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Journal of Combinatorial Chemistry Nov 2010A novel benzopyrano[4,3-d]pyrimidine scaffold was generated via a three-component one-pot reaction from iodochromone, alkyne, and an amidine through a Sonogashira...
A novel benzopyrano[4,3-d]pyrimidine scaffold was generated via a three-component one-pot reaction from iodochromone, alkyne, and an amidine through a Sonogashira coupling, condensation, and cycloaddition. This combinatorial synthetic approach provides an efficient, easy construction of a diversified heterocyclic compounds library.
Topics: Combinatorial Chemistry Techniques; Pyrans; Pyrimidines; Small Molecule Libraries
PubMed: 20849089
DOI: 10.1021/cc100173b -
Archiv Der Pharmazie Mar 2021Isocitrate dehydrogenase 2 (IDH2) is a key enzyme in the regulation of cell metabolism. Its mutated type can lead to the accumulation of 2-hydroxyglutarate, which is...
Isocitrate dehydrogenase 2 (IDH2) is a key enzyme in the regulation of cell metabolism. Its mutated type can lead to the accumulation of 2-hydroxyglutarate, which is often related to malignancies such as acute myeloid leukemia. Therefore, it is necessary to find new inhibitors targeting mutant IDH2. Discriminatory analysis-based molecular docking was employed to screen the ChemDiv compound library, which resulted in the identification of three new IDH2 inhibitors with moderate-to-good IC values. Among them, compounds 1 and 3 displayed good selectivity against other mutant or wild-type IDH proteins. The most potent compound 1, bearing the [1,2,4]triazolo[1,5-a]pyrimidin scaffold, was subjected to dynamic simulations to provide more information on the binding mode with IDH2 , providing structural clues to further optimize compound 1 as a new mutant IDH2 inhibitor.
Topics: Cell Line; Cell Survival; Dose-Response Relationship, Drug; Enzyme Inhibitors; Humans; Isocitrate Dehydrogenase; Molecular Docking Simulation; Molecular Structure; Pyrimidines; Structure-Activity Relationship
PubMed: 33184958
DOI: 10.1002/ardp.202000063 -
Bioorganic & Medicinal Chemistry Letters Jul 2011Histone deacetylases (HDACs) are enzymes involved in many important biological functions. They have been linked to a variety of cancers, psychiatric disorders, and other...
Histone deacetylases (HDACs) are enzymes involved in many important biological functions. They have been linked to a variety of cancers, psychiatric disorders, and other diseases. Since small molecules can serve as probes to study the relevant biological roles of HDACs, novel scaffolds are necessary to develop more efficient, selective drug candidates. Screening libraries of molecules may yield structurally diverse probes that bind these enzymes and modulate their functions in cells. Here we report a small molecule with a novel hydroxy-pyrimidine scaffold that inhibits multiple HDAC enzymes and modulates acetylation levels in cells. Analogs were synthesized in an effort to evaluate structure-activity relationships.
Topics: Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Pyrimidines; Structure-Activity Relationship
PubMed: 21696956
DOI: 10.1016/j.bmcl.2011.05.098 -
Nan Fang Yi Ke Da Xue Xue Bao = Journal... May 2011To synthesize cyclin-dependent kinase (CDKs) inhibitors and assay their antitumor activities.
OBJECTIVE
To synthesize cyclin-dependent kinase (CDKs) inhibitors and assay their antitumor activities.
METHODS
A series of pyrimidines containing different arylamino and 1-(methylsulfonyl)piperidin moieties were designed by combining the segments 1-(methylsulfonyl)piperidin and pyrimidine heterocycles according to the super-position principle of the reinforcement of biological activities.
RESULTS
Their structures were characterized by MS and 1H NMR spectra and all the synthesized compounds were screened for their antimicrobial activity with MTT assay.
CONCLUSION
The preliminary bioassay showed that compound 3 b displayed good antitumor activity (IC(50)=13.6 µmol/L). The preliminary structure activity relationship analysis of these analogues suggest that the steric factor may have important impact on the anti-tumor activity.
Topics: Antineoplastic Agents; Cell Line, Tumor; Drug Screening Assays, Antitumor; Humans; Pyrimidines; Structure-Activity Relationship
PubMed: 21602147
DOI: No ID Found -
Biochimie 1985This survey focuses on recent developments in the far ultraviolet photochemistry of nucleic acids and related model compounds. The photoproducts discussed are the... (Review)
Review
This survey focuses on recent developments in the far ultraviolet photochemistry of nucleic acids and related model compounds. The photoproducts discussed are the cyclobutidipyrimidines, the pyrimidine-pyrimidone adducts, the purine-pyrimidine adducts and the addition products of amino acids to pyrimidine bases. The specific aspects of the high-intensity laser photochemistry of nucleic acid components are also briefly reviewed.
