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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 -
Biochimica Et Biophysica Acta Jun 2015The biosynthesis of the molybdenum cofactor (Moco) has been intensively studied, in addition to its insertion into molybdoenzymes. In particular, a link between the... (Review)
Review
The biosynthesis of the molybdenum cofactor (Moco) has been intensively studied, in addition to its insertion into molybdoenzymes. In particular, a link between the assembly of molybdoenzymes and the biosynthesis of FeS clusters has been identified in the recent years: 1) the synthesis of the first intermediate in Moco biosynthesis requires an FeS-cluster containing protein, 2) the sulfurtransferase for the dithiolene group in Moco is also involved in the synthesis of FeS clusters, thiamin and thiolated tRNAs, 3) the addition of a sulfido-ligand to the molybdenum atom in the active site additionally involves a sulfurtransferase, and 4) most molybdoenzymes in bacteria require FeS clusters as redox active cofactors. In this review we will focus on the biosynthesis of the molybdenum cofactor in bacteria, its modification and insertion into molybdoenzymes, with an emphasis to its link to FeS cluster biosynthesis and sulfur transfer.
Topics: Bacteria; Bacterial Proteins; Coenzymes; Iron-Sulfur Proteins; Metalloproteins; Models, Biological; Models, Chemical; Molecular Structure; Molybdenum; Molybdenum Cofactors; Oxidoreductases; Pteridines
PubMed: 25268953
DOI: 10.1016/j.bbamcr.2014.09.021 -
Biomedical Chromatography : BMC Apr 2022Bioanalysis of an endogenous compound such as leucovorin is never an easy task on a liquid chromatography tandem mass spectrometer (LC-MSMS). Unless it is necessary,...
Sensitive and rapid simultaneous quantitation of leucovorin and its major active metabolite 5-methyl-tetrahydrofolate in human plasma using a liquid chromatography coupled with triple quadruple mass spectrometry.
Bioanalysis of an endogenous compound such as leucovorin is never an easy task on a liquid chromatography tandem mass spectrometer (LC-MSMS). Unless it is necessary, regulatory guidance discourages working with surrogate matrices for calibration curve standard preparation. Herein, a selective and sensitive liquid chromatography-tandem mass spectrometry method for simultaneous determination of leucovorin and 5-methyl tetrahydrofolic acid in human plasma was developed and validated. Stable labeled internal standards, i.e. leucovorin D and 5- methyl tetrahydrofolic acid C , were used as internal standards to track and compensate the parent compounds during processing and extraction from plasma. The method involves a rapid solid-phase extraction from plasma followed by reverse-phase gradient chromatography and mass spectrometry detection with a total run time of 5 min. The method was developed and validated from 5 to 2,202 ng/ml for leucovorin and from 5 to 1,300 ng/ml for 5-methyl tetrahydrofolic acid. The mean recoveries for leucovorin and 5-methyl tetrahydrofolic acid were 100.4 and 100.9% respectively. The validated method enabled the simultaneous analysis of leucovorin and 5-methyl tetrahydrofolic acid in samples from clinical pharmacokinetic studies of leucovorin. The peak concentrations of leucovorin and 5-methyl tetrahydrofolic acid were 651-883 and 518-635 ng/ml, respectively, in fasted and fed conditions. The terminal half-life values for leucovorin and 5-methyl tetrahydrofolic acid were 9.3-10.5 and 9.2-17.6 h, respectively.
Topics: Chromatography, Liquid; Humans; Leucovorin; Reproducibility of Results; Tandem Mass Spectrometry; Tetrahydrofolates
PubMed: 34913177
DOI: 10.1002/bmc.5299 -
Environmental Science & Technology Sep 2020Flavin-mediated electron transfer is an important pathway for Fe(III) reduction by dissimilatory iron-reducing bacteria. Although the mechanisms and kinetics of Fe(III)...
Flavin-mediated electron transfer is an important pathway for Fe(III) reduction by dissimilatory iron-reducing bacteria. Although the mechanisms and kinetics of Fe(III) reduction by reduced flavins have been widely studied, the reaction between Fe(II) and oxidized flavins is rarely investigated. Results of this study show that under anoxic conditions, Fe(II) can be oxidized by the oxidized forms of riboflavin (RBF) and flavin mononucleotide (FMN) at pH 7-9. For instance, at pH 9, 73% of 17.8 μM Fe(II) was oxidized by 10 μM RBF within 20 min. Both the rate and extent of oxidation increased with increasing concentrations of oxidized flavins and increasing solution pH. Thermodynamic calculations and kinetic analyses implied that the oxidation of Fe(II) proceeded predominantly via the autodecomposition of Fe-RBF and Fe-FMN complexes, along with minor contributions from direct oxidation of Fe(II) by flavins and flavin radicals. Our findings suggest that the reoxidation of Fe(II) by oxidized flavins may be a rate-controlling factor in microbial Fe(III) reduction via flavin-mediated electron transfer.
