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Bioorganic & Medicinal Chemistry Letters Aug 2021The G-coupled P2Y receptor (P2YR) is a component of the purinergic signaling system and functions in inflammatory, cardiovascular and metabolic processes. UDP, the...
The G-coupled P2Y receptor (P2YR) is a component of the purinergic signaling system and functions in inflammatory, cardiovascular and metabolic processes. UDP, the native P2YR agonist and P2YR partial agonist, is subject to hydrolysis by ectonucleotidases. Therefore, we have synthesized UDP/CDP analogues containing a stabilizing α,β-methylene bridge as P2YR agonists and identified compatible affinity-enhancing pyrimidine modifications. A distal binding region on the receptor was explored with 4-benzyloxyimino cytidine 5'-diphosphate analogues and their potency determined in a calcium mobilization assay. A 4-trifluoromethyl-benzyloxyimino substituent in 25 provided the highest human P2YR potency (MRS4554, 0.57 µM), and a 5-fluoro substitution of the cytosine ring in 28 similarly enhanced potency, with >175- and 39-fold selectivity over human P2YR, respectively. However, 3-alkyl (31-33, 37, 38), β-d-arabinofuranose (39) and 6-aza (40) substitution prevented P2YR activation. Thus, we have identified new α,β-methylene bridged N-extended CDP analogues as P2YR agonists that are highly selective over the P2YR.
Topics: Diphosphonates; Dose-Response Relationship, Drug; Humans; Molecular Structure; Pyrimidine Nucleotides; Receptors, Purinergic P2; Structure-Activity Relationship
PubMed: 34048882
DOI: 10.1016/j.bmcl.2021.128137 -
The Journal of Nutrition Jan 1994Nucleotides are phosphate esters of nucleosides that contain a sugar linked through a glycosidic linkage with purine and pyrimidine bases. Purine and pyrimidine... (Review)
Review
Nucleotides are phosphate esters of nucleosides that contain a sugar linked through a glycosidic linkage with purine and pyrimidine bases. Purine and pyrimidine nucleotides are major components of the cells that make up the monomeric units of DNA and RNA, and they function in all cellular processes. Biosynthesis, interconversion, catabolism and other aspects of nucleotide metabolism, along with various cellular roles of nucleotides, will be discussed, and the possible use of dietary sources of preformed purines and pyrimidines will be considered.
Topics: Animals; Humans; Purine Nucleotides; Pyrimidine Nucleotides
PubMed: 8283301
DOI: 10.1093/jn/124.suppl_1.124S -
Frontiers in Bioscience : a Journal and... May 2004Pyrimidine nucleotides represent one of the most fundamental of cellular components. They are the building blocks for the direct synthesis of DNA and RNA that function... (Review)
Review
Pyrimidine nucleotides represent one of the most fundamental of cellular components. They are the building blocks for the direct synthesis of DNA and RNA that function in information storage and retrieval within the cell, but they also participate in the metabolism of a large number of other cellular components from sugar interconversion to cellular polysaccharides to glycoproteins and phospholipids. Thus, the metabolism of pyrimidine nucleotides and their intracellular pool sizes influence vast areas of normal cellular metabolism. The first pyrimidine, UMP, is synthesized by a de novo pathway that appears to be mechanistically invariant in all organisms. UMP is then further modified to form other pyrimidines. Breakdown of deoxyribo- and ribonucleic acids, the main sink for pyrimidine nucleotides, allows pyrimidines to be reutilized for resynthesis of these important cellular components. Pyrimidines are salvaged by converting the modified components into the free base, uracil for reutilization. Finally, pyrimidines are degraded into simple cellular metabolites permitting reutilization of nitrogen and carbon from pyrimidine ring systems into cellular metabolic pools. The regulation of pyrimidine metabolism is tightly controlled in plants. Additionally, plants produce toxic secondary metabolites derived from pyrimidines for use as defense compounds.