Topics: Amino Acids; Base Sequence; Chemical Phenomena; Chemistry; Cyclobutanes; Cytosine; DNA; DNA Repair; Deoxyribodipyrimidine Photo-Lyase; Lasers; Lysine; Macromolecular Substances; Magnetic Resonance Spectroscopy; Nucleic Acid Conformation; Oligodeoxyribonucleotides; Photochemistry; Photolysis; Purines; Pyrimidine Dimers; Pyrimidines; Pyrimidinones; Spectrum Analysis; Thymine; Tryptophan; Ultraviolet Rays; X-Ray Diffraction
PubMed: 3929843
DOI: 10.1016/s0300-9084(85)80070-5 -
Current Topics in Medicinal Chemistry 2021The quantitative structure-activity relationship is an analysis method that can be applied for designing new molecules. In 1997, Hopfinger and coworkers developed the...
BACKGROUND
The quantitative structure-activity relationship is an analysis method that can be applied for designing new molecules. In 1997, Hopfinger and coworkers developed the 4DQSAR methodology aiming to eliminate the question of which conformation to use in a QSAR study. In this work, the 4D-QSAR methodology was used to quantitatively determine the influence of structural descriptors on the activity of aryl pyrimidine derivatives as inhibitors of the TGF-β1 receptor. The members of the TGF-β subfamily are interesting molecular targets, since they play an important function in the growth and development of cell cellular including proliferation, apoptosis, differentiation, Epithelial-Mesenchymal Transition (EMT), and migration. In late stages, TGF-β exerts tumor-promoting effects, increasing tumor invasiveness, and metastasis. Therefore, TGF-β is an attractive target for cancer therapy.
OBJECTIVE
The major goal of the current research is to develop 4D-QSAR models aiming to propose new structures of aryl pyrimidine derivatives.
MATERIALS AND METHODS
Molecular dynamics simulation was carried out to generate the conformational ensemble profile of a data set with aryl pyrimidine derivatives. The conformations were overlaid into a three-dimensional cubic box, according to the three-ordered atom alignment. The occupation of the grid cells by the interaction of pharmacophore elements provides the Grid Cell Occupancy Descriptors (GCOD), the dependent variables used to build the 4D-QSAR models. The best models were validated (internal and external validation) using several statistical parameters. Docking molecular studies were performed to better understand the binding mode of pyrimidine derivatives inside the TGF-β active site.
RESULTS
The 4D-QSAR model presented seven descriptors and acceptable statistical parameters (R = 0.89, q = 0.68, R = 0.65, r = 0.55, R = 0.68 and R = 0.21) besides pharmacophores groups important for the activity of these compounds. The molecular docking studies helped to understand the pharmacophoric groups and proposed substituents that increase the potency of aryl pyrimidine derivatives.
CONCLUSION
The best QSAR model showed adequate statistical parameters that ensure their fitness, robustness, and predictivity. Structural modifications were assessed, and five new structures were proposed as candidates for a drug for cancer treatment.
Topics: Humans; Molecular Dynamics Simulation; Pyrimidines; Quantitative Structure-Activity Relationship; Transforming Growth Factor beta1
PubMed: 34315368
DOI: 10.2174/1568026621666210727161431 -
Nature Chemistry Apr 2017Previous research has identified ribose aminooxazoline as a potential intermediate in the prebiotic synthesis of the pyrimidine nucleotides with remarkable properties....
Previous research has identified ribose aminooxazoline as a potential intermediate in the prebiotic synthesis of the pyrimidine nucleotides with remarkable properties. It crystallizes spontaneously from reaction mixtures, with an enhanced enantiomeric excess if initially enantioenriched, which suggests that reservoirs of this compound might have accumulated on the early Earth in an optically pure form. Ribose aminooxazoline can be converted efficiently into α-ribocytidine by way of 2,2'-anhydroribocytidine, although anomerization to β-ribocytidine by ultraviolet irradiation is extremely inefficient. Our previous work demonstrated the synthesis of pyrimidine β-ribonucleotides, but at the cost of ignoring ribose aminooxazoline, using arabinose aminooxazoline instead. Here we describe a long-sought route through ribose aminooxazoline to the pyrimidine β-ribonucleosides and their phosphate derivatives that involves an extraordinarily efficient photoanomerization of α-2-thioribocytidine. In addition to the canonical nucleosides, our synthesis accesses β-2-thioribouridine, a modified nucleoside found in transfer RNA that enables both faster and more-accurate nucleic acid template-copying chemistry.
