Fluorination Influences the Bioisostery of Myo-Inositol Pyrophosphate Analogs.
Chemistry
; 29(67): e202302426, 2023 Dec 01.
Article
em En
| MEDLINE
| ID: mdl-37773020
ABSTRACT
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.
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Base de dados:
MEDLINE
Assunto principal:
Difosfatos
/
Fosfatos de Inositol
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article