Joffrin Amélie M, Saunders Alex M, Barneda David, Flemington Vikki, Thompson Amber L, Sanganee Hitesh J, Conway Stuart J
Department of Chemistry, Chemistry Research Laboratory, University of Oxford Mansfield Road Oxford OX1 3TA UK
Inositide Laboratory, Babraham Institute Babraham Research Campus Cambridge CB22 3AT UK.
Chem Sci. 2020 Dec 28;12(7):2549-2557. doi: 10.1039/d0sc06219g. eCollection 2021 Feb 21.
Synthetic phosphatidylinositol phosphate (PtdIns ) derivatives play a pivotal role in broadening our understanding of PtdIns metabolism. However, the development of such tools is reliant on efficient enantioselective and regioselective synthetic strategies. Here we report the development of a divergent synthetic route applicable to the synthesis of deuterated PtdIns4 and PtdIns5 derivatives. The synthetic strategy developed involves a key enzymatic desymmetrisation step using Lipozyme TL-IM®. In addition, we optimised the large-scale synthesis of deuterated -inositol, allowing for the preparation of a series of saturated and unsaturated deuterated PtdIns4 and PtdIns5 derivatives. Experiments in MCF7 cells demonstrated that these deuterated probes enable quantification of the corresponding endogenous phospholipids in a cellular setting. Overall, these deuterated probes will be powerful tools to help improve our understanding of the role played by PtdIns in physiology and disease.
合成磷脂酰肌醇磷酸（PtdIns ）衍生物在拓宽我们对PtdIns 代谢的理解方面发挥着关键作用。然而，此类工具的开发依赖于高效的对映选择性和区域选择性合成策略。在此，我们报告了一种适用于合成氘代PtdIns4和PtdIns5衍生物的发散合成路线的开发。所开发的合成策略涉及使用Lipozyme TL-IM®的关键酶促去对称化步骤。此外，我们优化了氘代肌醇的大规模合成，从而能够制备一系列饱和和不饱和的氘代PtdIns4和PtdIns5衍生物。在MCF7细胞中的实验表明，这些氘代探针能够在细胞环境中对相应的内源性磷脂进行定量。总体而言，这些氘代探针将成为有力工具，有助于提高我们对PtdIns 在生理和疾病中所起作用的理解。
