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Medicinal Research Reviews Mar 2019Pteridines are aromatic compounds formed by fused pyrazine and pyrimidine rings. Many living organisms synthesize pteridines, where they act as pigments, enzymatic... (Review)
Review
Pteridines are aromatic compounds formed by fused pyrazine and pyrimidine rings. Many living organisms synthesize pteridines, where they act as pigments, enzymatic cofactors, or immune system activation molecules. This variety of biological functions has motivated the synthesis of a huge number of pteridine derivatives with the aim of studying their therapeutic potential. This review gathers the state-of-the-art of pteridine derivatives, describing their biological activities and molecular targets. The antitumor activity of pteridine-based compounds is one of the most studied and advanced therapeutic potentials, for which several molecular targets have been identified. Nevertheless, pteridines are also considered as very promising therapeutics for the treatment of chronic inflammation-related diseases. On the other hand, many pteridine derivatives have been tested for antimicrobial activities but, although some of them resulted to be active in preliminary assays, a deeper research is needed in this area. Moreover, pteridines may be of use in the treatment of many other diseases, such as diabetes, osteoporosis, ischemia, or neurodegeneration, among others. Thus, the diversity of the biological activities shown by these compounds highlights the promising therapeutic use of pteridine derivatives. Indeed, methotrexate, pralatrexate, and triamterene are Food and Drug Administration approved pteridines, while many others are currently under study in clinical trials.
Topics: Aminopterin; Animals; Anti-Infective Agents; Antidepressive Agents; Antihypertensive Agents; Antineoplastic Agents; Antiparasitic Agents; Clinical Trials as Topic; Humans; Inhibitory Concentration 50; Methotrexate; Pteridines; Triamterene
PubMed: 30341778
DOI: 10.1002/med.21529 -
Annual Review of Biochemistry 1967
Review
Topics: Animals; Biosynthetic Pathways; Coenzymes; Pigments, Biological; Pteridines
PubMed: 18257719
DOI: 10.1146/annurev.bi.36.070167.001131 -
Metabolomics : Official Journal of the... Dec 2021Pteridines include folate-derived metabolites that have been putatively associated with certain cancers in clinical studies. However, their biological significance in...
INTRODUCTION
Pteridines include folate-derived metabolites that have been putatively associated with certain cancers in clinical studies. However, their biological significance in cancer metabolism and role in cancer development and progression remains poorly understood.
OBJECTIVES
The purpose of this study was to examine the effects of tumorigenicity on pteridine metabolism by studying a panel of 15 pteridine derivatives using a progressive breast cancer cell line model with and without folic acid dosing.
METHODS
The MCF10A progressive breast cancer model, including sequentially derived MCF10A (benign), MCF10AT (premalignant), and MCF10CA1a (malignant) cell lines were dosed with 0, 100, and 250 mg/L folic acid. Pteridines were analyzed in both intracellular and extracellular contexts using an improved high-performance liquid chromatography-tandem mass spectrometry method.
RESULTS
Pteridines were located predominately in the extracellular media. Folic acid dosing increased extracellular levels of pterin, 6-hydroxylumazine, xanthopterin, 6-hydroxymethylpterin, and 6-carboxypterin in a dose-dependent manner. In particular, pterin and 6-hydroxylumazine levels were positively correlated with tumorigenicity upon folate dosing.
CONCLUSIONS
Folic acid is a primary driver for pteridine metabolism in human breast cell. Higher folate levels contribute to increased formation and excretion of pteridine derivatives to the extracellular media. In breast cancer, this metabolic pathway becomes dysregulated, resulting in the excretion of certain pteridine derivatives and providing in vitro evidence for the observation of elevated pteridines in the urine of breast cancer patients. Finally, this study reports a novel use of the MCF10A progressive breast cancer model for metabolomics applications that may readily be applied to other metabolites of interest.
Topics: Breast Neoplasms; Chromatography, High Pressure Liquid; Female; Humans; Metabolomics; Pteridines
PubMed: 34919200
DOI: 10.1007/s11306-021-01861-9 -
Metabolomics : Official Journal of the... Apr 2022Determining the biological significance of pteridines in cancer development and progression remains an important step in understanding the altered levels of urinary...
INTRODUCTION
Determining the biological significance of pteridines in cancer development and progression remains an important step in understanding the altered levels of urinary pteridines seen in certain cancers. Our companion study revealed that several folate-derived pteridines and lumazines correlated with tumorigenicity in an isogenic, progressive breast cancer cell model, providing direct evidence for the tumorigenic origin of pteridines.
