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1.
Chem Pharm Bull (Tokyo) ; 68(1): 77-90, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31902903

RESUMO

Novel 3,5-dimethylpyridin-4(1H)-one scaffold compounds were synthesized and evaluated as AMP-activated protein kinase (AMPK) activators. Unlike direct AMPK activators, this series of compounds showed selective cell growth inhibitory activity against human breast cancer cell lines. By optimizing the lead compound (4a) from our library, 2-[({1'-[(4-fluorophenyl)methyl]-2-methyl-1',2',3',6'-tetrahydro[3,4'-bipyridin]-6-yl}oxy)methyl]-3,5-dimethylpyridin-4(1H)-one (25) was found to have potent AMPK activating activity. Compound 25 also showed good aqueous solubility while maintaining the unique selectivity in cell growth inhibitory activity.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Piridonas/química , Proteínas Quinases Ativadas por AMP/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Humanos , Piridonas/síntese química , Piridonas/farmacologia , Solubilidade , Relação Estrutura-Atividade
2.
Chem Asian J ; 15(3): 360-364, 2020 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-31944607

RESUMO

A RhIII -catalyzed strategy was developed for the rapid construction of highly substituted 2-pyridone scaffolds using α,ß-unsaturated oximes and fluorinated diazomalonate. The reaction proceeds through direct, site-selective alkylation based on migratory insertion and subsequent cyclocondensation. A wide substrate scope with different functional groups was explored. The requirement of fluorinated diazomalonate was explored for this transformation. The developed methodology was further extended with the synthesis of the bioactive compound.


Assuntos
Diazometano/química , Piridonas/química , Ródio/química , Catálise , Halogenação , Cinética , Piridonas/síntese química
3.
Biomed Chromatogr ; 34(1): e4719, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31634417

RESUMO

A quality by design (QbD) based high-resolution HPLC method is described for determination of impurities in apixaban (APX) in the tablet dosage form. Employing a simple and stability-indicating HPLC method, nine known impurities were quantified with good peak resolution. Mobile phase A (MP-A) was prepared with buffer and acetonitrile 90:10 v/v, while mobile phase B (MP-B) contained water and acetonitrile 10:90 v/v. The gradient program was 0 min, MP-A 75%, B 25%; 20 min, MP-A 65%, B 35%; 30 min, MP-A 40%, B 60%; 40min, MP-A 40%, B 60%; 42 min, MP-A 75%, B 25%; and 50 min, MP-A 75%, B 25%. The chromatographic separation was achieved using a Zorbax RX C18 250 × 4.6 mm column, 5 µm (1.0 ml min-1 , 280 nm, 50 µl) and a column temperature of 40°C. Several separation studies were carried out using design of experiments to optimize the method. Validation results confirm the applicability of the developed method for quality analysis and stability studies of the regular product on the manufacturing stream.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Cromatografia de Fase Reversa/métodos , Contaminação de Medicamentos , Pirazóis/análise , Pirazóis/química , Piridonas/análise , Piridonas/química , Estabilidade de Medicamentos , Limite de Detecção , Modelos Lineares , Reprodutibilidade dos Testes , Comprimidos
4.
Eur J Med Chem ; 186: 111855, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31740051

RESUMO

There is an increasing interest in the field of cancer therapy for small compounds targeting pyrimidine biosynthesis, and in particular dihydroorotate dehydrogenase (DHODH), the fourth enzyme of this metabolic pathway. Three available DHODH structures, featuring three different known inhibitors, were used as templates to screen in silico an original chemical library from Erevan University. This process led to the identification of P1788, a compound chemically related to the alkaloid cerpegin, as a new class of pyrimidine biosynthesis inhibitors. In line with previous reports, we investigated the effect of P1788 on the cellular innate immune response. Here we show that pyrimidine depletion by P1788 amplifies cellular response to both type-I and type II interferons, but also induces DNA damage as assessed by γH2AX staining. Moreover, the addition of inhibitors of the DNA damage response led to the suppression of the P1788 stimulatory effects on the interferon pathway. This demonstrates that components of the DNA damage response are bridging the inhibition of pyrimidine biosynthesis by P1788 to the interferon signaling pathway. Altogether, these results provide new insights on the mode of action of novel pyrimidine biosynthesis inhibitors and their development for cancer therapies.