Topics: Electron Transport; Ferric Compounds; Ferrous Compounds; Flavin Mononucleotide; Flavins; Oxidation-Reduction; Riboflavin
PubMed: 32812763
DOI: 10.1021/acs.est.0c02916 -
Protein Science : a Publication of the... Sep 2023Within the cell, the trace element molybdenum (Mo) is only biologically active when complexed either within the nitrogenase-specific FeMo cofactor or within the...
Within the cell, the trace element molybdenum (Mo) is only biologically active when complexed either within the nitrogenase-specific FeMo cofactor or within the molybdenum cofactor (Moco). Moco consists of an organic part, called molybdopterin (MPT) and an inorganic part, that is, the Mo-center. The enzyme which catalyzes the Mo-center formation is the molybdenum insertase (Mo-insertase). Mo-insertases consist of two functional domains called G- and E-domain. The G-domain catalyzes the formation of adenylated MPT (MPT-AMP), which is the substrate for the E-domain, that catalyzes the actual molybdate insertion reaction. Though the functions of E- and G-domain have been elucidated to great structural and mechanistic detail, their combined function is poorly characterized. In this work, we describe a structural model of the eukaryotic Mo-insertase Cnx1 complex that was generated based on cross-linking mass spectrometry combined with computational modeling. We revealed Cnx1 to form an asymmetric hexameric complex which allows the E- and G-domain active sites to align in a catalytic productive orientation toward each other.
Topics: Arabidopsis Proteins; Calnexin; Arabidopsis; Molybdenum; Coenzymes; Metalloproteins; Pteridines
PubMed: 37572332
DOI: 10.1002/pro.4753 -
The New Phytologist Feb 2017Molybdenum (Mo) and iron (Fe) are essential micronutrients required for crucial enzyme activities in plant metabolism. Here we investigated the existence of a mutual...
Molybdenum (Mo) and iron (Fe) are essential micronutrients required for crucial enzyme activities in plant metabolism. Here we investigated the existence of a mutual control of Mo and Fe homeostasis in cucumber (Cucumis sativus). Plants were grown under single or combined Mo and Fe starvation. Physiological parameters were measured, the ionomes of tissues and the ionomes and proteomes of root mitochondria were profiled, and the activities of molybdo-enzymes and the synthesis of molybdenum cofactor (Moco) were evaluated. Fe and Mo were found to affect each other's total uptake and distribution within tissues and at the mitochondrial level, with Fe nutritional status dominating over Mo homeostasis and affecting Mo availability for molybdo-enzymes in the form of Moco. Fe starvation triggered Moco biosynthesis and affected the molybdo-enzymes, with its main impact on nitrate reductase and xanthine dehydrogenase, both being involved in nitrogen assimilation and mobilization, and on the mitochondrial amidoxime reducing component. These results, together with the identification of > 100 proteins differentially expressed in root mitochondria, highlight the central role of mitochondria in the coordination of Fe and Mo homeostasis and allow us to propose the first model of the molecular interactions connecting Mo and Fe homeostasis.
Topics: Cluster Analysis; Coenzymes; Cucumis sativus; Formate Dehydrogenases; Homeostasis; Iron; Metabolome; Metalloproteins; Mitochondria; Mitochondrial Proteins; Models, Biological; Molybdenum; Molybdenum Cofactors; Oxidoreductases; Plant Leaves; Plant Roots; Proteome; Pteridines
PubMed: 27735062
DOI: 10.1111/nph.14214 -
Comparative Biochemistry and... 20236-pyruvoyl-tetrahydropterin synthase (PTPS) is the second key enzyme of the pteridine biosynthetic pathway and it plays vital roles in fish body color formation. In this...
6-pyruvoyl-tetrahydropterin synthase (PTPS) is the second key enzyme of the pteridine biosynthetic pathway and it plays vital roles in fish body color formation. In this study, Ccptps of koi carp (Cyprinus carpio L.) was cloned, identified and characterized. The full-length cDNA of Ccptps was 1140 bp and encodes for 139 amino acids. Multiple alignments revealed that the amino acids sequence of CcPTPS shared the highest identity to that of C. carpio, and Ccptps was clustered with cyprinid fishes in phylogenetic tree. Liver tissues of koi carp exhibited the highest expression of Ccptps, followed by muscle and skin tissues. During early developmental stages, the expression of Ccptps declined from 2 dph to 4 dph, and increased from 4 dph to 12 dph. The expressions of Ccptps in three color-related tissues (skin, scale and caudal fin) of whole red (WR) koi carp were significantly higher than that of whole while (WW) koi carp. Immunohistochemistry results of skin tissues showed that CcPTPS was mainly located in epidermis, stratum compactum of dermis and muscle layer, with the signal intensities in stratum compactum and muscle layer were stronger in WR koi carp compared to WW koi carp. Co-expressions of CcPTPS, CcSPR and CcXDH were detected in skin tissues of WW and WR koi carps, with CcPTPS exhibited stronger signal intensity compared to CcSPR and CcXDH. These findings imply that Ccptps is potentially involved in koi carp body color formation through the pteridine synthesis pathway.
