Fluorination Influences the Bioisostery of Myo‐Inositol Pyrophosphate Analogs

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 a...

Full description

Saved in:
Bibliographic Details
Published in:Chemistry : a European journal 2023-12, Vol.29 (67), p.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: Article
Language:English
Subjects:
Analogs
Biological activity
Chemistry
Crystallization
Diphosphates
Fluorination
fluorine
Halogenation
Humans
Inositol
Inositol Phosphates - chemistry
inositol pyrophosphates
Inositols
Kinases
phosphoramidite
Phosphorylation
protein structures
Pyrophosphates
Reagents
Synthesis
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0947-6539
1521-3765
DOI:10.1002/chem.202302426