Topics: Models, Chemical; Plants; Pyrimidine Nucleotides; Pyrimidines
PubMed: 14977572
DOI: 10.2741/1349 -
Cold Spring Harbor Perspectives in... Jul 2021
Review
Topics: Animals; Humans; Nucleosides; Purine Nucleotides; Pyrimidine Nucleotides; Signal Transduction
PubMed: 34210662
DOI: 10.1101/cshperspect.a040592 -
Current Opinion in Biotechnology Dec 2017The development of broad-spectrum, host-acting antiviral therapies remains an important but elusive goal in anti-infective drug discovery. To replicate efficiently,... (Review)
Review
The development of broad-spectrum, host-acting antiviral therapies remains an important but elusive goal in anti-infective drug discovery. To replicate efficiently, viruses not only depend on their hosts for an adequate supply of pyrimidine nucleotides, but also up-regulate pyrimidine nucleotide biosynthesis in infected cells. In this review, we outline our understanding of mammalian de novo and salvage metabolic pathways for pyrimidine nucleotide biosynthesis. The available spectrum of experimental and FDA-approved drugs that modulate individual steps in these metabolic pathways is also summarized. The logic of a host-acting combination antiviral therapy comprised of inhibitors of dihydroorotate dehydrogenase and uridine/cytidine kinase is discussed.
Topics: Antiviral Agents; Dihydroorotate Dehydrogenase; Enzyme Inhibitors; Humans; Oxidoreductases Acting on CH-CH Group Donors; Pyrimidine Nucleotides; Viruses
PubMed: 28458037
DOI: 10.1016/j.copbio.2017.03.010 -
The International Journal of... 1988
Review
Topics: Animals; Cell Compartmentation; Cell Membrane; Cell Nucleus; Purine Nucleotides; Pyrimidine Nucleotides
PubMed: 3073978
DOI: 10.1016/0020-711x(88)90248-0 -
Journal of Medicinal Chemistry Apr 2019Cluster of differentiation 73 (CD73) converts adenosine 5'-monophosphate to immunosuppressive adenosine, and its inhibition was proposed as a new strategy for cancer...
Cluster of differentiation 73 (CD73) converts adenosine 5'-monophosphate to immunosuppressive adenosine, and its inhibition was proposed as a new strategy for cancer treatment. We synthesized 5'- O-[(phosphonomethyl)phosphonic acid] derivatives of purine and pyrimidine nucleosides, which represent nucleoside diphosphate analogues, and compared their CD73 inhibitory potencies. In the adenine series, most ribose modifications and 1-deaza and 3-deaza were detrimental, but 7-deaza was tolerated. Uracil substitution with N-methyl, but not larger groups, or 2-thio, was tolerated. 1,2-Diphosphono-ethyl modifications were not tolerated. N-(Aryl)alkyloxy-cytosine derivatives, especially with bulky benzyloxy substituents, showed increased potency. Among the most potent inhibitors were the 5'- O-[(phosphonomethyl)phosphonic acid] derivatives of 5-fluorouridine (4l), N-benzoyl-cytidine (7f), N-[ O-(4-benzyloxy)]-cytidine (9h), and N-[ O-(4-naphth-2-ylmethyloxy)]-cytidine (9e) ( K values 5-10 nM at human CD73). Selected compounds tested at the two uridine diphosphate-activated P2Y receptor subtypes showed high CD73 selectivity, especially those with large nucleobase substituents. These nucleotide analogues are among the most potent CD73 inhibitors reported and may be considered for development as parenteral drugs.
Topics: 5'-Nucleotidase; Animals; Enzyme Inhibitors; GPI-Linked Proteins; Humans; Purine Nucleotides; Pyrimidine Nucleotides; Rats; Structure-Activity Relationship
PubMed: 30895781
DOI: 10.1021/acs.jmedchem.9b00164 -
International Journal of Molecular... Nov 2022The activity of phosphate groups of phosphoethanolamine and pyrimidine nucleotides (thymidine 5-monophosphate, cytidine 5-monophosphate and uridine 5'monophosphate) in...
