in breast adenocarcinoma MCF7 cells. Additionally, we successfully tuned secondary interactions with transporter by modifying the fluorophore moiety, thus creating probes with properties suitable for passage through and adhesion to GLUT. Moreover, we aimed to sensitize triple-negative breast cancer (TNBC) to improve cisplatin treatment. To achieve these objectives, we employed both previously established coumarin-based glycoconjugates of 2,5-AM (ManCous) and a newly developed set of probes. We demonstrated that selective distribution of specific probes can be achieved by mimicking the conformational and configurational variations of fructose using molecular probes. Specifically, the fructofuranose mimetic was found to be predominantly transported via GLUT5, while the <em>β</em>-D-fructopyranose mimetic utilized GLUT2 for transport. Furthermore, we established that probe binding was generally well-tolerated by cells, while substrate transport elicited substantial cytotoxic reactions. Notably, our probes exhibited the ability to enhance cisplatin cytotoxicity in TNBC cells, namely MDA-MB-231 and MDA-MB-453, with cell cycle arrest in the G2/M phase contributing to a more than 6-fold increase in cisplatin toxicity. Overall, this study highlights the importance of fructose transporters in cellular processes, showcases the potential of fructose-mimicking probes for targeted interventions, and sheds light on the promising role of these probes in enhancing the efficacy of cisplatin treatment in TNBC.