59989-18-3

Usage

Uses

Used in Pharmaceutical Industry:
2,4(1H,3H)-Pyrimidinedione, 5-ethynyl(9CI) is used as an enzyme inhibitor for the enhancement of chemotherapeutic drug efficacy. It is particularly effective in combination with 5-fluorouracil (5-FU), a widely used anticancer drug. By inactivating DPD, Eniluracil prolongs the circulating concentrations of 5-FU, allowing for a more sustained and effective treatment of various types of cancer.
Used in Anticancer Applications:
Eniluracil is employed as a potent inactivator of Dihydropyrimidine dehydrogenase (DPD), which plays a crucial role in the metabolism of pyrimidine-based chemotherapeutic drugs. By inhibiting DPD, Eniluracil increases the availability and effectiveness of 5-FU, leading to improved treatment outcomes for patients with various types of cancer, including colorectal, breast, head and neck, and esophageal cancers.
Used in Drug Development and Research:
2,4(1H,3H)-Pyrimidinedione, 5-ethynyl(9CI) serves as a valuable compound in the development and research of new anticancer drugs and drug delivery systems. Its unique mechanism of action as an irreversible DPD inhibitor makes it an interesting candidate for further investigation and potential incorporation into novel therapeutic strategies for cancer treatment.

References

1) Porter?et al. (1992),?Mechanism-based Inactivation of Dihydropyrimidine Dehydrogenase by 5-Ethynyluracil; J. Biol. Chem.,?267?5236 2) Baccalnari?et al. (1993),?5-Ethynyluracil (776C85): a potent modulator of the pharmacokinetics and antitumor efficacy of 5-fluorouracil; Proc. Natl. Acad. Sci. USA,?90?11064 3) Schilsky and Kindler (2000)?Eniluracil: an irreversible inhibitor of dihydropyrimidine dehydrogenase; Expert Opin. Investig. Drugs,?9?1635

InChI:InChI=1/C6H4N2O2/c1-2-4-3-7-6(10)8-5(4)9/h1,3H,(H2,7,8,9,10)

Upstream product

• 83355-88-8 (2,4-dimethoxy-5-pyrimidinyl) acetylene 
• 83355-90-2 5-(trimethylsilylethynyl)uracil 
• 83355-89-9 2,4-Dimethoxy-5-trimethylsilanylethynyl-pyrimidine 
• 61751-45-9 5-(α-Chlorovinyl)-2,4-dichloropyrimidine 
• 69075-42-9 5-ethynyluridine 
• 61135-33-9 2'-deoxy-5-ethynyluridine 

Downstream Products

• 99121-93-4 N₁,N₃-Dibenzyloxymethyl-5-ethynyluracil 
• 1201797-27-4 [(η5-cyclopentadienyl)Ru(triphenylphosphine)2(ethynyluracyl(-H))] 
• 1201797-42-3 [(η5-cyclopentadienyl)Ru(triphenylphosphine)2(C(OMe)CH2(uracyl))]OTf*toluene 
• 1201797-30-9 [(η5-cyclopentadienyl)Ru(triphenylphosphine)2(E-CHC(PPh3)(uracyl))]OTf 
• 958456-89-8 [(η5-cyclopentadienyl)Ru(triphenylphosphine)2(CCH(uracyl))]OTf 
• 69075-42-9 5-ethynyluridine 
• 61135-33-9 2'-deoxy-5-ethynyluridine 

Relevant academic research and scientific papers

Synthesis and biological evaluation of 5-(alkyn-1-yl)-1-(p-toluenesulfonyl) uracil derivatives

Sonogashira coupling of 5-iodouracil (2) and trimethylsilylacetylene gave 5-(trimethylsilylethynyl)uracil (3), which was deprotected to give 5-ethynyluracil (4). Copper(I)-catalyzed cyclization of 4 gave furo[2,3-d]pyrimidin-2(3H)-one (5). Tosylation of 2 and 4 gave the 1-(p-toluenesulfonyl) derivatives 6 and 7, respectively. The tosylated compound 6 and trimethylsilylacetylene did not undergo Sonogashira coupling, and copper(I)-catalyzed cyclization of 7 did not occur. Coupling of 2 with several terminal alkynes gave 5-(alkyn-1-yl)uracil derivatives (9), which underwent tosylation to produce the targeted 5-(alkyn-1-yl)-1-(p-toluenesulfonyl)uracil compounds (11). Copper(I)-catalyzed cyclization of 9 gave the respective furopyrimidines (10) in low yields. Again, cyclization did not occur with the tosyl derivatives (11). Activity against varicella-zoster virus (VZV) was observed with longer-chain analogues of 9 and 11, and compound 7 showed activity against human cytomegalovirus (HCMV) at near cytotoxic levels.

