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Journal of the American Chemical Society Jan 2011The use of stable isotope labeling has revolutionized NMR studies of nucleic acids, and there is a need for methods of incorporation of specific isotope labels to...
The use of stable isotope labeling has revolutionized NMR studies of nucleic acids, and there is a need for methods of incorporation of specific isotope labels to facilitate specific NMR experiments and applications. Enzymatic synthesis offers an efficient and flexible means to synthesize nucleoside triphosphates from a variety of commercially available specifically labeled precursors, permitting isotope labeling of RNAs prepared by in vitro transcription. Here, we recapitulate de novo pyrimidine biosynthesis in vitro, using recombinantly expressed enzymes to perform efficient single-pot syntheses of UTP and CTP that bear a variety of stable isotope labeling patterns. Filtered NMR experiments on (13)C, (15)N, (2)H-labeled HIV-2 TAR RNA demonstrate the utility and value of this approach. This flexible enzymatic synthesis will make implementing detailed and informative RNA stable isotope labeling schemes substantially more cost-effective and efficient, providing advanced tools for the study of structure and dynamics of RNA molecules.
Topics: Enzymes; Nucleotides; Pyrimidines
PubMed: 21166398
DOI: 10.1021/ja1059685 -
Chemical Communications (Cambridge,... Jan 2022Both sequence enrichment and base resolution are essential for accurate sequencing analysis of low-abundance RNA. Yet they are hindered by the lack of molecular tools....
Both sequence enrichment and base resolution are essential for accurate sequencing analysis of low-abundance RNA. Yet they are hindered by the lack of molecular tools. Here we report a bifunctional chemical signature for RNA 4-thiouridine (4sU) enrichment sequencing with single-base resolution. This chemical signature is designed for specific 4sU labeling with two functional parts. One part is a distal alkynyl group for the biotin-assisted pulldown enrichment of target molecules click chemistry crosslinking. The other part is a -NH group proximal to the pyrimidine ring of 4sU. It allows 4sU-to-cytosine transition during the polymerase-catalyzed extension reaction based on altering hydrogen-bonding patterns. Ultimately, the 4sU-containing RNA molecules can be enriched and accurately analyzed by single-base resolution sequencing. The proposed method also holds great potential to investigate transcriptome dynamics integrated with high-throughput sequencing.
Topics: Click Chemistry; Cytosine; High-Throughput Nucleotide Sequencing; Mass Spectrometry; Nucleotide Motifs; Pyrimidines; RNA; RNA Stability; Sequence Analysis, RNA; Thiouridine
PubMed: 34985087
DOI: 10.1039/d1cc06080e -
Chemical Research in Toxicology Apr 2019After thymidine (dT) was treated with a Fenton-type reagent and further incubated for a long period (6 days) under physiological conditions (37 °C, pH 7.4), a new...
After thymidine (dT) was treated with a Fenton-type reagent and further incubated for a long period (6 days) under physiological conditions (37 °C, pH 7.4), a new product, named dT*, was detected by HPLC in addition to the free thymine base and the known oxidative dT damage, 5-formyl-2'-deoxyuridine (fdU). dT* was found to be formed from fdU. The structure of dT* was determined to be 3-amino-2-carbamoyl-2-propenal-N-2'-deoxyriboside, a pyrimidine ring-opened product from fdU, on the basis of H- and C NMR analyses and mass spectra. From the model compound 1-methyl-5-formyluracil, a similar ring-opened product was formed after the incubation. dT* was also detected in DNA treated with a Fenton-type reagent or γ-rays, followed by the prolonged incubation. dT* will be a new promising marker of oxidative DNA damage. The possible role of this product in oxy-radical-induced mutagenesis is discussed.
Topics: Animals; Cattle; DNA; DNA Damage; Deoxyuridine; Molecular Structure; Oxidation-Reduction; Pyrimidines
PubMed: 30785277
DOI: 10.1021/acs.chemrestox.8b00401 -
Chemical Communications (Cambridge,... Mar 2015Effects of hydrogen bonding clamps on the selectivity of triplex DNA receptors were studied. Incorporation of a 5-methyl-2-thiocytosine base to the parallel...
Effects of hydrogen bonding clamps on the selectivity of triplex DNA receptors were studied. Incorporation of a 5-methyl-2-thiocytosine base to the parallel homopyrimidine region of a triplex receptor enabled selective molecular recognition of an inosine ligand.
