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Archiv Der Pharmazie Dec 2022The present article is devoted to searching for biologically active agents among novel thio-containing pteridines. Synthetic protocols based on the condensation of...
The present article is devoted to searching for biologically active agents among novel thio-containing pteridines. Synthetic protocols based on the condensation of 5,6-diamino-2-thioxo-2,3-dihydropyrimidin-4(1H)-ones with dicarbonyl compounds were elaborated and used for the synthesis of target products. The directions for further modification of the obtained thio-containing pteridines were substantiated and realized. The spectral properties of the obtained compounds were studied and described. The results of the in silico study revealed that the predicted affinity of the obtained compounds to the dihydrofolate reductase (DHFR) active site is comparable with the affinity of methotrexate, despite the differences in the nature of the ligand-enzyme interactions. The in vitro study of DHFR-inhibiting activity revealed that the most active compounds 3.9 and 4.2 have lg IC values of -5.889 and -5.233, respectively, significantly inferior to methotrexate (lg IC = -7.605). Additionally, the synthesized compounds were studied for their antiradical activity as a possible mechanism of pharmacological effects. Among the obtained pteridines, compounds 5.1 (lg EC = -4.82) and 5.3 (lg EC = -4.92) have antiradical activity higher than the reference compound ascorbic acid (lg EC = -4.81). The conducted structure-activity relationship analysis provided valuable data for the further search for biologically active agents among thio-containing pteridines and related compounds.
Topics: Pteridines; Folic Acid Antagonists; Methotrexate; Structure-Activity Relationship; Tetrahydrofolate Dehydrogenase
PubMed: 36166689
DOI: 10.1002/ardp.202200252 -
Bioorganic & Medicinal Chemistry Letters Nov 2022Cyclin-dependent kinases play an important role in the regulation of cell cycle and transcription. Selective CDK4/6 inhibitors have been demonstrated to be effective in...
Cyclin-dependent kinases play an important role in the regulation of cell cycle and transcription. Selective CDK4/6 inhibitors have been demonstrated to be effective in the treatment of cancer. In this article, we described the design and synthesis of a series of pteridine-7(8H)-one derivatives as dual CDK4/6 inhibitors. Among them, the most promising compound L2 exhibited significant inhibitory activity against CDK4 and CDK6 with IC values of 16.7 nM and 30.5 nM respectively and showed excellent selectivity to CDK1/2/7/9. Moreover, compound L2 displayed potent antiproliferative activities at low digital micromolar range via inducing apoptosis in breast and colon cancer cells. In all, we developed a new series of pteridine-7(8H)-one derivatives which exhibited promising antitumor activities as selective CDK4/6 inhibitors.
Topics: Pteridines; Cyclin-Dependent Kinase 4; Cell Proliferation; Cell Cycle; Apoptosis; Protein Kinase Inhibitors; Antineoplastic Agents; Cell Line, Tumor; Structure-Activity Relationship
PubMed: 36130661
DOI: 10.1016/j.bmcl.2022.128991 -
Medicinal Chemistry (Shariqah (United... 2022Pteridine-based scaffolds have been widely prevalent in pharmaceuticals, such as kinase inhibitors targeting EGFR, FLT3 and PI3K/mTOR which are attractive targets for...
BACKGROUND
Pteridine-based scaffolds have been widely prevalent in pharmaceuticals, such as kinase inhibitors targeting EGFR, FLT3 and PI3K/mTOR which are attractive targets for the anticancer therapy.
OBJECTIVE
This work aimed at designing and synthesizing 6-2,2,2-trifluoroethoxy functionalized pteridine-based derivatives for investigation of their anti-cancer activities as EGFR inhibitor.
METHODS
Pteridine-based derivatives were synthesized in 6 steps involving amination, bromination, cyclization, alkoxylation, chlorination and coupling reactions. Cellular anti-proliferative activities and inhibition activities on EGFR signaling of these pteridine derivatives in vitro were determined by the MTT assay and western blot analysis, respectively. Molecular docking simulation studies were carried out by the crystallographic structure of the erlotinib/EGFR kinase domain [Protein Data Bank (PDB) code: 1M17].
RESULTS
The compound 7m, with IC50 values of 27.40 μM on A549 cell line, exhibited comparable anti-proliferative activity relative to the positive control. Besides, western blots showed its obvious down-regulation of p-EGFR and p-ERK expression at 0.8 μM. The molecular docking model displayed a hydrogen bond between Met-769 amide nitrogen and N-1 in pteridine motif of 7m which lied at the ATP binding site of EGFR kinase domain.
