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Molecules (Basel, Switzerland) Feb 2024A new series of thieno[2,3-][1,2,4]triazolo[1,5-]pyrimidines was designed and synthesized using readily available starting materials, specifically, -enaminoester. Their...
A new series of thieno[2,3-][1,2,4]triazolo[1,5-]pyrimidines was designed and synthesized using readily available starting materials, specifically, -enaminoester. Their cytotoxicity was screened against three cancer cell lines, namely, MCF-7, HCT-116, and PC-3. 2-(4-bromophenyl)triazole and 2-(anthracen-9-yl)triazole afforded excellent potency against MCF-7 cell lines (IC = 19.4 ± 0.22 and 14.5 ± 0.30 μM, respectively) compared with doxorubicin (IC = 40.0 ± 3.9 μM). The latter derivatives and were further subjected to in silico ADME and docking simulation studies against EGFR and PI3K and could serve as ideal leads for additional modification in the field of anticancer research.
Topics: Humans; Molecular Structure; Structure-Activity Relationship; Molecular Docking Simulation; Antineoplastic Agents; Pyrimidines; Triazoles; Drug Screening Assays, Antitumor; Cell Proliferation; Cell Line, Tumor; Drug Design
PubMed: 38474579
DOI: 10.3390/molecules29051067 -
Chemical & Pharmaceutical Bulletin Aug 2003The synthesis of 2-substituted isomers of the meridianins, a familiy of bioactive indole alkaloids isolated from the tunicate Aplidium meridianum, was undertaken. The...
The synthesis of 2-substituted isomers of the meridianins, a familiy of bioactive indole alkaloids isolated from the tunicate Aplidium meridianum, was undertaken. The synthetic route comprises six steps, with a microwave promoted Fischer cyclization as the key reaction.
Topics: Animals; Indole Alkaloids; Indoles; Pyrimidines; Urochordata
PubMed: 12913239
DOI: 10.1248/cpb.51.975 -
Marine Drugs Apr 2019The first total synthesis of the marine nucleoside Mycalisine B-a naturally occurring and structurally distinct 4,5-unsaturated 7-deazapurine nucleoside-has been...
The first total synthesis of the marine nucleoside Mycalisine B-a naturally occurring and structurally distinct 4,5-unsaturated 7-deazapurine nucleoside-has been accomplished in 10 linear steps with 27.5% overall yield from commercially available 1,2,3,5-tetra--acetyl-ribose and tetracyanoethylene. Key steps of the approach include: (1) I catalyzed acetonide formation from 1,2,3,5-tetra--acetylribose and acetone at large scale; (2) Vorbrüggen glycosylation using -benzoyl-5-cyano-6-bromo-7-pyrrolo[2,3-]pyrimidine as a nucleobase to avoid formation of -3 isomer; (3) mild and scalable reaction conditions.
Topics: Catalysis; Glycosylation; Isomerism; Nucleosides; Pyrimidines
PubMed: 31013980
DOI: 10.3390/md17040226 -
The Journal of Physiological Sciences :... May 2018This study aimed at evaluating the concentration of erythrocyte purine nucleotides (ATP, ADP, AMP, IMP) in trained and sedentary subjects before and after maximal...
Comparison of human erythrocyte purine nucleotide metabolism and blood purine and pyrimidine degradation product concentrations before and after acute exercise in trained and sedentary subjects.