OBJECTIVES
This study sought to elucidate the pteridine biosynthetic pathway in a progressive breast cancer model via direct pteridine dosing to determine how pteridine metabolism changes with tumorigenicity.
METHODS
First, MCF10AT breast cancer cells were dosed individually with 15 pteridines to determine which pteridines were being metabolized and what metabolic products were being produced. Second, pteridines that were significantly metabolized were dosed individually across the progressive breast cancer cell model (MCF10A, MCF10AT, and MCF10ACA1a) to determine the relationship between each metabolic reaction and breast cancer tumorigenicity.
RESULTS
Several pteridines were found to have altered metabolism in breast cancer cell lines, including pterin, isoxanthopterin, xanthopterin, sepiapterin, 6-biopterin, lumazine, and 7-hydroxylumazine (p < 0.05). In particular, isoxanthopterin and 6-biopterin concentrations were differentially expressed (p < 0.05) with respect to tumorigenicity following dosing with pterin and sepiapterin, respectively. Finally, the pteridine biosynthetic pathway in breast cancer cells was proposed based on these findings.
CONCLUSIONS
This study, along with its companion study, demonstrates that pteridine metabolism becomes disrupted in breast cancer tumor cells. This work highlights several key metabolic reactions within the pteridine biosynthetic pathway that may be targeted for further investigation and clinical applications.
Topics: Biopterins; Breast Neoplasms; Female; Humans; Metabolomics; Pteridines; Pterins
PubMed: 35482254
DOI: 10.1007/s11306-022-01885-9 -
Pigment Cell Research Jun 2003This review describes pteridine biosynthesis and its relation to the differentiation of neural crest derivatives in zebrafish. During the embryonic development of these... (Review)
Review
This review describes pteridine biosynthesis and its relation to the differentiation of neural crest derivatives in zebrafish. During the embryonic development of these fish, neural crest precursor cells segregate into neural elements, ectomesenchymal cells and pigment cells; the latter then diversifying into melanophores, iridophores and xanthophores. The differentiation of neural cells, melanophores, and xanthophores is coupled closely with the onset of pteridine synthesis which starts from GTP and is regulated through the control of GTP cyclohydrolase I activity. De novo pteridine synthesis in embryos of this species increases during the first 72-h postfertilization, producing H4biopterin, which serves as a cofactor for neurotransmitter synthesis in neural cells and for tyrosine production in melanophores. Thereafter, sepiapterin (6-lactoyl-7,8-dihydropterin) accumulates as yellow pigment in xanthophores, together with 7-oxobiopterin, isoxanthopterin and 2,4,7-trioxopteridine. Sepiapterin is the key intermediate in the formation of 7-oxopteridines, which depends on the availability of enzymes belonging to the xanthine oxidoreductase family. Expression of the GTP cyclohydrolase I gene (gch) is found in neural cells, in melanoblasts and in early xanthophores (xanthoblasts) of early zebrafish embryos but steeply declines in xanthophores by 42-h postfertilization. The mechanism(s) whereby sepiapterin branches off from the GTP-H4biopterin pathway is currently unknown and will require further study. The surge of interest in zebrafish as a model for vertebrate development and its amenability to genetic manipulation provide powerful tools for analysing the functional commitment of neural crest-derived cells and the regulation of pteridine synthesis in mammals.
Topics: Animals; Biopterins; Cell Lineage; GTP Cyclohydrolase; Gene Expression Regulation, Developmental; Guanosine Triphosphate; Melanophores; Models, Biological; Models, Chemical; Mutation; Neural Crest; Neurons; Phenotype; Pigments, Biological; Pteridines; Pterins; Signal Transduction; Time Factors; Tyrosine; Xanthine Dehydrogenase; Xanthine Oxidase; Xanthopterin; Zebrafish
PubMed: 12753383
DOI: 10.1034/j.1600-0749.2003.00044.x -
Current Drug Metabolism Apr 2002Pteridine derivatives which have a widespread occurrence in nature have been investigated upon their interactions with free radicals and free radical mediated reactions... (Review)
Review
Pteridine derivatives which have a widespread occurrence in nature have been investigated upon their interactions with free radicals and free radical mediated reactions utilizing a number of different experimental systems. Searching for biological functions, which are still unknown for the majority of pteridine compounds, the effect of pteridines in systems like luminol-induced chemiluminescence, enzyme activity, DNA photodamage, EPR experiments or radical induced injury--just to name a few--have been investigated. The general view during the initial phase of investigations on this special field was, that reduced pterins, i. e., tetra- as well as dihydropterins, generally act as radical scavengers, while aromatic pterins, if not inactive, exert radical promoting activity. Meanwhile the data available provide a more complex view: pteridines of all oxidation states have been shown to act anti- or prooxidatively, depending on the special conditions of the experiment. The reason is that reduced pterins, besides of being scavengers of free radicals, also are strongly reducing agents and therefore, in the presence of transition metal ions promote Fenton chemistry. Aromatic pterins have been described as inhibitors or substrates of enzymes involved--in vitro and in vivo--in free radical generation. Together with the unknown local concentrations of, e.g., neopterin and dihydroneopterin occurring in vivo, these reasons make it impossible to unequivocally predict a physiological net effect of pterins of different oxidation states concerning free radical mediated reactions in real biological systems.
