Fluorination Influences the Bioisostery of Myo‐Inositol Pyrophosphate Analogs

• Published in: Chemistry : a European journal Vol. 29; no. 67; pp. e202302426 - n/a
• Main Authors: Hostachy, Sarah, Wang, Huanchen, Zong, Guangning, Franke, Katy, Riley, Andrew M., Schmieder, Peter, Potter, Barry V. L., Shears, Stephen B., Fiedler, Dorothea
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 01.12.2023; Wiley Subscription Services, Inc
• Subjects: Analogs; Biological activity; Chemistry; Chemistry, Multidisciplinary; Crystallization; Diphosphates; Fluorination; fluorine; Halogenation; Humans; Inositol; Inositol Phosphates - chemistry; inositol pyrophosphates; Inositols; Kinases; phosphoramidite; Phosphorylation; Physical Sciences; protein structures; Pyrophosphates; Reagents; Science & Technology; Synthesis; DIPHOSPHOINOSITOL PENTAKISPHOSPHATE; phosphoramidite; METABOLISM; inositol pyrophosphates; KINASE; protein structures; POLYPHOSPHATES; phosphorylation; EUKARYOTIC PHOSPHATE HOMEOSTASIS; fluorine
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.202302426

Inositol pyrophosphates (PP−IPs) are densely phosphorylated messenger molecules involved in numerous biological processes. PP−IPs contain one or two pyrophosphate group(s) attached to a phosphorylated myo‐inositol ring. 5PP−IP5 is the most abundant PP−IP in human cells. To investigate the function and regulation by PP−IPs in biological contexts, metabolically stable analogs have been developed. Here, we report the synthesis of a new fluorinated phosphoramidite reagent and its application for the synthesis of a difluoromethylene bisphosphonate analog of 5PP−IP5. Subsequently, the properties of all currently reported analogs were benchmarked using a number of biophysical and biochemical methods, including co‐crystallization, ITC, kinase activity assays and chromatography. Together, the results showcase how small structural alterations of the analogs can have notable effects on their properties in a biochemical setting and will guide in the choice of the most suitable analog(s) for future investigations. How do pyrophosphate analogs compare? The synthesis of a fluorinated analog of an inositol pyrophosphate messenger is reported. Comparison of the physicochemical and biochemical properties of a range of closely related analogs showcases that subtle modifications can distinctly influence the behavior of molecules.