This study aimed at evaluating the concentration of erythrocyte purine nucleotides (ATP, ADP, AMP, IMP) in trained and sedentary subjects before and after maximal physical exercise together with measuring the activity of purine metabolism enzymes as well as the concentration of purine (hypoxanthine, xanthine, uric acid) and pyrimidine (uridine) degradation products in blood. The study included 15 male elite rowers [mean age 24.3 ± 2.56 years; maximal oxygen uptake (VO) 52.8 ± 4.54 mL/kg/min; endurance and strength training 8.2 ± 0.33 h per week for 6.4 ± 2.52 years] and 15 sedentary control subjects (mean age 23.1 ± 3.41 years; VO 43.2 ± 5.20 mL/kg/min). Progressive incremental exercise testing until refusal to continue exercising was conducted on a bicycle ergometer. The concentrations of ATP, ADP, AMP, IMP and the activities of adenine phosphoribosyltransferase (APRT), hypoxanthine-guanine phosphoribosyltransferase (HGPRT) and phosphoribosyl pyrophosphate synthetase (PRPP-S) were determined in erythrocytes. The concentrations of hypoxanthine, xanthine, uric acid and uridine were determined in the whole blood before exercise, after exercise, and 30 min after exercise testing. The study demonstrated a significantly higher concentration of ATP in the erythrocytes of trained subjects which, in part, may be explained by higher metabolic activity on the purine re-synthesis pathway (significantly higher PRPP-S, APRT and HGPRT activities). The ATP concentration, just as the ATP/ADP ratio, as well as an exercise-induced increase in this ratio, correlates with the VO level in these subjects which allows them to be considered as the important factors characterising physical capacity and exercise tolerance. Maximal physical exercise in the group of trained subjects results not only in a lower post-exercise increase in the concentration of hypoxanthine, xanthine and uric acid but also in that of uridine. This indicates the possibility of performing high-intensity work with a lower loss of not only purine but also pyrimidine.
Topics: Adult; Erythrocytes; Exercise; Humans; Hypoxanthine; Hypoxanthine Phosphoribosyltransferase; Male; Purine Nucleotides; Purines; Pyrimidines; Uric Acid; Xanthine; Young Adult
PubMed: 28432611
DOI: 10.1007/s12576-017-0536-x -
International Journal of Cancer Apr 2022Adult T-cell leukemia-lymphoma (ATL) is an aggressive neoplasm derived from T-cells transformed by human T-cell lymphotropic virus-1 (HTLV-1). Recently, we reported that...
Adult T-cell leukemia-lymphoma (ATL) is an aggressive neoplasm derived from T-cells transformed by human T-cell lymphotropic virus-1 (HTLV-1). Recently, we reported that regional DNA hypermethylation in HTLV-1-infected T-cells reflects the disease status of ATL and the anti-ATL effects of DNA demethylating agents, including azacitidine (AZA), decitabine (DAC) and a new DAC prodrug, OR-2100 (OR21), which we developed. Here, to better understand the mechanisms underlying drug resistance, we generated AZA-, DAC- and OR21-resistant (AZA-R, DAC-R and OR21-R, respectively) cells from the ATL cell line TL-Om1 and the HTLV-1-infected cell line MT-2 via long-term drug exposure. The efficacy of OR21 was almost the same as that of DAC, indicating that the pharmacodynamics of OR21 were due to release of DAC from OR21. Resistant cells did not show cellular responses observed in parental cells induced by treatment with drugs, including growth suppression, depletion of DNA methyltransferase DNMT1 and DNA hypomethylation. We also found that reduced expression of deoxycytidine kinase (DCK) correlated with lower susceptibility to DAC/OR21 and that reduced expression of uridine cytidine kinase2 (UCK2) correlated with reduced susceptibility to AZA. DCK and UCK2 catalyze phosphorylation of DAC and AZA, respectively; reconstitution of expression reversed the resistant phenotypes. A large homozygous deletion in DCK and a homozygous splice donor site mutation in UCK2 were identified in DAC-R TL-Om1 and AZA-R TL-Om1, respectively. Both genomic mutations might lead to loss of protein expression. Thus, inactivation of UCK2 and DCK might be a putative cause of phenotypes that are resistant to AZA and DAC/OR21, respectively.
Topics: Antineoplastic Agents; Azacitidine; Cell Line, Tumor; DNA Methylation; Decitabine; Deoxycytidine Kinase; Drug Resistance, Neoplasm; Humans; Leukemia-Lymphoma, Adult T-Cell; Pyridines; Pyrimidines; Uridine Kinase
PubMed: 34913485
DOI: 10.1002/ijc.33901 -
Pharmacogenetics and Genomics Nov 2011Responses to therapies, either with regard to toxicities or efficacy, are expected to involve complex relationships of gene products within the same molecular pathway or...
OBJECTIVE
Responses to therapies, either with regard to toxicities or efficacy, are expected to involve complex relationships of gene products within the same molecular pathway or functional gene set. Therefore, pathways or gene sets, as opposed to single genes, may better reflect the true underlying biology and may be more appropriate units for analysis of pharmacogenomic studies. Application of such methods to pharmacogenomic studies may enable the detection of more subtle effects of multiple genes in the same pathway that may be missed by assessing each gene individually.