Topics: Animals; Biopterins; Free Radical Scavengers; Humans; Oxidation-Reduction; Oxidative Stress; Pteridines; Pterins
PubMed: 12003351
DOI: 10.2174/1389200024605127 -
Molecular Neurobiology Feb 1999Tetrahydrobiopterin (BH4) is synthesized from guanosine triphosphate (GTP) by GTP cyclohydrolase I (GCH), 6-pyruvoyltetrahydropterin synthase (PTS), and sepiapterin... (Review)
Review
Tetrahydrobiopterin (BH4) is synthesized from guanosine triphosphate (GTP) by GTP cyclohydrolase I (GCH), 6-pyruvoyltetrahydropterin synthase (PTS), and sepiapterin reductase (SPD). GCH is the rate-limiting enzyme. BH4 is a cofactor for three pteridine-requiring monooxygenases that hydroxylate aromatic L-amino acids, i.e., tyrosine hydroxylase (TH), tryptophan hydroxylase (TPH), and phenylalanine hydroxylase (PAH), as well as for nitric oxide synthase (NOS). The intracellular concentrations of BH4, which are mainly determined by GCH activity, may regulate the activity of TH (an enzyme-synthesizing catecholamines from tyrosine), TPH (an enzyme-synthesizing serotonin and melatonin from tryptophan), PAH (an enzyme required for complete degradation of phenylalanine to tyrosine, finally to CO2 + H2O), and also the activity of NOS (an enzyme forming NO from arginine), Dominantly inherited hereditary progressive dystonia (HPD), also termed DOPA-responsive dystonia (DRD) or Segawa's disease, is a dopamine deficiency in the nigrostriatal dopamine neurons, and is caused by mutations of one allele of the GCH gene. GCH activity and BH4 concentrations in HPD/DRD are estimated to be 2-20% of the normal value. By contrast, recessively inherited GCH deficiency is caused by mutations of both alleles of the GCH gene, and the GCH activity and BH4 concentrations are undetectable. The phenotypes of recessive GCH deficiency are severe and complex, such as hyperphenylalaninemia, muscle hypotonia, epilepsy, and fever episode, and may be caused by deficiencies of various neurotransmitters, including dopamine, norepinephrine, serotonin, and NO. The biosynthesis of dopamine, norepinephrine, epinephrine, serotonin, melatonin, and probably NO by individual pteridine-requiring enzymes may be differentially regulated by the intracellular concentration of BH4, which is mainly determined by GCH activity. Dopamine biosynthesis in different groups of dopamine neurons may be differentially regulated by TH activity, depending on intracellular BH4 concentrations and GCH activity. The nigrostriatal dopamine neurons may be most susceptible to a partial decrease in BH4, causing dopamine deficiency in the striatum and the HPD/DRD phenotype.