Process research and development of a dihydropyrimidine dehydrogenase inactivator: Large-scale preparation of eniluracil using a sonogashira coupling

Eniluracil (5-ethynyluracil) is a potent inactivator of the enzyme dihydropyrimidine dehydrogenase, which is the rate-limiting enzyme in the metabolism of 5-fluorouracil, a widely used anti-cancer drug. The process research and development of a three-stag

5-Triazolyluracils and their N1-sulfonyl derivatives: Intriguing reactivity differences in the sulfonation of triazole N1′-substituted and N1′-unsubstituted uracil molecules

We describe the synthesis of novel C5-triazolyl derived N1-sulfonylpyrimidines through CuI-catalyzed alkyne-azide cycloaddition followed by sulfonylation of the formed C5-triazolyl derivatives with various sulfonyl chlorides under basic conditions. In the latter step, an intriguing difference in the reactivity of the pyrimidine N1 was observed that depended on the nature of the substituent at a distant triazole N1′ site. The N1′-unsubstituted compounds gave very small amounts of sulfonylation products, whereas N1′-substituted systems produced high yields of the respective N1-sulfonyl-5-(1,2,3-triazol-4-yl)uracils. Computational analysis revealed a close correlation between the strength of the employed base catalysts and their abilities to increase the nucleophilicity of the uracil N1 atom through subsequent deprotonation, leading to more products. Following this step, the phosphazene tBu-P4 superbase was applied in the sulfonylation, resulting in exclusive formation of the triazole N1′-unsubstituted N1-sulfonylpyrimidines. The synthesis of C5-triazolyl-substituted pyrimidines and C5-triazolyl derived N1-sulfonylpyrimidines is described. Computational studies of the sulfonation step shed light on the differences in reactivity and revealed a connection between the strength of the employed base and its tendency to increase the nucleophilicity of the reacting uracil N1 atom by deprotonation.

Synthesis of 2,4-Dimethoxy-5-(3-oxo-1-alkynyl)pyrimidines, 2,4-Dimethoxy-5-(3-oxoalkyl)pyrimidines, and 5-(3-Oxoalkyl)uracils by a Highly Convenient Procedure

A simple synthesis of 2,4-dimethoxy-5-(3-oxoalkynyl)pyrimidines from the readily available 5-ethynyl-2,4-dimethoxypyrimidine is described.The sequence proceeds via an ethynylboron intermediate which is acylated with carboxylic anhydrides.The 5-(3-oxo-1-alkynyl)products are hydrogenated to the saturated analogs and these are O-dealkylated with chlorotrimethylsilane/sodium iodide to give 5-(3-oxoalkyl)uracils, e.g., 5-(3-oxobutyl)-, 5-(3-oxopentyl)-, and 5-(3-oxohexyl)uracil.These compounds and the nucleosides derived therefrom are of interest as anticancer and antiviral agents.

The Peculiar Case of the Hyper-thermostable Pyrimidine Nucleoside Phosphorylase from Thermus thermophilus**

The poor solubility of many nucleosides and nucleobases in aqueous solution demands harsh reaction conditions (base, heat, cosolvent) in nucleoside phosphorylase-catalyzed processes to facilitate substrate loading beyond the low millimolar range. This, in turn, requires enzymes that can withstand these conditions. Herein, we report that the pyrimidine nucleoside phosphorylase from Thermus thermophilus is active over an exceptionally broad pH (4–10), temperature (up to 100 °C) and cosolvent space (up to 80 % (v/v) nonaqueous medium), and displays tremendous stability under harsh reaction conditions with predicted total turnover numbers of more than 106 for various pyrimidine nucleosides. However, its use as a biocatalyst for preparative applications is critically limited due to its inhibition by nucleobases at low concentrations, which is unprecedented among nonspecific pyrimidine nucleoside phosphorylases.