Topics: Animals; Carps; Phylogeny; DNA, Complementary; Amino Acids; Pteridines; Fish Diseases
PubMed: 36400267
DOI: 10.1016/j.cbpb.2022.110814 -
Journal of Drug Targeting Apr 2023Rheumatoid arthritis (RA) is a common autoimmune and inflammatory disease. Activated macrophages in arthritic joints play a prominent role in the initiation and...
Rheumatoid arthritis (RA) is a common autoimmune and inflammatory disease. Activated macrophages in arthritic joints play a prominent role in the initiation and persistence of RA. Despite great progress in the clinical treatment of RA, poor response and high discontinuation due to systemic toxicity remain unsolved issues, especially the well-known methotrexate (MTX). Therefore, active targeted delivery of therapeutic drugs to pathogenic cells in arthritic joints is essential to increase activity and decrease systemic toxicity. Here, we developed an MTX-loaded macrophage-targeted nano-emulsion (NE) based on the overexpression of folate receptor (FR) on activated macrophages, the inherent high affinity of FR for folate (FA), as well as the property of MTX and phospholipids to form complexes (MTX@PC). Intravenous injection of DID-labelled MTX@PC-FA NEs into adjuvant-induced arthritis (AIA) mice, images and flow cytometry results revealed that the NEs were highly targeted to inflamed joints and macrophages, respectively. Therapeutic studies suggested that this strategy was conducive to achieve high efficacy and low toxicity of MTX in the treatment of RA. Our research highlights MTX@PC-FA NEs as a potential treatment option for RA targeting the FR-expressed activated macrophages.
Topics: Mice; Animals; Methotrexate; Phospholipids; Arthritis, Rheumatoid; Folic Acid; Macrophages; Antirheumatic Agents
PubMed: 36724823
DOI: 10.1080/1061186X.2023.2175832 -
Ecology Letters Oct 2021Carotenoids are important pigments producing integument colouration; however, their dietary availability may be limited in some environments. Many species produce yellow...
Carotenoids are important pigments producing integument colouration; however, their dietary availability may be limited in some environments. Many species produce yellow to red hues using a combination of carotenoids and self-synthesised pteridine pigments. A compelling hypothesis is that pteridines replace carotenoids in environments where carotenoid availability is limited. To test this hypothesis, we quantified concentrations of five carotenoid and six pteridine pigments in multiple skin colours and individuals from 27 species of agamid lizards. We show that environmental gradients predict the ratio of carotenoids to pteridines; carotenoid concentrations are lower and pteridine concentrations higher in arid environments with low vegetation productivity. Both carotenoid and pteridine pigments were present in all species, but only pteridine concentrations explained colour variation among species and there were no correlations between carotenoid and pteridine pigments with a similar hue. These results suggest that in arid environments, where carotenoids are likely limited, species may compensate by synthesising more pteridines but do not necessarily replace carotenoids with pteridines of similar hue.
Topics: Animals; Carotenoids; Humans; Lizards; Pigmentation; Pteridines; Skin Pigmentation
PubMed: 34350679
DOI: 10.1111/ele.13850 -
Molecules (Basel, Switzerland) Sep 2022Antimetabolites of folic acid represent a large group of drugs and drug candidates, including those for cancer chemotherapy. In this current review, the most common... (Review)
Review
Antimetabolites of folic acid represent a large group of drugs and drug candidates, including those for cancer chemotherapy. In this current review, the most common methods and approaches are presented for the synthesis of therapeutically significant antimetabolites of folic acid, which are Methotrexate (MTX), Raltitrexed (Tomudex, ZD1694), Pralatrexate, Pemetrexed, TNP-351, and Lometrexol. In addition, the applications or uses of these folic acid antimetabolites are also discussed.
Topics: Antimetabolites; Folic Acid; Folic Acid Antagonists; Methotrexate; Pemetrexed; Quinazolines; Thiophenes
PubMed: 36234766
DOI: 10.3390/molecules27196229