Tracking Glycosylation State with Fluorinated Glycosides Probes

项目摘要 糖基化的天然产物广泛存在于自然界中，并且在生物学中具有突出的作用。 治疗人类多种疾病。抗生素，万古霉素和红霉素，以及抗癌药物 药物多柔比星和博来霉素是显著的例子。此外，一些药物已经 由糖基化的天然产物设计，最近的例子是天然产物的开发， 根皮苷，进入钠-葡萄糖协同转运蛋白-2（SGLT 2）类抗糖尿病药物，其中卡格列净 （kana®）是一流的。在这种情况下，根皮苷显示葡萄糖，这对于其在葡萄糖代谢中的相互作用至关重要。 SGLT 2转运蛋白;然而，糖苷键不稳定，并迅速去糖基化。因此， 对去糖基化具有抗性的根皮苷衍生物有助于将其转化为卡格列净。 最近，糖基化的多酚类天然产物，称为花青素，已经显示出大量的 在与年龄相关的神经退行性疾病和疾病，如帕金森氏症和阿尔茨海默氏症的潜力。 不幸的是，临床研究表明，糖基化花色苷的糖部分很快就会被分解， 在消化过程中水解得到花青素苷元，并且各个苷元的溶解性差， 不稳定，并且通常没有生物效应。花青素的这种代谢能力阻碍了它们的生长。 平移势然而，有一个关键的生物医学需要发现新的治疗策略，在所有 这三个条件。在这个项目中，我们将设计花青素的衍生物，其中糖基 不能水解。在我们的体内研究中，我们已经证实了天然花青素的存在， 经口给药后大鼠的合并血清，但在匀浆肝脏样品中不存在。我们最近 开发了一种新的合成方法，用稳定的氟化甲基取代不稳定的糖基键， 组此外，这些氟化基团将用作通过F-NMR跟踪糖基化状态的探针。我们 目标是设计和跟踪代谢稳定的糖基化花青素，并证明增强的稳定性 在体外和啮齿动物中。这个项目有可能产生重大影响，因为一种方法可以增加 氟化糖转化为有机分子是一个尚未解决的挑战。此外，跟踪增强的 花青素苷的氟化衍生物的代谢稳定性将有助于促进花青素苷的翻译。 这些糖基化天然产物的潜力。

Project Summary 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.