Preparation of Synthetically Challenging Nucleotides Using Cyanoethyl P-Imidazolides and Microwaves

Strenkowska, Malwina; Wanat, Przemysław; Ziemniak, Marcin; Jemielity, Jacek; Kowalska, Joanna

doi:10.1021/ol302071f

Cited by 47 publications

(58 citation statements)

References 33 publications

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“…A solution to this problem was proposed by introducing electrophilic phosphorylating reagents, such as cyanoethyl phosphate or thiophosphate P-imidazolides, which are capable of reacting with non-activated nucleotides (Fig. 7) [89]. Such reagents were shown to react with a series of phosphates, phosphorothioates, and seleno-and borano-phosphates, which was followed by one-step removal of cyanoethyl-protecting groups, provided straightforward access to a-modified nucleoside diphosphates and b-modified triphosphates.…”

Section: Synthesis Of Rna Caps: P-imidazolides and MCL 2 -Mediated Comentioning

confidence: 99%

Applications of Phosphate Modification and Labeling to Study (m)RNA Caps

Warmiński

Sikorski

Kowalska

et al. 2017

Phosphate Labeling and Sensing in Chemical Biology

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The cap is a natural modification present at the 5 0 ends of eukaryotic messenger RNA (mRNA), which because of its unique structural features, mediates essential biological functions during the process of gene expression. The core structural feature of the mRNA cap is an N7-methylguanosine moiety linked by a 5 0 -5 0 triphosphate chain to the first transcribed nucleotide. Interestingly, other RNA 5 0 end modifications structurally and functionally resembling the m 7 G cap have been discovered in different RNA types and in different organisms. All these structures contain the 'inverted' 5 0 -5 0 oligophosphate bridge, which is necessary for interaction with specific proteins and also serves as a cleavage site for phosphohydrolases regulating RNA turnover. Therefore, cap analogs containing oligophosphate chain modifications or carrying spectroscopic labels attached to phosphate moieties serve as attractive molecular tools for studies on RNA metabolism and modification of natural RNA properties. Here, we review chemical, enzymatic, and chemoenzymatic approaches that enable preparation of modified cap structures and RNAs carrying such structures, with emphasis on phosphate-modified mRNA cap analogs and their potential applications.M. Warminski and P. J. Sikorski have contributed equally to this work.

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Section: Synthesis Of Rna Caps: P-imidazolides and MCL 2 -Mediated Comentioning

confidence: 99%

Applications of Phosphate Modification and Labeling to Study (m)RNA Caps

Warmiński

Sikorski

Kowalska

et al. 2017

Phosphate Labeling and Sensing in Chemical Biology

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“…1) were synthesized as previously described: compound 2 (Kalek et al 2005), compound 3 (Rydzik et al 2012), compounds 4a, 4b (Strenkowska et al 2012), compound 5 (Baranowski et al 2015), compounds 9-11, 12-15 (Ziemniak et al 2015, compounds 1, 6, 16, 17 (Jemielity et al 2003).…”

Section: Compound Librarymentioning

confidence: 99%

“…Compounds 7 and 8 were prepared using the same methods as described in Strenkowska et al (2012). The structure and purity for all compounds was confirmed by RP HPLC analysis, HRMS, and NMR before biological experiments.…”

Section: Compound Librarymentioning

confidence: 99%

Two-headed tetraphosphate cap analogs are inhibitors of the Dcp1/2 RNA decapping complex

Ziemniak

Mugridge

Kowalska

et al. 2016

RNA

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Dcp1/2 is the major eukaryotic RNA decapping complex, comprised of the enzyme Dcp2 and activator Dcp1, which removes the 5 ′ m 7 G cap from mRNA, committing the transcript to degradation. Dcp1/2 activity is crucial for RNA quality control and turnover, and deregulation of these processes may lead to disease development. The molecular details of Dcp1/2 catalysis remain elusive, in part because both cap substrate (m 7 GpppN) and m 7 GDP product are bound by Dcp1/2 with weak (mM) affinity. In order to find inhibitors to use in elucidating the catalytic mechanism of Dcp2, we screened a small library of synthetic m 7 G nucleotides (cap analogs) bearing modifications in the oligophosphate chain. One of the most potent cap analogs, m 7 Gp S ppp S m 7 G, inhibited Dcp1/2 20 times more efficiently than m 7 GpppN or m 7 GDP. NMR experiments revealed that the compound interacts with specific surfaces of both regulatory and catalytic domains of Dcp2 with submillimolar affinities. Kinetics analysis revealed that m 7 Gp S ppp S m 7 G is a mixed inhibitor that competes for the Dcp2 active site with micromolar affinity. m 7 Gp S ppp S m 7 G-capped RNA undergoes rapid decapping, suggesting that the compound may act as a tightly bound cap mimic. Our identification of the first small molecule inhibitor of Dcp2 should be instrumental in future studies aimed at understanding the structural basis of RNA decapping and may provide insight toward the development of novel therapeutically relevant decapping inhibitors.

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“…1 Over the last ~25-50 years, a small number of key methods have been adopted for the preparation of NTPs and other phosphoanhydrides, 2 although new methods are now becoming available. [3][4][5][6][7][8][9][10][11][12][13][14] Often, these approaches rely on triand tetralkylammonium salts as organic-solvent-soluble sources of nucleophilic phosphate. Unfortunately, these salts are extremely hygroscopic, [15][16][17][18][19][20] with deleterious consequences on the water-sensitive reactions that use them.…”

Section: Introductionmentioning

confidence: 99%

PPN Pyrophosphate: A New Reagent for the Preparation of Nucleoside Triphosphates

Korhonen

Bolt

Vicente-Gines

et al. 2015

Phosphorus, Sulfur, and Silicon and the Related Elements

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Preparation of Synthetically Challenging Nucleotides Using Cyanoethyl P-Imidazolides and Microwaves

Cited by 47 publications

References 33 publications

Applications of Phosphate Modification and Labeling to Study (m)RNA Caps

Applications of Phosphate Modification and Labeling to Study (m)RNA Caps

Two-headed tetraphosphate cap analogs are inhibitors of the Dcp1/2 RNA decapping complex

PPN Pyrophosphate: A New Reagent for the Preparation of Nucleoside Triphosphates

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