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Molecules (Basel, Switzerland) Nov 2023The parasites () and () cause the tropical diseases sleeping sickness, nagana, and cutaneous leishmaniasis. Every year, millions of humans, as well as animals, living...
The parasites () and () cause the tropical diseases sleeping sickness, nagana, and cutaneous leishmaniasis. Every year, millions of humans, as well as animals, living in tropical to subtropical climates fall victim to these illnesses' health threats. The parasites' frequent drug resistance and widely spread natural reservoirs heavily impede disease prevention and treatment. Due to pteridine auxotrophy, trypanosomatid parasites have developed a peculiar enzyme system consisting of dihydrofolate reductase-thymidylate synthase (DHFR-TS) and pteridine reductase 1 (PTR1) to support cell survival. Extending our previous studies, we conducted a comparative study of the . (DHFR, PTR1) and . (DHFR, PTR1) enzymes to identify lead structures with a dual inhibitory effect. A pharmacophore-based in silico screening of three natural product databases (approximately 4880 compounds) was performed to preselect possible inhibitors. Building on the in silico results, the inhibitory potential of promising compounds was verified in vitro against the recombinant DHFR and PTR1 of both parasites using spectrophotometric enzyme assays. Twelve compounds were identified as dual inhibitors against the enzymes (0.2 μM < IC < 85.1 μM) and ten against the respective enzymes (0.6 μM < IC < 84.5 μM). These highly promising results may represent the starting point for the future development of new leads and drugs utilizing the trypanosomatid pteridine metabolism as a target.
Topics: Humans; Animals; Tetrahydrofolate Dehydrogenase; Leishmania major; Trypanosoma brucei brucei; Pteridines; Trypanosomiasis, African
PubMed: 38005256
DOI: 10.3390/molecules28227526 -
International Journal of Molecular... Jul 2022Ligand modification by substituting chemical groups within the binding pocket is a popular strategy for kinase drug development. In this study, a series of...
Ligand modification by substituting chemical groups within the binding pocket is a popular strategy for kinase drug development. In this study, a series of pteridin-7(8)-one derivatives targeting wild-type FMS-like tyrosine kinase-3 (FLT3) and its D835Y mutant (FL3) were studied using a combination of molecular modeling techniques, such as docking, molecular dynamics (MD), binding energy calculation, and three-dimensional quantitative structure-activity relationship (3D-QSAR) studies. We determined the protein-ligand binding affinity by employing molecular mechanics Poisson-Boltzmann/generalized Born surface area (MM-PB/GBSA), fast pulling ligand (FPL) simulation, linear interaction energy (LIE), umbrella sampling (US), and free energy perturbation (FEP) scoring functions. The structure-activity relationship (SAR) study was conducted using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA), and the results were emphasized as a SAR scheme. In both the CoMFA and CoMSIA models, satisfactory correlation statistics were obtained between the observed and predicted inhibitory activity. The MD and SAR models were co-utilized to design several new compounds, and their inhibitory activities were anticipated using the CoMSIA model. The designed compounds with higher predicted pIC values than the most active compound were carried out for binding free energy evaluation to wild-type and mutant receptors using MM-PB/GBSA, LIE, and FEP methods.
Topics: Binding Sites; Ligands; Molecular Docking Simulation; Molecular Dynamics Simulation; Protein Binding; Pteridines; Quantitative Structure-Activity Relationship; fms-Like Tyrosine Kinase 3
PubMed: 35887060
DOI: 10.3390/ijms23147696 -
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 -
Leukemia Jan 2015Owing to their integral involvement in cell cycle regulation, the Polo-like kinase (Plk) family, particularly Plk1, has emerged as an attractive therapeutic target in... (Review)
Review
Owing to their integral involvement in cell cycle regulation, the Polo-like kinase (Plk) family, particularly Plk1, has emerged as an attractive therapeutic target in oncology. In recent years, several Plk1 inhibitors have been developed, with some agents showing encouraging results in early-phase clinical trials. This review focuses on volasertib (BI 6727; an investigational agent), a potent and selective Plk inhibitor. Volasertib has shown promising activity in various cancer cell lines and xenograft models of human cancer. Trials performed to date suggest that volasertib has clinical efficacy in a range of malignancies, with the most promising results seen in patients with acute myeloid leukemia (AML). Encouragingly, recent phase II data have demonstrated that volasertib combined with low-dose cytarabine (LDAC) was associated with higher response rates and improved event-free survival than LDAC alone in patients with previously untreated AML. Based on these observations, and its presumably manageable safety profile, volasertib is currently in phase III development as a potential treatment for patients with AML who are ineligible for intensive remission induction therapy. Given that many patients with AML are of an older age and frail, this constitutes an area of major unmet need. In this review, we discuss the biologic rationale for Plk1 inhibitors in cancer, the clinical development of volasertib to date in solid tumors and AML, and the future identification of biomarkers that might predict response to volasertib and help determine the role of this agent in the clinic.
