Download MendeleySynthesis of an alpha-phosphono-alpha , alpha-difluoroacetamide analogue of the diphosphoinositol pentakisphosphate 5-InsP7.
Riley, A.M., Wang, H., Shears, S.B., Potter, B.V.L.(2019) Medchemcomm 10: 1165-1172
- PubMed: 31391889
- DOI: https://doi.org/10.1039/c9md00163h
- Primary Citation of Related Structures:
6N5C - PubMed Abstract:
Diphosphoinositol phosphates (PP-InsPs) are an evolutionarily ancient group of signalling molecules that are essential to cellular and organismal homeostasis. As the detailed mechanisms of PP-InsP signalling begin to emerge, synthetic analogues of PP-InsPs containing stabilised mimics of the labile diphosphate group can provide valuable investigational tools. We synthesised 5-PCF 2 Am-InsP 5 ( 1 ), a novel fluorinated phosphonate analogue of 5-PP-InsP 5 , and obtained an X-ray crystal structure of 1 in complex with diphosphoinositol pentakisphosphate kinase 2 (PPIP5K2). 5-PCF 2 Am-InsP 5 binds to the kinase domain of PPIP5K2 in a similar orientation to that of the natural substrate 5-PP-InsP 5 and the PCF 2 Am structure can mimic many aspects of the diphosphate group in 5-PP-InsP 5 . We propose that 1 , the structural and electronic properties of which are in some ways complementary to those of existing phosphonoacetate and methylenebisphosphonate analogues of 5-PP-InsP 5 , may be a useful addition to the expanding array of chemical tools for the investigation of signalling by PP-InsPs. The PCF 2 Am group may also deserve attention for wider application as a diphosphate mimic.
Organizational Affiliation:
Medicinal Chemistry and Drug Discovery , Department of Pharmacology , University of Oxford , Mansfield Road , Oxford OX1 3QT , UK . Email: [email protected] ; ; Tel: +44 (0)1865 271945.