CONCLUSION
The inhibition of 7m on cellular growth was comparable to that of the positive control. The inhibitory activities of 7m on EGFR phosphorylation and ERK phosphorylation in A549 cell line were relatively superior to that of the positive control. Both results suggested that the antiproliferative activity of 7m against A549 cell line was caused by inhibition of EGFR signaling pathway, providing a new perspective for the modification of pteridine-based derivatives as EGFR inhibitor.
Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Drug Screening Assays, Antitumor; ErbB Receptors; Molecular Docking Simulation; Molecular Structure; Protein Kinase Inhibitors; Pteridines; Structure-Activity Relationship
PubMed: 34097593
DOI: 10.2174/1573406417666210604105923 -
Annual Review of Nutrition Aug 2017Neural tube defects (NTDs) are the most severe congenital malformations of the central nervous system. The etiology is complex, with both genetic and environmental... (Review)
Review
Neural tube defects (NTDs) are the most severe congenital malformations of the central nervous system. The etiology is complex, with both genetic and environmental factors having important contributions. Researchers have known for the past two decades that maternal periconceptional use of the B vitamin folic acid can prevent many NTDs. Though this finding is arguably one of the most important recent discoveries in birth defect research, the mechanism by which folic acid exerts this benefit remains unknown. Research to date has focused on the hypothesis that an underlying genetic susceptibility interacts with folate-sensitive metabolic processes at the time of neural tube closure. Little progress has been made searching for risk-causative variants in candidate genes; therefore, more complex genetic and epigenetic methodologies are now being considered. This article reviews the research to date that has been targeted on this important gene-nutrient locus.
Topics: Animals; Female; Folic Acid; Genetic Predisposition to Disease; Humans; Male; Mice; Neural Tube Defects; Risk Factors
PubMed: 28628360
DOI: 10.1146/annurev-nutr-071714-034235 -
Metallomics : Integrated Biometal... Oct 2019Bacterial molybdoenzymes are key enzymes involved in the global sulphur, nitrogen and carbon cycles. These enzymes require the insertion of the molybdenum cofactor... (Review)
Review
Bacterial molybdoenzymes are key enzymes involved in the global sulphur, nitrogen and carbon cycles. These enzymes require the insertion of the molybdenum cofactor (Moco) into their active sites and are able to catalyse a large range of redox-reactions. Escherichia coli harbours nineteen different molybdoenzymes that require a tight regulation of their synthesis according to substrate availability, oxygen availability and the cellular concentration of molybdenum and iron. The synthesis and assembly of active molybdoenzymes are regulated at the level of transcription of the structural genes and of translation in addition to the genes involved in Moco biosynthesis. The action of global transcriptional regulators like FNR, NarXL/QP, Fur and ArcA and their roles on the expression of these genes is described in detail. In this review we focus on what is known about the molybdenum- and iron-dependent regulation of molybdoenzyme and Moco biosynthesis genes in the model organism E. coli. The gene regulation in E. coli is compared to two other well studied model organisms Rhodobacter capsulatus and Shewanella oneidensis.
Topics: Bacteria; Bacterial Proteins; Biosynthetic Pathways; Coenzymes; Escherichia coli; Gene Expression Regulation, Bacterial; Genes, Bacterial; Iron; Metalloproteins; Molybdenum; Molybdenum Cofactors; Multigene Family; Pteridines; Rhodobacter capsulatus; Shewanella
PubMed: 31517366
DOI: 10.1039/c9mt00186g -
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 -
Journal of Molecular Microbiology and... 2016Ethylbenzene dehydrogenase initiates the anaerobic bacterial degradation of ethylbenzene and propylbenzene. Although the enzyme is currently only known from a few... (Review)
Review
Ethylbenzene dehydrogenase initiates the anaerobic bacterial degradation of ethylbenzene and propylbenzene. Although the enzyme is currently only known from a few closely related denitrifying bacterial strains affiliated to the Rhodocyclaceae, it clearly marks a universally occurring mechanism used for attacking recalcitrant substrates in the absence of oxygen. Ethylbenzene dehydrogenase belongs to subfamily 2 of the DMSO reductase-type molybdenum enzymes together with paralogous enzymes involved in the oxygen-independent hydroxylation of p-cymene, the isoprenoid side chains of sterols and even possibly n-alkanes; the subfamily also extends to dimethylsulfide dehydrogenases, selenite, chlorate and perchlorate reductases and, most significantly, dissimilatory nitrate reductases. The biochemical, spectroscopic and structural properties of the oxygen-independent hydroxylases among these enzymes are summarized and compared. All of them consist of three subunits, contain a molybdenum-bis-molybdopterin guanine dinucleotide cofactor, five Fe-S clusters and a heme b cofactor of unusual ligation, and are localized in the periplasmic space as soluble enzymes. In the case of ethylbenzene dehydrogenase, it has been determined that the heme b cofactor has a rather high redox potential, which may also be inferred for the paralogous hydroxylases. The known structure of ethylbenzene dehydrogenase allowed the calculation of detailed models of the reaction mechanism based on the density function theory as well as QM-MM (quantum mechanics - molecular mechanics) methods, which yield predictions of mechanistic properties such as kinetic isotope effects that appeared consistent with experimental data.
