Synthesis of an α-phosphono-α,α-difluoroacetamide analogue of the diphosphoinositol pentakisphosphate 5-InsP

• Published in: MedChemComm Vol. 1; no. 7; pp. 1165 - 1172
• Main Authors: Riley, Andrew M, Wang, Huanchen, Shears, Stephen B, Potter, Barry V. L
• Format: Journal Article
• Language: English
• Published: CAMBRIDGE Royal Soc Chemistry 17.07.2019
• Subjects: Biochemistry & Molecular Biology; Chemistry, Medicinal; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Science & Technology; MEDICINAL CHEMISTRY; INHIBITORS; PHOSPHONATE ANALOGS; DERIVATIVES; BINDING; TOOLS
• ISSN: 2040-2503; 2040-2511
• DOI: 10.1039/c9md00163h

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. A synthetic, fluorinated analogue of 5-InsP 7 binds to the kinase domain of PPIP5K2, suggesting new strategies for designing diphosphoinositol phosphate mimics.