The activity of phosphate groups of phosphoethanolamine and pyrimidine nucleotides (thymidine 5-monophosphate, cytidine 5-monophosphate and uridine 5'monophosphate) in the process of complexation metal ions in aqueous solution was studied. Using the potentiometric method with computer calculation of the data and spectroscopic methods such as UV-Vis, EPR, C and P NMR as well as FT-IR, the overall stability constants of the complexes as well as coordination modes were obtained. At lower pH, copper(II) ions are complexed only by phosphate groups, whereas the endocyclic nitrogen atom of nucleotides has been identified as a negative center interacting with the -NH groups of phosphoethanolamine.
Topics: Pyrimidine Nucleotides; Copper; Phosphates; Spectroscopy, Fourier Transform Infrared; Ions; Cytidine Monophosphate
PubMed: 36430195
DOI: 10.3390/ijms232213718 -
Nephron 1985Uremia causes major increases in the erythrocyte (RBC) purine nucleotides, presumably secondary to phosphate retention, but no previous study has been made of the...
Uremia causes major increases in the erythrocyte (RBC) purine nucleotides, presumably secondary to phosphate retention, but no previous study has been made of the pyrimidine nucleotides, normally absent from RBC. This investigation was prompted by demonstration of the abnormal presence of RBC pyrimidine nucleotides, primarily cytidine triphosphate (CTP) plus cytidine diphosphate-choline (CDP-C) and cytidine diphosphate-ethanolamine (CDP-E), in two types of congenital hemolytic anemia as well as in lead poisoning. These observations suggested an analogy to the RBC membrane dysfunction of uremia. This is a report of the identification of CDP-C and CDP-E as the predominant abnormal pyrimidine nucleotides in the RBC hemolysates of uremic subjects. High-performance liquid chromatography of hemolysates from uremic adults showed a 50% increase in purine nucleotides and the abnormal presence of pyrimidine nucleotides and diesters at approximately 10% of the concentration of the purine nucleotides. By means of UV spectra and 31P nuclear magnetic resonance, these were identified as CDP-C and CDP-E. The increased purine and abnormal pyrimidine nucleotides of uremic RBC were unrelated to the pre- or posthemodialysis state, allopurinol, levels of blood lead, copper and zinc, or RBC pyrimidine 5'-nucleotidase, the cytosolic enzyme that specifically dephosphorylates the pyrimidine nucleotides. Although the accumulation of CTP, CDP-C and CDP-E may be an epiphenomenon of phosphate retention, it also suggests a common pathway to the accelerated hemolysis of chronic renal insufficiency.
Topics: 5'-Nucleotidase; Adult; Aged; Chromatography, High Pressure Liquid; Copper; Cytidine Diphosphate; Cytidine Diphosphate Choline; Cytidine Triphosphate; Erythrocytes; Ethanolamines; Hemolysis; Humans; Lead; Middle Aged; Nucleotidases; Purine Nucleotides; Pyrimidine Nucleotides; Uremia; Zinc
PubMed: 2983249
DOI: 10.1159/000183366 -
Organic & Biomolecular Chemistry Oct 2016The syntheses of 5-arylsulfanyl- or 5-arylselanylpyrimidine and 7-arylsulfanyl- or 7-arylselanyl-7-deazapurine nucleosides and nucleotides were developed by the...
The syntheses of 5-arylsulfanyl- or 5-arylselanylpyrimidine and 7-arylsulfanyl- or 7-arylselanyl-7-deazapurine nucleosides and nucleotides were developed by the Cu-mediated sulfanylations or selanylations of the corresponding 5-iodopyrimidine or 7-iodo-7-deazapurine nucleosides or nucleotides with diaryldisulfides or -diselenides. The reactions were also applicable for direct modifications of 2'-deoxycytidine triphosphate and the resulting 5-arylsulfanyl or 5-arylselanyl-dCTP served as substrates for the polymerase synthesis of modified DNA bearing arylsulfanyl or arylselanyl groups in the major groove.
Topics: Catalysis; Copper; Purines; Pyrimidine Nucleotides
PubMed: 27722411
DOI: 10.1039/c6ob01917j