Topics: Humans; Neoplasms; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Pteridines
PubMed: 25027517
DOI: 10.1038/leu.2014.222 -
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 -
Postgraduate Medical Journal Feb 1986Patients with phenylalanine hydroxylase deficiency show increased concentrations of biopterins and neopterins, and reduced concentrations of serotonin and... (Review)
Review
Patients with phenylalanine hydroxylase deficiency show increased concentrations of biopterins and neopterins, and reduced concentrations of serotonin and catecholamines, when phenylalanine concentrations are raised. The pterin rise reflects increased synthesis of dihydroneopterin and tetrahydrobiopterin, and the amine fall a reduction in amine synthesis due to inhibition by phenylalanine of tyrosine and tryptophan transport into neurones. The pterin and amine changes appear to be independent of each other and are present in the central nervous system as well as the periphery; they disappear when phenylalanine concentrations are reduced to normal. Patients with arginase deficiency show a similar amine disturbance but have normal pterin levels. The amine changes probably contribute neurological symptoms but pterin disturbance is not known to affect brain function. Patients with defective biopterin metabolism exhibit severely impaired amine synthesis due to tetrahydrobiopterin deficiency. Pterin concentrations vary with the site of the defect. Symptoms include profound hypokinesis and other features of basal ganglia disease. Neither symptoms nor amine changes are relieved by controlling phenylalanine concentrations. Patients with dihydropteridine reductase (DHPR) deficiency accumulate dihydrobiopterins and develop secondary folate deficiency which resembles that occurring in patients with defective 5,10-methylene tetrahydrofolate reductase activity. The latter disorder is also associated with Parkinsonism and defective amine and pterin turnover in the central nervous system, and a demyelinating illness occurs in both disorders. In DHPR deficiency cerebral calcification may develop in a similar distribution to that seen in congenital folate malabsorption and methotrexate toxicity. Symptoms are ameliorated by therapy with 5-formyltetrahydrofolate but exacerbated by folic acid.
Topics: Amines; Biopterins; Folic Acid; Humans; Nervous System; Phenylalanine; Phenylalanine Hydroxylase; Phenylketonurias; Pteridines
PubMed: 3540926
DOI: 10.1136/pgmj.62.724.113 -
Parasite (Paris, France) 2014The life-threatening diseases alveolar and cystic echinococcoses are caused by larvae of the tapeworms Echinococcus multilocularis and E. granulosus, respectively. In... (Review)
Review
The life-threatening diseases alveolar and cystic echinococcoses are caused by larvae of the tapeworms Echinococcus multilocularis and E. granulosus, respectively. In both cases, intermediate hosts, such as humans, are infected by oral uptake of oncosphere larvae, followed by asexual multiplication and almost unrestricted growth of the metacestode within host organs. Besides surgery, echinococcosis treatment relies on benzimidazole-based chemotherapy, directed against parasite beta-tubulin. However, since beta-tubulins are highly similar between cestodes and humans, benzimidazoles can only be applied at parasitostatic doses and are associated with adverse side effects. Mostly aiming at identifying alternative drug targets, the nuclear genome sequences of E. multilocularis and E. granulosus have recently been characterized, revealing a large number of druggable targets that are expressed by the metacestode. Furthermore, recent cell biological investigations have demonstrated that E. multilocularis employs pluripotent stem cells, called germinative cells, which are the only parasite cells capable of proliferation and which give rise to all differentiated cells. Hence, the germinative cells are the crucial cell type mediating proliferation of E. multilocularis, and most likely also E. granulosus, within host organs and should also be responsible for parasite recurrence upon discontinuation of chemotherapy. Interestingly, recent investigations have also indicated that germinative cells might be less sensitive to chemotherapy because they express a beta-tubulin isoform with limited affinity to benzimidazoles. In this article, we briefly review the recent findings concerning Echinococcus genomics and stem cell research and propose that future research into anti-echinococcosis drugs should also focus on the parasite's stem cell population.