Topics: Cytosine; DNA; Hydrogen Bonding; Inosine; Ligands; Models, Molecular; Molecular Conformation; Pyrimidines; Receptors, Cell Surface
PubMed: 25358435
DOI: 10.1039/c4cc07805e -
Organic & Biomolecular Chemistry May 2024Post-synthetic conversion of the trifluoromethyl group to a heteroaryl group at the C5 position of the pyrimidine base in DNA oligonucleotides was achieved....
Post-synthetic conversion of the trifluoromethyl group to a heteroaryl group at the C5 position of the pyrimidine base in DNA oligonucleotides was achieved. Specifically, the oligonucleotides containing 5-trifluoromethylpyrimidine bases were treated with -phenylenediamines and -aminothiophenols as nucleophiles to afford the corresponding 5-(benzimidazol-2-yl)- and 5-(benzothiazol-2-yl)-pyrimidine-modified bases. Furthermore, evaluation of the fluorescence properties of the obtained oligonucleotides revealed that among them the oligonucleotide containing 5-(5-methylbenzimidazol-2-yl)cytosine exhibited the highest fluorescence intensity. These results indicated that post-synthetic trifluoromethyl conversion, which is practical and operationally simple, is a powerful tool for exploring functional oligonucleotides.
Topics: Pyrimidines; Oligonucleotides; Fluorescent Dyes; Molecular Structure
PubMed: 38619422
DOI: 10.1039/d4ob00402g -
European Journal of Medicinal Chemistry May 2022The chemokine receptor CXCR2 and its ligands mediate neutrophil migration to the inflammation site, function as growth factors in many tumor cells and are involved in...
The chemokine receptor CXCR2 and its ligands mediate neutrophil migration to the inflammation site, function as growth factors in many tumor cells and are involved in angiogenesis. Moreover, CXCR2 mediated recruitment of myeloid-derived suppressor cells results in tumor immunosuppression. Consequently, CXCR2 antagonism is a promising strategy for cancer immunotherapy and treatment of inflammatory disorders. Over a decade ago, several thiazolo[4,5-d]pyrimidines were reported as potent CXCR2 antagonists. Optimization of this scaffold focused mainly on the ring substituents, while the aromatic core was mostly unexplored. In this study, a scaffold hopping strategy was applied to the unsubstituted thiazolo moiety. Fourteen novel bicyclic heteroaromatic and cycloaliphatic systems were prepared and evaluated for CXCR2 antagonism using binding and calcium mobilization assays. This study revealed that the triazolo[4,5-d]pyrimidine, the isoxazolo[5,4-d]pyrimidine and the pyrido[3,4-d]pyrimidine scaffolds were endowed with IC values below 1 μM in both assays and therefore are promising skeletons for further optimization.
Topics: Cell Movement; Pyrimidines; Receptors, Interleukin-8B; Structure-Activity Relationship
PubMed: 35313168
DOI: 10.1016/j.ejmech.2022.114268 -
Physiological Reviews Jul 1952
Topics: Nucleic Acids; Purines; Pyrimidines
PubMed: 12983226
DOI: 10.1152/physrev.1952.32.3.303 -
Acta Pharmaceutica (Zagreb, Croatia) Dec 2008New series of 2-hydrazino-7,8-dihydro-6H-cyclopenta[5,6] pyrido[2,3-d]pyrimidines and its 1,7,8,9-tetrahydrocyclopenta[5,6]pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidine,...
