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Proceedings of the National Academy of... Jan 2023Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, in which prognosis is determined by liver fibrosis. A common variant in hydroxysteroid...
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, in which prognosis is determined by liver fibrosis. A common variant in hydroxysteroid 17-beta dehydrogenase 13 (, rs72613567-A) is associated with a reduced risk of fibrosis in NAFLD, but the underlying mechanism(s) remains unclear. We investigated the effects of this variant in the human liver and in knockdown in mice by using a state-of-the-art metabolomics approach. We demonstrate that protection against liver fibrosis conferred by the rs72613567-A variant in humans and by the knockdown in mice is associated with decreased pyrimidine catabolism at the level of dihydropyrimidine dehydrogenase. Furthermore, we show that hepatic pyrimidines are depleted in two distinct mouse models of NAFLD and that inhibition of pyrimidine catabolism by gimeracil phenocopies the -induced protection against liver fibrosis. Our data suggest pyrimidine catabolism as a therapeutic target against the development of liver fibrosis in NAFLD.
Topics: Animals; Humans; Mice; Liver; Liver Cirrhosis; Non-alcoholic Fatty Liver Disease; Pyrimidines
PubMed: 36669104
DOI: 10.1073/pnas.2217543120 -
Molecules (Basel, Switzerland) Nov 2019Pyrido[2,3-]pyrimidines () are a type of privileged heterocyclic scaffolds capable of providing ligands for several receptors in the body. Among such structures, our... (Review)
Review
Pyrido[2,3-]pyrimidines () are a type of privileged heterocyclic scaffolds capable of providing ligands for several receptors in the body. Among such structures, our group and others have been particularly interested in pyrido[2,3-]pyrimidine-7(8)-ones () due to the similitude with nitrogen bases present in DNA and RNA. Currently there are more than 20,000 structures described which correspond to around 2900 references (half of them being patents). Furthermore, the number of references containing compounds of general structure have increased almost exponentially in the last 10 years. The present review covers the synthetic methods used for the synthesis of pyrido[2,3-]pyrimidine-7(8)-ones (), both starting from a preformed pyrimidine ring or a pyridine ring, and the biomedical applications of such compounds.
Topics: Chemistry Techniques, Synthetic; Molecular Structure; Pyrimidines; Pyrimidinones; Structure-Activity Relationship
PubMed: 31744155
DOI: 10.3390/molecules24224161 -
Bioorganic & Medicinal Chemistry Letters Oct 2010A series of pyrimidine derivatives as acid pump antagonists (APAs) was synthesized and the inhibitory activities against H(+)/K(+) ATPase isolated from hog gastric...
A series of pyrimidine derivatives as acid pump antagonists (APAs) was synthesized and the inhibitory activities against H(+)/K(+) ATPase isolated from hog gastric mucosa were determined. After elaborating on substituents at C2 and C4 position of the pyrimidine scaffold, we have observed that the compound 7h is a potent APA with H(+)/K(+) ATPase, IC(50) = 52 nM.
Topics: Animals; Enzyme Inhibitors; Gastric Mucosa; H(+)-K(+)-Exchanging ATPase; Isoquinolines; Kinetics; Proton Pump Inhibitors; Pyrimidines; Structure-Activity Relationship; Swine
PubMed: 20810280
DOI: 10.1016/j.bmcl.2010.08.007 -
Future Medicinal Chemistry 2024Cancer as a devastating malignancy, seriously threatens human life and health, but most chemotherapeutics have long been criticized for unsatisfactory therapeutic... (Review)
Review
Cancer as a devastating malignancy, seriously threatens human life and health, but most chemotherapeutics have long been criticized for unsatisfactory therapeutic efficacy due to drug resistance and severe off-target toxicity. Pyrimidines, including fused pyrimidines, are privileged scaffolds for various biological cancer targets and are the most important class of metalloenzyme carbonic anhydrase inhibitors. Pyrimidine-sulfonamide hybrids can act on different targets in cancer cells simultaneously and possess potent activity against various cancers, revealing that hybridization of pyrimidine with sulfonamide is a promising approach to generate novel effective anticancer candidates. This review aims to summarize the recent progress of pyrimidine-sulfonamide hybrids with anticancer potential, covering papers published from 2020 to present, to facilitate further rational design of more effective candidates.