Assuntos
Furanos/farmacologia , Piridinas/farmacologia , Piridonas/farmacologia , Pirimidinas/antagonistas & inibidores , Células Cultivadas , Dano ao DNA , Relação Dose-Resposta a Droga , Furanos/síntese química , Furanos/química , Células HEK293 , Humanos , Modelos Moleculares , Estrutura Molecular , Piridinas/síntese química , Piridinas/química , Piridonas/química , Pirimidinas/biossíntese , Relação Estrutura-Atividade
5.
Chem Commun (Camb) ; 56(1): 74-77, 2020 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-31790117

RESUMO

We developed a new method for the de novo formation of fluorophores based on citrate (DNFC) in biological samples. Use of an amide coupling reagent and microwave irradiation greatly facilitates the fluorophore formation on peptides and proteins with N-terminal cysteine or serine. Since N-terminal cysteine and serine can form thiazolopyridone- or oxazolopyridone-based fluorophores emitting blue and green fluorescence, respectively, by the DNFC staining, each organelle, cell and tissue exhibited a characteristic fluorescence distribution. The DNFC staining is able to provide a new potential protocol for future cell imaging, histology and diagnosis.


Assuntos
Corantes Fluorescentes/metabolismo , Sondas Moleculares/metabolismo , Peptídeos/metabolismo , Proteínas/metabolismo , Animais , Linhagem Celular Tumoral , Ácido Cítrico/metabolismo , Cisteína/química , Fluorescência , Corantes Fluorescentes/química , Células HEK293 , Humanos , Camundongos , Microscopia Confocal/métodos , Microscopia de Fluorescência/métodos , Sondas Moleculares/química , Células NIH 3T3 , Peptídeos/química , Estudo de Prova de Conceito , Proteínas/química , Piridonas/química , Piridonas/metabolismo , Serina/química , Tiazóis/química , Tiazóis/metabolismo
6.
Biochem Med (Zagreb) ; 30(1): 010702, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31839722

RESUMO

Introduction: Clinical application of rivaroxaban and apixaban does not require therapeutic monitoring. Commercial anti-activated factor X (anti-FXa) inhibition methods for all anti-FXa drugs are based on the same principle, so there are attempts to evaluate potential clinical application of heparin-calibrated anti-FXa assay as an alternative method for direct FXa inhibitors. We aimed to evaluate relationship between anti-FXa methods calibrated with low molecular weight heparin (LMWH) and with drug specific calibrators, and to determine whether commercial LMWH anti-FXa assay can be used to exclude the presence of clinically relevant concentrations of rivaroxaban and apixaban. Materials and methods: Low molecular weight heparin calibrated reagent (Siemens Healthineers, Marburg, Germany) was used for anti-FXa activity measurement. Innovance heparin (Siemens Healthineers, Marburg, Germany) calibrated with rivaroxaban and apixaban calibrators (Hyphen BioMed, Neuville-sur-Oise, France) was used for quantitative determination of FXa inhibitors. Results: Analysis showed good agreement between LMWH calibrated and rivaroxaban calibrated activity (κ = 0.76) and very good agreement with apixaban calibrated anti-Xa activity (κ = 0.82), respectively. Low molecular weight heparin anti-FXa activity cut-off values of 0.05 IU/mL and 0.1 IU/mL are suitable for excluding the presence of clinically relevant concentrations (< 30 ng/mL) of rivaroxaban and apixaban, respectively. Concentrations above 300 ng/mL exceeded upper measurement range for LMWH anti-FXa assay and cannot be determined by this method. Conclusion: Low molecular weight heparin anti-FXa assay can be used in emergency clinical conditions for ruling out the presence of clinically relevant concentrations of rivaroxaban and apixaban. However, use of LMWH anti-FXa assay is not appropriate for their quantitative determination as an interchangeable method.