Topics: Amino Acid Sequence; Animals; Biopterins; Coenzymes; Enzyme Activation; Enzymes; Humans; Metabolism, Inborn Errors; Molecular Sequence Data; Pteridines
PubMed: 10321973
DOI: 10.1007/BF02741379 -
Pathobiology : Journal of... 1991We investigated intracellular pteridine concentrations, activities of pteridine biosynthetic enzymes and formation of nitrogen oxides from arginine in human... (Review)
Review
We investigated intracellular pteridine concentrations, activities of pteridine biosynthetic enzymes and formation of nitrogen oxides from arginine in human peripheral-blood-derived macrophages and in myelomonocytoma (THP-1) cells, as well as in murine peritoneal and spleen-derived macrophages and in murine macrophage lines (P388-D1, J774-A.1). Interferon-gamma (IFN-gamma) induces the activity of GTP-cyclohydrolase I up to 40-fold in human cells. In human macrophages and THP-1 cells, this induced activity is higher than the constitutively present activity of the subsequent enzyme, the 6-pyruvoyltetrahydropterin synthase. As a consequence, large amounts of neopterin are formed during IFN-gamma-triggered synthesis of tetrahydrobiopterin. Murine macrophages constitutively synthesize tetrahydrobiopterin. The activity of GTP-cyclohydrolase I remains unchanged by treatment with IFN-gamma or tumor necrosis factor-alpha. This activity is lower than the subsequent 6-pyruvoyltetrahydropterin synthase activity, thus explaining the lack of neopterin in murine cells, tissues and body fluids. Inhibition and reconstitution of pteridine synthesis in activated murine macrophages by specific drugs demonstrate that tetrahydrobiopterin regulates the amount of nitrogen oxides formed from arginine in intact cells, thus providing a rationale for therapeutic intervention.
Topics: Alcohol Oxidoreductases; Animals; Cells, Cultured; GTP Cyclohydrolase; Humans; Macrophages; Nitric Oxide; Phosphorus-Oxygen Lyases; Pteridines
PubMed: 1883524
DOI: 10.1159/000163662 -
Journal of Medicinal Chemistry Feb 2022Bruton's tyrosine kinase (BTK) is an attractive therapeutic target in the treatment of cancer, inflammation, and autoimmune diseases. Covalent and noncovalent BTK...
Bruton's tyrosine kinase (BTK) is an attractive therapeutic target in the treatment of cancer, inflammation, and autoimmune diseases. Covalent and noncovalent BTK inhibitors have been developed, among which covalent BTK inhibitors have shown great clinical efficacy. However, some of them could produce adverse effects, such as diarrhea, rash, and platelet dysfunction, which are associated with the off-target inhibition of ITK and EGFR. In this study, we disclosed a series of pteridine-7(8)-one derivatives as potent and selective covalent BTK inhibitors, which were optimized from , an EGFR inhibitor previously reported by our group. Among them, compound exhibited great BTK inhibition activity (IC = 4.0 nM) and high selectivity in both enzymatic (ITK >250-fold, EGFR >2500-fold) and cellular levels (ITK >227-fold, EGFR 27-fold). In U-937 xenograft models, significantly inhibited tumor growth (TGI = 57.85%) at a 50 mg/kg dosage. Accordingly, is a new BTK inhibitor worthy of further development.
Topics: Agammaglobulinaemia Tyrosine Kinase; Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; G1 Phase Cell Cycle Checkpoints; Humans; Male; Mice, Inbred BALB C; Mice, Nude; Molecular Docking Simulation; Molecular Structure; Neoplasms; Protein Binding; Protein Kinase Inhibitors; Pteridines; Rats, Sprague-Dawley; Structure-Activity Relationship; Xenograft Model Antitumor Assays; Mice; Rats
PubMed: 35099969
DOI: 10.1021/acs.jmedchem.1c02208 -
Cell Biochemistry and Biophysics 2001Pteridine nucleoside analog probes are highly fluorescent and offer different approaches to monitor subtle DNA interactions with other molecules. Similarities in... (Review)
Review
Pteridine nucleoside analog probes are highly fluorescent and offer different approaches to monitor subtle DNA interactions with other molecules. Similarities in structure and size to native nucleosides make it possible to incorporate these probes into oligonucleotides through the standard deoxyribose linkage. These probes are formulated as phosphoramidites and incorporated into oligonucleotides using automated DNA synthesis. Their position within the oligonucleotide renders them exquisitely sensitive to changes in structure as the oligonucleotide meets and reacts with other molecules. Changes are measured through fluorescence intensity, anisotropy, lifetimes, spectral shifts, and energy transfer. The fluorescence properties of pteridine nucleoside analogs as monomers and incorporated into single and double stranded oligonucleotides are reviewed. The two guanosine analogs, 3MI and 6MI, and two adenosine analogs, 6MAP and DMAP, are reviewed in detail along with applications utilizing them.
Topics: Adenine; Anisotropy; DNA; Fluorescent Dyes; Guanosine; Models, Chemical; Oligonucleotides; Pteridines; Spectrometry, Fluorescence; Temperature; Time Factors
PubMed: 11898867
DOI: 10.1385/CBB:34:2:257