Tracking Glycosylation State with Fluorinated Glycosides Probes

项目摘要 糖基化天然产物在自然界中广泛存在，并在 治疗人类的许多疾病。抗生素、万古霉素和红霉素以及抗癌药物 阿霉素和博莱霉素就是值得注意的例子。此外，一些药品已经被 由糖基化的天然产品设计而成，最近的一个例子是天然产品的开发， 根皮苷，转化为钠-葡萄糖共转运体-2(SGLT2)类降糖药物，其中卡那利平 (INVOKANA®)是一流的。在这种情况下，根茎苷显示葡萄糖，这对它在 SGLT2转运体；然而，糖苷链是不稳定的，并且迅速去糖基化。因此，设计的 根茎苷衍生物具有抗去糖基化作用，有助于其转化为卡那格列酮。 最近，被称为花青素的糖基化多酚天然产物显示出大量的 与年龄相关的神经退化以及帕金森氏症和阿尔茨海默病等疾病的潜在风险。 不幸的是，临床研究表明，糖基化花色苷的糖份含量很快 在消化过程中水解得到花青素苷元，并且各自的苷元难于溶解， 不稳定的，通常没有生物效应。花青素的这种代谢性阻碍了它们的 翻译潜力。然而，有一个关键的生物医学需要发现新的治疗策略。 其中三种情况。在这个项目中，我们将设计花青素的衍生物，其中糖基 不能被水解。在我们的活体研究中，我们已经证实了天然花青素的存在 口服给药后大鼠的混合血清，但在匀浆的肝脏样本中不存在。我们最近做了 开发了一种新的合成方法，用稳定的含氟甲基取代不稳定的糖基键 一群人。此外，这些氟化基团将作为通过F-核磁共振跟踪糖基化状态的探针。我们的 目标是设计和跟踪代谢稳定的糖基化花青素，并展示增强的稳定性 在体外和啮齿动物体内。这个项目有可能产生实质性的影响，因为添加一个方法 将氟化糖转化为有机分子是一个尚未解决的挑战。此外，跟踪 花色苷含氟衍生物的代谢稳定性将有助于促进翻译 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.