Glycosylated natural products are widespread in nature and have secured a prominent role in the treatment of many diseases in humans. The antibiotics, vancomycin and erythromycin, and the anticancer agents, doxorubicin and bleomycin, are remarkable examples. Additionally, some pharmaceuticals have been designed from glycosylated natural products, and a recent instance is the development of the natural product, phlorizin, into the sodium-glucose co-transporter-2 (SGLT2) class of antidiabetic drugs in which canagliflozin (Invokana) was the first-in-class. In this case, phlorizin displays glucose which is crucial for its interaction at the SGLT2 transporter; however, the glycoside linkage is unstable and rapidly de-glycosylated. Thus, the design of derivatives of phlorizin that were resistant to de-glycosylation was instrumental in its translation to canagliflozin. Recently, glycosylated polyphenolic natural products called anthocyanins have demonstrated substantial potential in age-related neurodegeneration and diseases such as Parkinson's and Alzheimer's disease. Unfortunately, clinical studies have shown that the sugar moieties of the glycosylated anthocyanins are rapidly hydrolyzed during digestion to give the anthocyanin aglycones, and the respective aglycones are poorly soluble, unstable, and generally devoid of biological effects. This metabolic liability of the anthocyanins has blocked their translational potential. However, there is a critical biomedical need to discover new treatment strategies in all three of these conditions. In this project, we will design derivatives of anthocyanins, where the sugar group cannot be hydrolyzed. In our in vivo studies, we have already validated the presence of a natural anthocyanin in the pooled serum of rats following oral dosing but its absence in homogenized liver samples. We have recently developed a new synthetic method to replace an unstable glycosyl linkage with a stable, fluorinated methyl group. Additionally, these fluorinated groups will serve as probes for tracking glycosylation state by F-NMR. Our goal is to design and track metabolically stable glycosylated anthocyanins and demonstrate enhanced stability in vitro and in rodents. This project has the potential to deliver a substantial impact, because a method to add fluorinated sugars to organic molecules is an unaddressed challenge. Also, tracking an enhancement in the metabolic stability of fluorinated derivatives of the anthocyanins will contribute to advancing the translational potential of these glycosylated natural products.