METHODS
A gene set analysis of 3821 gene sets is presented assessing the association between basal messenger RNA expression and drug cytotoxicity using ethnically defined human lymphoblastoid cell lines for two classes of drugs: pyrimidines [gemcitabine (dFdC) and arabinoside] and purines [6-thioguanine and 6-mercaptopurine].
RESULTS
The gene set nucleoside-diphosphatase activity was found to be significantly associated with both dFdC and arabinoside, whereas gene set γ-aminobutyric acid catabolic process was associated with dFdC and 6-thioguanine. These gene sets were significantly associated with the phenotype even after adjusting for multiple testing. In addition, five associated gene sets were found in common between the pyrimidines and two gene sets for the purines (3',5'-cyclic-AMP phosphodiesterase activity and γ-aminobutyric acid catabolic process) with a P value of less than 0.0001. Functional validation was attempted with four genes each in gene sets for thiopurine and pyrimidine antimetabolites. All four genes selected from the pyrimidine gene sets (PSME3, CANT1, ENTPD6, ADRM1) were validated, but only one (PDE4D) was validated for the thiopurine gene sets.
CONCLUSION
In summary, results from the gene set analysis of pyrimidine and purine therapies, used often in the treatment of various cancers, provide novel insight into the relationship between genomic variation and drug response.
Topics: Antimetabolites; Antineoplastic Agents; Area Under Curve; Cell Line, Tumor; Deoxycytidine; Genes, Neoplasm; Humans; Neoplasms; Phenotype; Purines; Pyrimidines; Reproducibility of Results; Thioguanine; Gemcitabine
PubMed: 21869733
DOI: 10.1097/FPC.0b013e32834a48a9 -
Molecules (Basel, Switzerland) Apr 2013Our recent achievements relating to photofunctional molecules are addressed. Section 1 discloses a new concept of photoisomerization. Pyridylpyrimidine-copper complexes... (Review)
Review
Our recent achievements relating to photofunctional molecules are addressed. Section 1 discloses a new concept of photoisomerization. Pyridylpyrimidine-copper complexes undergo a ring inversion that can be modulated by the redox state of the copper center. In combination with an intermolecular photoelectron transfer (PET) initiated by the metal-to-ligand charge transfer (MLCT) transition of the Cu(I) state, we realize photonic regulation of the ring inversion. Section 2 reports on the first examples of heteroleptic bis(dipyrrinato)zinc(II) complexes. Conventional homoleptic bis(dipyrrinato)zinc(II) complexes suffered from low fluorescence quantum yields, whereas the heteroleptic ones feature bright fluorescence even in polar solvents. Section 3 describes our new findings on Pechmann dye, which was first synthesized in 1882. New synthetic procedures for Pechmann dye using dimethyl bis(arylethynyl)fumarate as a starting material gives rise to its new structural isomer. We also demonstrate potentiality of a donor-acceptor-donor type of Pechmann dye in organic electronics.
Topics: Copper; Crystallography, X-Ray; Electrochemistry; Ligands; Models, Molecular; Molecular Structure; Photochemistry; Pyridines; Pyrimidines; Quantum Theory; Zinc
PubMed: 23563859
DOI: 10.3390/molecules18044091 -
Journal of Medicinal Chemistry Jan 2021-Acylphosphatidylethanolamine phospholipase D (NAPE-PLD) is regarded as the main enzyme responsible for the biosynthesis of -acylethanolamines (NAEs), a family of...