New series of 2-hydrazino-7,8-dihydro-6H-cyclopenta[5,6] pyrido[2,3-d]pyrimidines and its 1,7,8,9-tetrahydrocyclopenta[5,6]pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidine, 1,7,8,9-tetrahydrocyclopenta[5,6]pyrido[2,3-d][1,2,3,4]tetrazolo[4,5-a]pyrimidine, 8,9-dihydro-7H-cyclopenta[5,6]pyrido[2,3-d]imidazolo[1,2-a]pyrimidine, 2-(pyrazol-1-yl)-7,8-dihydro-6H-cyclopenta[5,6]pyrido[2,3-d]pyrimidine derivatives were prepared in order to obtain new compounds with potential anti-inflammatory and analgesic activity and low ulcerogenic effect. The compounds possessing potent anti-inflammatory activity were further tested for their analgesic and ulcerogenic activities. Compounds 3-amino-6-(4-aryl)-9-(4-arylmethylene)-cyclopenta[5,6]pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidin-5(H)-one (4c), 1-amino-2-methyl-6-(4-aryl)-9-(4-aryl-methylene)-cyclopenta[5,6]pyrido[2,3-d]imidazolo[1,2-a]pyrimidin-5(H)-one (6a), 2-amino-5-(4-aryl)-8-(4-arylmethylene)-cyclopenta[5,6]pyrido-[2,3-d]pyrimidine-4(H)-one (9), 2-(3-amino-5-hydroxypyrazol- 1-yl)-5-(4-aryl)-8-(4-arylmethylene)-cyclopenta[5,6]-pyrido[2,3-d]pyrimidin-4(H)-one (10a) and 3-thioxo-6-(4-aryl)-9-(4-arylmethylene)-cyclopenta[5,6]pyrido[2,3-d]-[1,2,4]triazolo[4,3-a]pyrimidin-5(H)-one (13) showed significant analgesic effects. Compound 2-(3-amino-5-hydroxypyrazol-1-yl)-5-(4-aryl)-8-(4-arylmethylene)-cyclopenta [5,6]pyrido[2,3-d]pyrimidin-4(H)-one (10a) was evaluated as the lead compound having higher anti-inflammatory activity (82.8%) than ibuprofen (79.5%) and lower ulcerogenic effect.
Topics: Analgesics; Animals; Anti-Inflammatory Agents; Female; Male; Mice; Pyrimidines; Rats; Rats, Sprague-Dawley; Stomach Ulcer; Structure-Activity Relationship; Triazoles
PubMed: 19103572
DOI: 10.2478/v10007-008-0024-1 -
Chemistry & Biodiversity May 2021Abnormalities in the FGFRs signaling pathway and VEGFR2 amplification often occur in a variety of tumors, and they synergistically promote tumor angiogenesis. Studies...
Abnormalities in the FGFRs signaling pathway and VEGFR2 amplification often occur in a variety of tumors, and they synergistically promote tumor angiogenesis. Studies have shown that the up-regulation of FGF-2 is closely related to the resistance of VEGFR2 inhibitors. Activation of the FGFRs signal is a signal of compensatory angiogenesis after VEGFR2 resistance. Dual VEGFR2/FGFR1 inhibitors contribute to overcoming the resistance of VEGFR2 inhibitors and inhibit tumor growth significantly. Based on this, we designed and synthesized a series of 4,6-disubstituted pyrimidine derivatives as dual VEGFR2/FGFR1 inhibitors by the molecular hybridization strategy. 3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-{6-[(4-methoxyphenyl)amino]pyrimidin-4-yl}-1-methylurea (8b) had the best inhibitory activities against VEGFR2 and FGFR1 at 10 μM (82.2 % and 101.0 %, respectively), it showed moderate antiproliferative activities against A549 and KG-1 cell lines as well. Besides, molecular docking was also carried out to study the binding mode of 3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-{6-[(4-methoxyphenyl)-amino]-pyrimidin-4-yl}-1-methylurea (8b) with VEGFR2 and FGFR1. These studies reveal that this series of compounds deserve further optimization.
Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Drug Discovery; Drug Screening Assays, Antitumor; Humans; Molecular Docking Simulation; Molecular Structure; Protein Kinase Inhibitors; Pyrimidines; Receptor, Fibroblast Growth Factor, Type 1; Vascular Endothelial Growth Factor Receptor-2
PubMed: 33829649
DOI: 10.1002/cbdv.202100095 -
Molecular Diversity Nov 2020In this study, the one-pot reaction between primary amines, 1,1-bis-(methylthio)-2-nitroethene, ninhydrin, and barbituric acid as an enolizable C-H-activated compound...
In this study, the one-pot reaction between primary amines, 1,1-bis-(methylthio)-2-nitroethene, ninhydrin, and barbituric acid as an enolizable C-H-activated compound provides a simple method for the preparation of 5-(2-(alkylamino)-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-6-hydroxypyrimidine-2,4(1H,3H)-dione derivatives with potential synthetic and pharmacological interest. This reaction shows attractive characteristics, such as substrate availability, good yields, existence of numerous hydrogen-bonding possibilities in product, and its mild conditions in ethanol media.
Topics: Amines; Barbiturates; Hydrogen Bonding; Ninhydrin; Pyrimidines
PubMed: 31679084
DOI: 10.1007/s11030-019-10009-w