Topics: Humans; Sulfonamides; Pyrimidines; Antineoplastic Agents; Neoplasms; Carbonic Anhydrase Inhibitors; Molecular Structure; Animals
PubMed: 38624011
DOI: 10.4155/fmc-2024-0010 -
Current Medicinal Chemistry 2016It is well known that disorders of pyrimidine pathways may lead to neurological, hematological, immunological diseases, renal impairments, and association with... (Review)
Review
It is well known that disorders of pyrimidine pathways may lead to neurological, hematological, immunological diseases, renal impairments, and association with malignancies. Nucleotide homeostasis depends on the three stages of pyrimidine metabolism: de novo synthesis, catabolism and recycling of these metabolites. Cytidine and uridine, in addition to be used as substrates for pyrimidine nucleotide salvaging, also act as the precursors of cytidine triphosphate used in the biosynthetic pathway of both brain's phosphatidylcholine and phosphatidylethanolamine via the Kennedy cycle. The synthesis in the brain of phosphatidylcholine and other membrane phosphatides can utilize, in addition to glucose, three compounds present in the blood stream: choline, uridine, and a polyunsaturated fatty acids like docosahexaenoic acid. Some authors, using rat models, found that oral administration of two phospholipid precursors such as uridine and omega-3 fatty acids, along with choline from the diet, can increase the amount of synaptic membrane generated by surviving striatal neurons in rats with induced Parkinson's disease. Other authors found that in hypertensive rat fed with uridine and choline, cognitive deficit resulted improved. Uridine has also been recently considered as a neuroactive molecule, because of its involvement in important neurological functions by improving memory, sleep disorders, anti-epileptic effects, as well as neuronal plasticity. Cytidine and uridine are uptaken by the brain via specific receptors and successively salvaged to the corresponding nucleotides. The present review is devoted to the enzymology of pyrimidine pathways whose importance has attracted the attention of several researchers investigating on the mechanisms underlying the physiopathology of brain.
Topics: Animals; Humans; Neurodegenerative Diseases; Pyrimidines
PubMed: 27063261
DOI: 10.2174/0929867323666160411125803 -
Journal of Bacteriology Nov 1961Løvtrup, Søren (University of Göteborg, Sweden) and David Shugar. Utilization of pyrimidines and pyrimidine deoxynucleosides by Thermobacterium acidophilum...
Løvtrup, Søren (University of Göteborg, Sweden) and David Shugar. Utilization of pyrimidines and pyrimidine deoxynucleosides by Thermobacterium acidophilum (Lactobacillus acid-ophilus). J. Bacteriol. 82:623-631. 1961.-The utilization of pyrimidine deoxynucleosides was investigated by means of deoxyribosides of unnatural pyrimidines, especially by halogen-substituted uracil derivatives. All investigated deoxyribosides could be used, except that of N-methylthymidine. It was concluded that this substance cannot be a substrate for the enzyme trans-N-deoxyribosylase, which has been shown to be active in the utilization of deoxyribosides in this microorganism. With uracil as the only pyrimidine source, the halogen-substituted deoxyuridines had a certain inhibitory effect on growth. Contrary to previous findings, it was observed that normal growth occurs in the presence of thymine as the only pyrimidine source. The utilization of this substance is less efficient than that of uracil; a 1:10 dilution leads to a decrease in the extent of growth with the former, but not with the latter. From these results, complemented with experiments in which halogen-substituted uracil derivatives and the corresponding ribosides or deoxyribosides were used as inhibitors, it has been possible to account for most of the metabolic interconversions of pyrimidines in the investigated microorganism.
Topics: Lactobacillus; Lactobacillus acidophilus; Nucleosides; Nucleotides; Pentosyltransferases; Pyrimidines; Sweden; Thymidine; Thymine; Uracil
PubMed: 14466913
DOI: 10.1128/jb.82.5.623-631.1961 -
Current Pharmaceutical Design 2002Pyrimidine nucleotides, including UTP, UDP and UDP-glucose, are important signaling molecules which activate G protein-coupled membrane receptors of the P2Y family. Four... (Review)
Review
Pyrimidine nucleotides, including UTP, UDP and UDP-glucose, are important signaling molecules which activate G protein-coupled membrane receptors of the P2Y family. Four distinct pyrimidine nucleotide-sensitive P2Y receptor subtypes have been cloned, P2Y(2), P2Y(4), P2Y(6) and P2Y(14). Pharmacological experiments indicate that further subtypes may exist. P2Y(2) and P2Y(4) receptors are activated by UTP (the P2Y(2) and the rat, but not the human P2Y(4) receptor are also activated by ATP), the P2Y(6) receptor is activated by UDP, and the P2Y(14) receptor by UDP-glucose. Derivatives and analogs of the physiological nucleotides UTP, UDP and ATP have been synthesized and evaluated in order to obtain enzymatically stable, subtype-selective agonists. P2Y(2) agonists are currently in clinical development for cystic fibrosis and dry eye syndrome. Selective antagonists for pyrimidinergic P2Y receptors are still lacking.