Topics: Animals; Anthelmintics; Benzimidazoles; Cell Division; Drug Design; Drug Evaluation, Preclinical; Echinococcosis; Echinococcus; Echinococcus multilocularis; Genomics; Helminth Proteins; Hydroxyurea; Larva; Molecular Targeted Therapy; Parasitology; Pluripotent Stem Cells; Pteridines; Transcriptome; Tubulin
PubMed: 25526547
DOI: 10.1051/parasite/2014070 -
Biochimica Et Biophysica Acta Jun 2015X-ray absorption (XAS) and X-ray emission spectroscopy (XES) provide element specific probes of the geometric and electronic structures of metalloprotein active sites.... (Review)
Review
X-ray absorption (XAS) and X-ray emission spectroscopy (XES) provide element specific probes of the geometric and electronic structures of metalloprotein active sites. As such, these methods have played an integral role in nitrogenase research beginning with the first EXAFS studies on nitrogenase in the late 1970s. Herein, we briefly explain the information that can be extracted from XAS and XES. We then highlight the recent applications of these methods in nitrogenase research. The influence of X-ray spectroscopy on our current understanding of the atomic structure and electronic structure of iron molybdenum cofactor (FeMoco) is emphasized. Contributions of X-ray spectroscopy to understanding substrate interactions and cluster biosynthesis are also discussed. This article is part of a Special Issue entitled: Fe/S proteins: Analysis, structure, function, biogenesis and diseases.
Topics: Coenzymes; Iron; Metalloproteins; Models, Molecular; Molecular Structure; Molybdenum Cofactors; Nitrogenase; Protein Conformation; Pteridines; Spectrometry, X-Ray Emission; X-Ray Absorption Spectroscopy
PubMed: 25486459
DOI: 10.1016/j.bbamcr.2014.11.027 -
Marine Drugs Feb 2021Two new fluorescent pteridine alkaloids, tedaniophorbasins A () and B (), together with the known alkaloid -methyltryptamine, were isolated, through application of mass...
Two new fluorescent pteridine alkaloids, tedaniophorbasins A () and B (), together with the known alkaloid -methyltryptamine, were isolated, through application of mass directed purification, from the sponge collected from northern New South Wales, Australia. The structures of tedaniophorbasins A and B were deduced from the analysis of 1D/2D NMR and MS data and through application of C NMR DFT calculations. Tedaniophorbasin A possesses a novel 2-imino-1,3-dimethyl-2,3,7,8-tetrahydro-1H-[1,4]thiazino[3,2-g]pteridin-4(6)-one skeleton, while tedaniophorbasin B is its 2-oxo derivative. The compounds show significant Stokes shifts (~14,000 cm) between excitation and emission wavelengths in their fluorescence spectra. The new compounds were tested for bioactivity against chloroquine-sensitive and chloroquine-resistant strains of the malaria parasite , breast and pancreatic cancer cell lines, and the protozoan parasite but were inactive against all targets at 40 µM.
Topics: Alkaloids; Animals; Antineoplastic Agents; Cell Line, Tumor; Humans; Magnetic Resonance Spectroscopy; Plasmodium falciparum; Porifera; Pteridines; Trypanosoma brucei brucei
PubMed: 33562248
DOI: 10.3390/md19020095 -
Marine Drugs Feb 2021Chemical investigation of secondary metabolites from the marine-derived fungus Y32-2 resulted in the isolation of two new prenylated indole alkaloid homodimers,...
Chemical investigation of secondary metabolites from the marine-derived fungus Y32-2 resulted in the isolation of two new prenylated indole alkaloid homodimers, di-6-hydroxydeoxybrevianamide E () and dinotoamide J (), one new pteridine alkaloid asperpteridinate A (), with eleven known compounds (-). Their structures were elucidated by various spectroscopic methods including HRESIMS and NMR, while their absolute configurations were determined by ECD calculations. Each compound was evaluated for pro-angiogenic, anti-inflammatory effects in zebrafish models and cytotoxicity for HepG2 human liver carcinoma cells. As a result, compounds , , , , exhibited pro-angiogenic activity in a PTK787-induced vascular injury zebrafish model in a dose-dependent manner, compounds , , , displayed anti-inflammatory activity in a CuSO-induced zebrafish inflammation model, and compound showed significant cytotoxicity against HepG2 cells with an IC value of 30 µg/mL.
Topics: Angiogenesis Inducing Agents; Animals; Anti-Inflammatory Agents; Aspergillus; Hep G2 Cells; Humans; Indole Alkaloids; Magnetic Resonance Spectroscopy; Pteridines; Water Microbiology; Zebrafish
PubMed: 33572212
DOI: 10.3390/md19020098