5-Substituted UTP derivatives as P2Y2 receptor agonists

Knoblauch, B. H. Α.; Müller, Christian; Järlebark, Leif; Lawoko, Grace; Kottke, Thomas; Wikström, M.; Heilbronn, Edith

doi:10.1016/s0223-5234(99)00211-1

Cited by 20 publications

(33 citation statements)

References 17 publications

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“…Despite its poor to moderate yields, the Ludwig procedure is one of the most widely used methods for NTP synthesis because of its simplicity (use of unprotected nucleosides, one-pot reaction, short reaction times) and its applicability to a wide range of nucleoside analogues modified either on the base moiety ,− and/or on the sugar moiety. , Carbocyclic 134 and acyclic 135 and 136 derivatives (Figure ) have been synthesized in 25–35% yields according to this procedure.…”

Section: Nucleoside 5′-triphosphatesmentioning

confidence: 99%

Recent Trends in Nucleotide Synthesis

et al. 2016

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Focusing on the recent literature (since 2000), this review outlines the main synthetic approaches for the preparation of 5'-mono-, 5'-di-, and 5'-triphosphorylated nucleosides, also known as nucleotides, as well as several derivatives, namely, cyclic nucleotides and dinucleotides, dinucleoside 5',5'-polyphosphates, sugar nucleotides, and nucleolipids. Endogenous nucleotides and their analogues can be obtained enzymatically, which is often restricted to natural substrates, or chemically. In chemical synthesis, protected or unprotected nucleosides can be used as the starting material, depending on the nature of the reagents selected from P(III) or P(V) species. Both solution-phase and solid-support syntheses have been developed and are reported here. Although a considerable amount of research has been conducted in this field, further work is required because chemists are still faced with the challenge of developing a universal methodology that is compatible with a large variety of nucleoside analogues.

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Section: Nucleoside 5′-triphosphatesmentioning

confidence: 99%

Recent Trends in Nucleotide Synthesis

et al. 2016

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“…28 In a previous study, in which 5-substituted UTP derivatives were synthesized, we had observed that phosphorylation of the 2′-and 3′-hydroxy groups as a side reaction was associated with bulky substitution of the pyrimidine base. 29 The phosphorylation of compounds such as 5-butyluridine had yielded a particularly high percentage of side products, including 5-butyl-UTP 2′phosphate, 3′-phosphate, and 2′,3′-cyclophosphate. Electronic effects as well as steric interaction of the bulky butyl residue with the 5′-hydroxyl function in polar aprotic solvents might be responsible for the increased rate of phosphorylation of the secondary hydroxyl groups at C2′and C3′.…”

Section: Synthesismentioning

confidence: 99%

Synthesis and Structure−Activity Relationships of Uracil Nucleotide Derivatives and Analogues as Agonists at Human P2Y₂, P2Y₄, and P2Y₆ Receptors

2006

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A series of UTP, UDP, and UMP derivatives and analogues were synthesized and evaluated at the human pyrimidinergic P2Y receptor subtypes P2Y2, P2Y4, and P2Y6 stably expressed in 1321N1 astrocytoma cells. Substituents at N3 of UTP were poorly tolerated by P2Y2 and P2Y4 receptors. In contrast, a large phenacyl substituent at N3 of UDP was well tolerated by the P2Y6 receptor, yielding a potent and selective P2Y6 receptor agonist (3-phenacyl-UDP, EC50=70 nM, >500-fold selective). The most potent and selective P2Y2 receptor agonist of the present series was 2-thio-UTP (EC50=50 nM, >or=30-fold selective vs P2Y4 and P2Y6). All modifications at the uracil base of UTP led to a decrease in potency at the P2Y4 receptor. A beta,gamma-dichloromethylene modification in the triphosphate chain of 5-bromo-UTP was tolerated by all three receptor subtypes, thus opening up a new strategy to obtain ectonucleotide diphosphohydrolase- and phosphatase-resistant P2Y2, P2Y4, and P2Y6 receptor agonists.

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“…Most of these approaches require either the prior synthesis and isolation of a monophosphorylated substrate followed by its activation and reaction with pyrophosphate or the reaction of the nucleoside with a reagent that yields an activated phosphorus species that is either isolated or reacted in situ with pyrophosphate. − Among the latter approaches, the one-pot triphosphorylation procedure developed by Ludwig et al, which involves reacting an unprotected nucleoside with POCl 3 followed by reaction of the resulting nucleoside dichlorophosphoridate with pyrophosphate and hydrolysis of the resulting cyclic intermediate, is one of the most widely used . However, the formation of byproducts and product purification is often an issue with this methodology, though recent modifications to Ludwig’s procedure appear to help minimize these issues . The procedure of Ludwig and Eckstein has also seen widespread use. , In their procedure, a 2′-3′-protected nucleoside is reacted with salicylphosphorochloridite.…”

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confidence: 99%

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

Mohamady

Taylor

2016

Org. Lett.

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Chemists have been attempting to triphosphorylate nucleosides and other alcohols using trimetaphosphate (TriMP) since the 1960s. However, this route appears to have been abandoned due to poor yields. The first practical syntheses of nucleoside triphosphates (NTPs) are reported using TriMP as the key reagent. This was achieved by reacting the tetrabutylammonium salt of TriMP with mesitylenesulfonyl chloride in the presence of DABCO in pyridine followed by the addition of an appropriately protected nucleoside and phthalimide. Quenching the reaction with aqueous buffer followed by hydrolysis of the OH protecting groups gave the NTPs in good yield.

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5-Substituted UTP derivatives as P2Y2 receptor agonists

Cited by 20 publications

References 17 publications

Recent Trends in Nucleotide Synthesis

Recent Trends in Nucleotide Synthesis

Synthesis and Structure−Activity Relationships of Uracil Nucleotide Derivatives and Analogues as Agonists at Human P2Y₂, P2Y₄, and P2Y₆ Receptors

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

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5-Substituted UTP derivatives as P2Y2 receptor agonists

Cited by 20 publications

References 17 publications

Recent Trends in Nucleotide Synthesis

Recent Trends in Nucleotide Synthesis

Synthesis and Structure−Activity Relationships of Uracil Nucleotide Derivatives and Analogues as Agonists at Human P2Y2, P2Y4, and P2Y6 Receptors

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

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Synthesis and Structure−Activity Relationships of Uracil Nucleotide Derivatives and Analogues as Agonists at Human P2Y₂, P2Y₄, and P2Y₆ Receptors