Synthesis of Nucleoside Triphosphates from 2′-3′-Protected Nucleosides Using Trimetaphosphate

Mohamady, Samy; Taylor, Scott D.

doi:10.1021/acs.orglett.5b03624

Cited by 25 publications

(41 citation statements)

References 38 publications

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“…Synthesis of dF‐dUTP (4) : Compound 4 was prepared by use of the triphosphorylation procedure of Mohamady and Taylor . DABCO (2.95 mmol, 332 mg, 5.4 equiv) and mesitylenesulfonyl chloride (2.54 mmol, 556 mg, 4.6 equiv) were added to a solution of TriMP ⋅ TBA (2.74 mmol, 2.64 g, 5 equiv) in dry pyridine (30 mL).…”

Section: Methodsmentioning

confidence: 99%

“…Synthesis of dF-dUTP (4):C ompound 4 was prepared by use of the triphosphorylation procedure of Mohamady and Ta ylor. [85] DABCO (2.95 mmol, 332 mg, 5.4 equiv) and mesitylenesulfonyl chloride (2.54 mmol, 556 mg, 4.6 equiv) were added to as olution of TriMP·TBA (2.74 mmol, 2.64 g, 5equiv) in dry pyridine (30 mL). The mixture was stirred at room temperature for one minute, compound 3 (0.55 mmol, 168 mg, 1equiv) was then added, and the reaction mixture was allowed to stir at room temperature for 4min.…”

Section: Preparationmentioning

confidence: 99%

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Exploring the Potent Inhibition of CTP Synthase by Gemcitabine‐5′‐Triphosphate

et al. 2016

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CTP synthase (CTPS) catalyzes the conversion of UTP to CTP and is a target for the development of antiviral, anticancer, antiprotozoal, and immunosuppressive agents. Exposure of cell lines to the antineoplastic cytidine analogue gemcitabine causes depletion of intracellular CTP levels, but the direct inhibition of CTPS by its metabolite gemcitabine-5'-triphosphate (dF-dCTP) has not been demonstrated. We show that dF-dCTP is a potent competitive inhibitor of Escherichia coli CTPS with respect to UTP [K =(3.0±0.1) μm], and that its binding affinity exceeds that of CTP ≈75-fold. Site-directed mutagenesis studies indicated that Glu149 is an important binding determinant for both CTP and dF-dCTP. Comparison of the binding affinities of the 5'-triphosphates of 2'-fluoro-2'-deoxycytidine and 2'-fluoro-2'-deoxyarabinocytidine revealed that the 2'-F-arabino group contributes markedly to the strong binding of dF-dCTP. Geminal 2'-F substitution on UTP (dF-dUTP) did not result in an increase in binding affinity with CTPS. Remarkably, CTPS catalyzed the conversion of dF-dUTP into dF-dCTP, thus suggesting that dF-dCTP might be regenerated in vivo from its catabolite dF-dUTP.

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Section: Methodsmentioning

confidence: 99%

Section: Preparationmentioning

confidence: 99%

Exploring the Potent Inhibition of CTP Synthase by Gemcitabine‐5′‐Triphosphate

et al. 2016

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“…Several reports have demonstrated that cTmp is capable of phosphorylating a number of different substrates, including nucleosides [20–27] . However, these reactions typically require conditions that are not generally favorable for RNA stability, such as high pH, additional cofactors, high temperatures, and urea [28–30] .…”

Section: Methodsmentioning

confidence: 99%

Enzymatic RNA Production from NTPs Synthesized from Nucleosides and Trimetaphosphate**

et al. 2021

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A mechanism of nucleoside triphosphorylation would have been critical in an evolving “RNA world” to provide high‐energy substrates for reactions such as RNA polymerization. However, synthetic approaches to produce ribonucleoside triphosphates (rNTPs) have suffered from conditions such as high temperatures or high pH that lead to increased RNA degradation, as well as substrate production that cannot sustain replication. Previous reports have demonstrated that cyclic trimetaphosphate (cTmp) can react with nucleosides to form rNTPs under prebiotically‐relevant conditions, but their reaction rates were unknown and the influence of reaction conditions not well‐characterized. Here we established a sensitive assay that allowed for the determination of second‐order rate constants for all four rNTPs, ranging from 1.7×10−6 to 6.5×10−6 M−1 s−1. The ATP reaction shows a linear dependence on pH and Mg2+, and an enthalpy of activation of 88±4 kJ/mol. At millimolar nucleoside and cTmp concentrations, the rNTP production rate is sufficient to facilitate RNA synthesis by both T7 RNA polymerase and a polymerase ribozyme. We suggest that the optimized reaction of cTmp with nucleosides may provide a viable connection between prebiotic nucleotide synthesis and RNA replication.

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“…The same group again reported an analogous technique to synthesize nucleoside triphosphate (NTP) 96 by the reaction of tritertiarybutyl ammonium salt of trimetaphosphate 92 with 1,4-diazabicyclo[2.2.2]octane (DABCO), mesitylenesulfonyl chloride (MsCl) and phthalimide although the role of phthalimide in that reaction is uncertain [ 84 ]. Both methods used organic solvent for the phosphorylation reactions ( Figure 22 ).…”

Section: Role Of P–n Species In Oligonucleotide Chemistrymentioning

confidence: 99%

Nitrogenous Derivatives of Phosphorus and the Origins of Life: Plausible Prebiotic Phosphorylating Agents in Water

Karki

Gibard

Bhowmik

et al. 2017

Life

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Phosphorylation under plausible prebiotic conditions continues to be one of the defining issues for the role of phosphorus in the origins of life processes. In this review, we cover the reactions of alternative forms of phosphate, specifically the nitrogenous versions of phosphate (and other forms of reduced phosphorus species) from a prebiotic, synthetic organic and biochemistry perspective. The ease with which such amidophosphates or phosphoramidate derivatives phosphorylate a wide variety of substrates suggests that alternative forms of phosphate could have played a role in overcoming the “phosphorylation in water problem”. We submit that serious consideration should be given to the search for primordial sources of nitrogenous versions of phosphate and other versions of phosphorus.

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Synthesis of Nucleoside Triphosphates from 2′-3′-Protected Nucleosides Using Trimetaphosphate

Cited by 25 publications

References 38 publications

Exploring the Potent Inhibition of CTP Synthase by Gemcitabine‐5′‐Triphosphate

Exploring the Potent Inhibition of CTP Synthase by Gemcitabine‐5′‐Triphosphate

Enzymatic RNA Production from NTPs Synthesized from Nucleosides and Trimetaphosphate**

Nitrogenous Derivatives of Phosphorus and the Origins of Life: Plausible Prebiotic Phosphorylating Agents in Water

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