Thermodynamic Reaction Control of Nucleoside Phosphorolysis

Nucleoside analogs represent a class of important drugs for cancer and antiviral treatments. Nucleoside phosphorylases (NPases) catalyze the phosphorolysis of nucleosides and are widely employed for the synthesis of pentose-1-phosphates and nucleoside analogs, which are difficult to access via conventional synthetic methods. However, for the vast majority of nucleosides, it has been observed that either no or incomplete conversion of the starting materials is achieved in NPase-catalyzed reactions. For some substrates, it has been shown that these reactions are reversible equilibrium reactions that adhere to the law of mass action. In this contribution, we broadly demonstrate that nucleoside phosphorolysis is a thermodynamically controlled endothermic reaction that proceeds to a reaction equilibrium dictated by the substrate-specific equilibrium constant of phosphorolysis, irrespective of the type or amount of NPase used, as shown by several examples. Furthermore, we explored the temperature-dependency of nucleoside phosphorolysis equilibrium states and provide the apparent transformed reaction enthalpy and apparent transformed reaction entropy for 24 nucleosides, confirming that these conversions are thermodynamically controlled endothermic reactions. This data allows calculation of the Gibbs free energy and, consequently, the equilibrium constant of phosphorolysis at any given reaction temperature. Overall, our investigations revealed that pyrimidine nucleosides are generally more susceptible to phosphorolysis than purine nucleosides. The data disclosed in this work allow the accurate prediction of phosphorolysis or transglycosylation yields for a range of pyrimidine and purine nucleosides and thus serve to empower further research in the field of nucleoside biocatalysis. (Figure presented.).

Design and synthesis of O-GlcNAcase inhibitors via 'click chemistry' and biological evaluations

Protein O-GlcNAcylation has been shown to play an important role in a number of biological processes, including regulation of the cell cycle, DNA transcription and translation, signal transduction, and protein degradation. O-GlcNAcase (OGA) is responsible for the removal of O-linked β-N-acetylglucosamine (O-GlcNAc) from serine or threonine residues, and thus plays a key role in O-GlcNAc metabolism. Potent OGA inhibitors are useful tools for studying the cellular processes of O-GlcNAc, and may be developed as drugs for the treatment neurodegenerative diseases. In this study, Cu(I)-catalyzed 'Click' cycloaddition reactions between glycosyl azides and alkynes were exploited to generate inhibitory candidates of OGA. Enzymatic kinetic screening revealed that compound 7 was a potent competitive inhibitor of human O-GlcNAcase (Ki = 185.6 μM). Molecular docking simulations of compound 7 into CpOGA (Clostridium perfringens OGA) suggested that strong π-π stacking interaction between the compound and W490 considerably contributed to improving the inhibitory activity. Crown Copyright

Rigid rod and tetrahedral hybrid compounds featuring nucleobase and nucleoside End-capped structures

Being aimed at a new type of porous solids, a moduled design strategy of molecular tectons, making use of the conjugation between a shape defined artificial backbone and the bioinspired molecular fragments of nucleobases or nucleobase derivatives as functional end-caps, has been developed. This led to the formation of the new hybrid compounds 1-13 of linear and tetrahedral geometry, containing uracil, adenine, adenosine, guanosine and its acylated analogs as the sticky end-cap sites. The compounds were synthesized from a halogen or ethynyl substituted nucleobase component and the corresponding ethynylated spacer unit following a metal assisted coupling process as the key reaction step. X-Ray crystal structure analysis demonstrates that the parent compound 1 is a solvent complex with DMSO (1:2), showing the DMSO molecules incorporated in a hydrogen bonded layer structure. Specific dependencies of the fluorescence properties of the new compounds in solution on the structure of the molecules are reported. A selection of solid compounds has been studied in respect of their ability to adsorb organic vapours. They revealed significant differences both in the sorption capacity and the selectivity towards particular solvent vapours.

Uracil reductase inactivators

The present invention relates to a group of 5-substituted uracil derivatives which are inactivators of uracil reductase and which are particularily useful in cancer chemotherapy, especially in combination with antimetabolite antineoplastic agents such as 5-fluorouracil (5-FU).

Pharmaceutical compositions of 5-substituted uracil compounds

Pharmaceutical compositions containing 5-substituted uracil compounds are disclosed. The compositions are preferably in the form of a tablet or capsule.