Combined Phosphoramidite‐Phosphodiester Reagents for the Synthesis of Methylene Bisphosphonates

Engelsma, Sander B.; Meeuwenoord, Nico J.; Overkleeft, Hermen S.; Marel, Gijsbert A. van der; Filippov, Dmitri V.

doi:10.1002/anie.201611878

Cited by 21 publications

(21 citation statements)

References 33 publications

(36 reference statements)

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“…Very recently, a new approach for the activation of cyclotriphosphate has been developed by Cummins . In a wider context, the development of a P III ‐based triphosphorylation procedure including mixed oxidation states has been pioneered by Ludwig and Eckstein and a phosphoramidite (P‐amidite) for the introduction of methylene bisphosphonates has recently been reported by Filippov . However, no P‐amidite reagents without protecting groups are available for triphosphorylations.…”

Section: Methodsmentioning

confidence: 99%

A Phosphoramidite Analogue of Cyclotriphosphate Enables Iterative Polyphosphorylations

Singh

Steck

et al. 2019

Angew Chem Int Ed

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An iterative polyphosphorylation approach is described, which is based on ap hosphoramidite (P-amidite) derived reagent (c-PyPA) obtained from the cyclization of pyrophosphate with areactive diisopropylaminodichlorophosphine.T his type of reagent is unprecedented as it represents ar eactive P-amidite without protecting groups.T he reagent proved to be stable in solution over several weeks.Its utility is described in the context of iterative monodirectional and bidirectional polyphosphorylations.T he ensuing functionalized cyclotriphosphate can be opened with av ariety of nucleophiles providing ready access to diverse functionalized polyphosphate chains of defined length with several tags, including both P-N and P-O labels.Their interaction with exoand endopolyphosphatases is described.

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Section: Methodsmentioning

confidence: 99%

A Phosphoramidite Analogue of Cyclotriphosphate Enables Iterative Polyphosphorylations

Singh

Steck

et al. 2019

Angew Chem Int Ed

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“…Removal of all protecting groups by catalytic hydrogenolysis then yields the target PP-InsP. We reasoned that it might be possible to employ methylsulfonylethyl (MSE)23,24 as a temporary phosphate protecting group in this sequence. The MSE group can be removed by β-elimination, similar to the better-known β-cyanoethyl (β-CE)22,25 group.…”

Section: Resultsmentioning

confidence: 99%

A synthetic diphosphoinositol phosphate analogue of inositol trisphosphate

et al. 2018

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a Diphosphoinositol phosphates (PP-InsPs) are inositol phosphates (InsPs) that contain PP (diphosphate) groups. Converting a phosphate group in an InsP into a diphosphate has been reported to enhance affinity for some binding proteins. We synthesised 1-PP-InsĲ4,5)P 2 , the first diphosphate analogue of the intracellular signalling molecule InsP 3 , and examined its effects on InsP 3 receptors, which are intracellular Ca 2+ channels. 1-PP-InsĲ4,5)P 2 was indistinguishable from InsP 3 in its ability to bind to and activate type 1 InsP 3 receptors, indicating that the diphosphate modification of InsP 3 affected neither affinity nor efficacy. Nevertheless, 1-PP-InsĲ4,5)P 2 is the most potent 1-phosphate modified analogue of InsP 3 yet identified.PP-InsPs are generally hydrolysed by diphosphoinositol polyphosphate phosphohydrolases (DIPPs), but 1-PPInsĲ4,5)P 2 was not readily metabolised by human DIPPs. Differential scanning fluorimetry showed that 1-PP-InsĲ4,5)P 2 stabilises DIPP proteins, but to a lesser extent than naturally occurring substrates 1-PPInsP 5 and 5-PP-InsP 5 . The non-hydrolysable InsP 7 analogues 1-PCP-InsP 5 and 5-PCP-InsP 5 showed comparable stabilising abilities to their natural counterparts and may therefore be promising substrate analogues for co-crystallisation with DIPPs.

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“…To make the synthesis of ADPr-peptides more practical, it is imperative to develop a synthetic methodology that does not require significant alterations in the standard SPPS protocols such as the use of alkali labile side-chain protection and linkers. Another important avenue of research is the development of more chemically robust derivatives, for example, mono-ADPr-peptides that contain carba-ribose 62 residues instead of native ribofuranose and methylene bisphosphonate 63 as pyrophosphate isosteres. Such stabilized derivatives of ADP-ribosylated biomolecules may prove invaluable for structural studies on the native enzymes because one can then forego the use of catalytically inactive mutants.…”

Section: Discussionmentioning

confidence: 99%