Topics: Animals; Humans; Ligands; Purinergic P2 Receptor Agonists; Purinergic P2 Receptor Antagonists; Pyrimidines; Receptors, Purinergic P2
PubMed: 12369950
DOI: 10.2174/1381612023392937 -
Trends in Molecular Medicine Sep 2005Genetic defects involving enzymes essential for pyrimidine nucleotide metabolism have provided new insights into the vital physiological functions of these molecules in... (Review)
Review
Genetic defects involving enzymes essential for pyrimidine nucleotide metabolism have provided new insights into the vital physiological functions of these molecules in addition to nucleic acid synthesis. Such aberrations disrupt the haematological, nervous or mitochondrial systems and can cause adverse reactions to analogue therapy. Regulation of pyrimidine pathways is also known to be disrupted in malignancies. Nine genetic defects have now been identified but only one is currently treatable. Diagnosis is aided by the accumulation of specific metabolites. Recently, progress has been made in understanding the molecular mechanisms underlying inborn errors of pyrimidine metabolism, together with the key clinical issues and the implications for the future development of novel drugs and therapeutic strategies.
Topics: Health; Humans; Purine-Pyrimidine Metabolism, Inborn Errors; Pyrimidines; Signal Transduction
PubMed: 16098809
DOI: 10.1016/j.molmed.2005.07.003 -
Cells Feb 2022Nucleotides are synthesized through two distinct pathways: de novo synthesis and nucleoside salvage. Whereas the de novo pathway synthesizes nucleotides from amino acids... (Review)
Review
Nucleotides are synthesized through two distinct pathways: de novo synthesis and nucleoside salvage. Whereas the de novo pathway synthesizes nucleotides from amino acids and glucose, the salvage pathway recovers nucleosides or bases formed during DNA or RNA degradation. In contrast to high proliferating non-malignant cells, which are highly dependent on the de novo synthesis, cancer cells can switch to the nucleoside salvage pathways to maintain efficient DNA replication. Pyrimidine de novo synthesis remains the target of interest in cancer therapy and several inhibitors showed promising results in cancer cells and in vivo models. In the 1980s and 1990s, poor responses were however observed in clinical trials with several of the currently existing pyrimidine synthesis inhibitors. To overcome the observed limitations in clinical trials, targeting pyrimidine salvage alone or in combination with pyrimidine de novo inhibitors was suggested. Even though this approach showed initially promising results, it received fresh attention only recently. Here we discuss the re-discovery of targeting pyrimidine salvage pathways for DNA replication alone or in combination with inhibitors of pyrimidine de novo synthesis to overcome limitations of commonly used antimetabolites in various preclinical cancer models and clinical trials. We also highlight newly emerged targets in pyrimidine synthesis as well as pyrimidine salvage as a promising target in immunotherapy.
Topics: Neoplasms; Nucleosides; Nucleotides; Pyrimidines
PubMed: 35203388
DOI: 10.3390/cells11040739 -
Drug Development Research Apr 2021In this article, a series of 29 new pyrimidine N-acylhydrazone hybrids were synthesized and evaluated in vitro against Leishmania amazonensis and Trypanosoma cruzi...
In this article, a series of 29 new pyrimidine N-acylhydrazone hybrids were synthesized and evaluated in vitro against Leishmania amazonensis and Trypanosoma cruzi protozoa that cause the neglected diseases cutaneous leishmaniasis and Chagas disease, respectively. Eight of the target compounds showed significant antiprotozoal activities with IC values in 4.3-33.6 μM range. The more active compound 4f exhibited selectivity index greater than 15 and drug-like properties based on Lipinski's rule.
Topics: Animals; Antiparasitic Agents; Humans; Hydrazones; Leishmania braziliensis; Pyrimidines; Trypanosoma cruzi
PubMed: 32996619
DOI: 10.1002/ddr.21745