-Acylphosphatidylethanolamine phospholipase D (NAPE-PLD) is regarded as the main enzyme responsible for the biosynthesis of -acylethanolamines (NAEs), a family of bioactive lipid mediators. Previously, we reported -(cyclopropylmethyl)-6-(()-3-hydroxypyrrolidin-1-yl)-2-(()-3-phenylpiperidin-1-yl)pyrimidine-4-carboxamide (, ) as the first potent and selective NAPE-PLD inhibitor that decreased NAEs in the brains of freely moving mice and modulated emotional behavior [Mock , 2020, 16, 667-675]. Here, we describe the structure-activity relationship (SAR) of a library of pyrimidine-4-carboxamides as inhibitors of NAPE-PLD that led to the identification of . A high-throughput screening hit was modified at three different substituents to optimize its potency and lipophilicity. Conformational restriction of an -methylphenethylamine group by replacement with an ()-3-phenylpiperidine increased the inhibitory potency 3-fold. Exchange of a morpholine substituent for an ()-3-hydroxypyrrolidine reduced the lipophilicity and further increased activity by 10-fold, affording as a nanomolar potent inhibitor with drug-like properties. is a suitable pharmacological tool compound to investigate NAPE-PLD function and .
Topics: Amides; Carboxylic Acids; Enzyme Inhibitors; Phosphatidylethanolamines; Phospholipases; Pyrimidines; Structure-Activity Relationship
PubMed: 33382264
DOI: 10.1021/acs.jmedchem.0c01441 -
Biomolecules Nov 2023Adenosine receptors are largely distributed in our organism and are promising therapeutic targets for the treatment of many pathologies. In this perspective,...
Adenosine receptors are largely distributed in our organism and are promising therapeutic targets for the treatment of many pathologies. In this perspective, investigating the structural features of the ligands leading to affinity and/or selectivity is of great interest. In this work, we have focused on a small series of pyrazolo-triazolo-pyrimidine antagonists substituted in positions 2, 5, and N8, where bulky acyl moieties at the N5 position and small alkyl groups at the N8 position are associated with affinity and selectivity at the A adenosine receptor even if a good affinity toward the A adenosine receptor has also been observed. Conversely, a free amino function at the 5 position induces high affinity at the A and A receptors with selectivity vs. the A subtype. A molecular modeling study suggests that differences in affinity toward A, A, and A receptors could be ascribed to two residues: one in the EL2, E168 in human A/E172 in human A, that is occupied by the hydrophobic residue V169 in the human A receptor; and the other in TM6, occupied by H250/H251 in human A and A receptors and by a less bulky S247 in the A receptor. In the end, these findings could help to design new subtype-selective adenosine receptor ligands.
Topics: Humans; Structure-Activity Relationship; Purinergic P1 Receptor Antagonists; Receptors, Purinergic P1; Models, Molecular; Pyrimidines
PubMed: 38002292
DOI: 10.3390/biom13111610 -
International Journal of Molecular... Mar 2020Riboswitches are naturally occurring RNA aptamers that control the expression of essential bacterial genes by binding to specific small molecules. The binding with both...
Riboswitches are naturally occurring RNA aptamers that control the expression of essential bacterial genes by binding to specific small molecules. The binding with both high affinity and specificity induces conformational changes. Thus, riboswitches were proposed as a possible molecular target for developing antibiotics and chemical tools. The adenine riboswitch can bind not only to purine analogues but also to pyrimidine analogues. Here, long molecular dynamics (MD) simulations and molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) computational methodologies were carried out to show the differences in the binding model and the conformational changes upon five ligands binding. The binding free energies of the guanine riboswitch aptamer with C74U mutation complexes were compared to the binding free energies of the adenine riboswitch (AR) aptamer complexes. The calculated results are in agreement with the experimental data. The differences for the same ligand binding to two different aptamers are related to the electrostatic contribution. Binding dynamical analysis suggests a flexible binding pocket for the pyrimidine ligand in comparison with the purine ligand. The 18 μs of MD simulations in total indicate that both ligand-unbound and ligand-bound aptamers transfer their conformation between open and closed states. The ligand binding obviously affects the conformational change. The conformational states of the aptamer are associated with the distance between the mass center of two key nucleotides (U51 and A52) and the mass center of the other two key nucleotides (C74 and C75). The results suggest that the dynamical character of the binding pocket would affect its biofunction. To design new ligands of the adenine riboswitch, it is recommended to consider the binding affinities of the ligand and the conformational change of the ligand binding pocket.
Topics: Adenine; Bacterial Proteins; Guanine; Ligands; Models, Molecular; Molecular Dynamics Simulation; Mutation; Nucleic Acid Conformation; Purines; Pyrimidines; Riboswitch
PubMed: 32168940
DOI: 10.3390/ijms21061926