Topics: Alkanes; Anaerobiosis; Bacteria, Anaerobic; Biodegradation, Environmental; Cholesterol; Coenzymes; Hydroxylation; Metalloproteins; Mixed Function Oxygenases; Models, Molecular; Molybdenum Cofactors; Oxidoreductases; Oxygen; Pteridines; Rhodocyclaceae
PubMed: 26960184
DOI: 10.1159/000441357 -
International Journal of Rheumatic... Dec 2023
Topics: Humans; Methotrexate
PubMed: 38041651
DOI: 10.1111/1756-185X.14879 -
Psychiatry Research Mar 2021Increasing evidence points to a causal involvement of inflammation in the pathogenesis of neuropsychiatric disorders, including major depressive disorder (MDD) and...
Increasing evidence points to a causal involvement of inflammation in the pathogenesis of neuropsychiatric disorders, including major depressive disorder (MDD) and schizophrenia (SZ). Neopterin and biopterin may link peripheral immune system activation and central neurotransmitter alterations. However, it is not fully established whether these alterations are transdiagnostic or disorder-specific and whether they are associated with reward-related psychopathologies. We investigated group differences in neopterin and biopterin in the plasma of healthy comparison (HC) (n=19), SZ (n=45) and MDD (n=43) participants. We then correlated plasma proteins with CRP as a measure for inflammation. Lastly, plasma proteins were correlated with the reward-related psychopathological domain apathy. We found a trend-level difference in biopterin levels and no significant difference in neopterin levels between groups. Within both patient groups, but not HC, we show a significant positive correlation of CRP with neopterin but not with biopterin. Further, we observed no significant correlations of plasma proteins with reward-related psychopathology in HC, MDD or SZ. While our study shows trend-level alterations of biopterin with relevance for future research, it does not support the hypothesis that peripheral neopterin or biopterin are associated with reward-related psychopathology.
Topics: Biopterins; Depression; Depressive Disorder, Major; Humans; Neopterin; Schizophrenia
PubMed: 33524773
DOI: 10.1016/j.psychres.2021.113745 -
Journal of Environmental Sciences... May 2017Methotrexate (MTX) is a cytotoxic drug widely used in the treatment of tumors, autoimmune diseases and severe asthma. jen00883This drug has been frequently detected in...
Methotrexate (MTX) is a cytotoxic drug widely used in the treatment of tumors, autoimmune diseases and severe asthma. jen00883This drug has been frequently detected in the aquatic environment with concentrations up to μg/L levels. The MTX present in environmental water might be transformed and removed during chlorination disinfection treatment. In this work, the fate of MTX during aqueous chlorination was investigated in laboratory batch experiments, and the transformation products of MTX were identified. Aqueous solutions of MTX (1mg/L) were chlorinated by sodium hypochlorite solution at room temperature under neutral pH conditions. Chlorinated products were pre-concentrated with solid-phase extraction (SPE) cartridges and determined by liquid chromatography electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS). The reaction of MTX chlorination exhibited pseudo-first-order kinetics and the half-life time of MTX degradation was calculated to be 1.65min, when the initial chlorine concentration was 2mg/L. Two chlorinated MTX congeners, 4-amino-3-chlorinated-N10-methylpteroylglutamic (monochloro-MTX) and 4-amino-3,5-dichloro-N10-methylpteroylglutamic (dichloro-MTX) were found in the chlorinated solution. Monochloro-MTX was successfully fractionated by high performance liquid chromatography (HPLC) and its structure was further identified using H nuclear magnetic resonance (NMR) analysis. The presence of the two products in real hospital wastewater was then examined and both compounds were detected. Finally, the effects of MTX and monochloro-MTX on the cell cycle progression in vitro were evaluated using zebrafish liver cell line. It was found that both compounds could inhibit the proliferation of zebrafish liver cells through S phase arrest and their effects on the cell cycle profile had no significant difference.
Topics: Halogenation; Kinetics; Methotrexate; Models, Chemical; Water Pollutants, Chemical
PubMed: 28477802
DOI: 10.1016/j.jes.2016.06.024