Topics: Evolution, Chemical; Molecular Conformation; Oxazoles; Phosphates; Photochemical Processes; Pyrimidines; Ribonucleosides; Ribose
PubMed: 28338689
DOI: 10.1038/nchem.2664 -
Molecules (Basel, Switzerland) Apr 2015This work concerns the design and synthesis of novel, substituted 5-alkoxythieno[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine derivatives 5a-p prepared from...
This work concerns the design and synthesis of novel, substituted 5-alkoxythieno[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine derivatives 5a-p prepared from 3-amino-2-thiophenecarboxylic acid methyl ester. The final compounds were screened for their in vivo anticonvulsant activity using maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) tests. Neurotoxicity (NT) was tested using a rotarod test. The structure-anticonvulsant activity relationship analysis revealed that the most effective structural motif involves a substituted phenol, especially when substituted with a single chlorine, fluorine or trifluoromethyl group (at the meta-position), or two chlorine atoms. These molecules possessed high activity according to the MES and scPTZ models. Quantitative assessment of the compounds after intraperitoneal administration in mice showed that the most active compound was 5-[3-(trifluoromethyl)phenoxy]thieno[2,3-e] [1,2,4]triazolo[4,3-c]pyrimidine (5o) with ED50 values of 11.5 mg/kg (MES) and 58.9 mg/kg (scPTZ). Furthermore, compound 5o was more effective in the MES and scPTZ tests than the well-known anticonvulsant drugs carbamazepine and ethosuximide.
Topics: Animals; Anticonvulsants; Disease Models, Animal; Mice; Molecular Structure; Pyrimidines; Seizures; Structure-Activity Relationship
PubMed: 25884556
DOI: 10.3390/molecules20046827 -
Methods in Molecular Biology (Clifton,... 2016Pyrimidine diseases result from deficiencies in pyrimidine de novo synthesis, degradation, and salvage pathways. Enzymatic deficiencies in pyrimidine catabolism lead to...
Pyrimidine diseases result from deficiencies in pyrimidine de novo synthesis, degradation, and salvage pathways. Enzymatic deficiencies in pyrimidine catabolism lead to mitochondrial neurogastrointestinal encephalopathy (MNGIE), pyrimidinuria, dihydropyrimidinuria, ureidopropionic aciduria, and other disorders. While MNGIE presents with gastrointestinal dysmotility, cachexia, and leukoencephalopathy, pyrimidinuria and dihydropyrimidinuria may show symptoms of epilepsy, autism, mental retardation, and dysmorphic features. The application of HPLC-MS/MS facilitates rapid screening of pyrimidine metabolites. Here we describe an LCMS method for determination of uracil, thymine, thymidine, dihydrouracil, and dihydrothymine that are diagnostic biomarkers of MNGIE, pyrimidinuria, and dihydropyrimidinuria.
Topics: Chromatography, High Pressure Liquid; Humans; Pyrimidines; Tandem Mass Spectrometry; Urinalysis
PubMed: 26602135
DOI: 10.1007/978-1-4939-3182-8_25 -
Bioorganic & Medicinal Chemistry Sep 2019Aiming to develop potent JAK inhibitors, two series of 4-(1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine derivatives (8a-8p and 11a-11i) were designed and synthesized by...
Aiming to develop potent JAK inhibitors, two series of 4-(1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine derivatives (8a-8p and 11a-11i) were designed and synthesized by coalescing various N-acylpiperidine motifs with baricitinib. The pharmacological results based on enzymatic and cellular assays identified the optimized compound 11e, which exerted over 90% inhibition rates against JAK1 and JAK2, and displayed the most compelling anti-inflammatory efficacy superior to baricitinib by inhibiting NO generation from LPS-induced RAW264.7 macrophages. Importantly, low cytotoxity of 11e was revealed by the IC value of 88.2 μM against normal RAW264.7 cells. The binding mode of 11e with JAK1 and JAK2 identified the essential structural bases in accord with SARs analysis. Furthermore, cellular morphology observation and western blot analysis disclosed the ability of 11e to relieve cells inflammatory damage by significantly down-regulating LPS-induced high expression of JAK1, JAK2, as well as pro cytokine IL-1β. Together, 11e was verified as a promising lead for JAK inhibitors for the treatment of inflammatory diseases.
Topics: Humans; Janus Kinase Inhibitors; Pyrimidines
PubMed: 31378597
DOI: 10.1016/j.bmc.2019.07.037