Assuntos
Anticoagulantes/química , Testes de Coagulação Sanguínea/métodos , Heparina de Baixo Peso Molecular/química , Pirazóis/química , Piridonas/química , Rivaroxabana/química , Anticoagulantes/metabolismo , Área Sob a Curva , Testes de Coagulação Sanguínea/normas , Calibragem , Compostos Cromogênicos/química , Fator Xa/química , Fator Xa/metabolismo , Inibidores do Fator Xa/química , Inibidores do Fator Xa/metabolismo , Heparina de Baixo Peso Molecular/metabolismo , Humanos , Pirazóis/metabolismo , Piridonas/metabolismo , Curva ROC
7.
J Chromatogr B Analyt Technol Biomed Life Sci ; 1134-1135: 121877, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31785533

RESUMO

PH-797804 is a selective p38 MAPK inhibitor currently evaluated in clinical trials. This study described a validated UPLC-MS/MS combined with one-step protein precipitation extraction method for determination of PH-797804 in rat plasma. After protein precipitation with acetonitrile, the plasma sample was analyzed by a Waters Acquity UPLC BEH C18 column, with acetonitrile/0.1% formic acid (70:30) as the mobile phase. Mass spectrometric detection was conducted with a Waters TQ-S mass spectrometer via electrospray, positive-mode ionization, with target quantitative ion pairs of m/z 476.895 → 126.860 for PH-797804, and 482.726 → 269.707 for regorafenib (internal standard). The assay showed a good linearity over the range of 1.0-1600 ng/mL, with acceptable accuracy (RE from -7.8% to 8.5%) and precision (RSD within 8.4%) values. Recovery from plasma was 81.4-90.2% and matrix effect was negligible (93.3-95.4%). The validated method presented a quantification method of PH-797804 in detail for the first time and utilized for a pharmacokinetic study at three dose concentrations after oral administration in Wistar rats. The pharmacokinetic profiles of PH-797804 showed a linear relationship between drug concentration and dose, which provided dosage and safety information on further clinical studies.


Assuntos
Benzamidas/sangue , Benzamidas/farmacocinética , Cromatografia Líquida de Alta Pressão/métodos , Piridonas/sangue , Piridonas/farmacocinética , Espectrometria de Massas em Tandem/métodos , Animais , Benzamidas/química , Modelos Lineares , Masculino , Piridonas/química , Ratos , Ratos Wistar , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores
8.
Eur J Med Chem ; 184: 111728, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31610375

RESUMO

A new series of 3-(((9H-purin-6-yl)amino)methyl)-4,6-dimethylpyridin-2(1H)-one derivatives were designed, synthesized and demonstrated to act as tubulin polymerization inhibitors. These new derivatives showed significant antitumor activities, among which SKLB0533 demonstrated to be the most potent compound, with IC50 values ranging from 44.5 to 135.5 nM against seven colorectal carcinoma (CRC) cell lines. Remarkably, SKLB0533 exhibited no activity against other potential targets, such as 420 kinases and EZH2. Besides, SKLB0533 inhibited tubulin polymerization, arrested the cell cycle at the G2/M phase and induced apoptosis in CRC cells. Furthermore, SKLB0533 suppressed tumour growth in the HCT116 xenograft model without inducing notable major organ-related toxicity, suggesting that SKLB0533 could be used as a promising lead compound for the development of new antitumor agents.


Assuntos
Antineoplásicos/farmacologia , Descoberta de Drogas , Purinas/farmacologia , Piridonas/farmacologia , Tubulina (Proteína)/metabolismo , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Modelos Moleculares , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Polimerização/efeitos dos fármacos , Purinas/síntese química , Purinas/química , Piridonas/síntese química , Piridonas/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas
9.
Eur J Med Chem ; 183: 111734, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31569004

RESUMO

Despite the initial benefit demonstrated in clinical setting with ALK inhibitors, the challenging resistant mutants (F1174L, L1196M and G1202R) invariably developed. In this work, a series of 2-aminopyridine derivatives were designed and synthesized by C-5 position incorporation of a 2-pyridone moiety and bioisosteric replacement of the C-3 position linkers. Optimization of the 2-aminopyridine derivatives led to the identification of hit 18d displaying a significant growth inhibition against a variety of ALK-addicted cancer cells. Especially in the case of ALK-positive Karpas-299 cell, 18d exhibited excellent anti-proliferative potency with an IC50 value of about 40 nM. Moreover, 18d demonstrated encouraging activities against wild-type ALK (19 nM), ROS1 (2.3 nM) as well as challenging crizotinib-resistant ALKL1196M and ALKG1202R mutants with IC50 values of 45 nM and 22 nM, respectively. Additionally flow cytometric analysis indicates that 18d inhibited Karpas-299 cell viability via G1 phase arrest. Taken together, this work provided a promising ALK inhibitor to circumvent the clinical crizotinib-resistant mutants.


Assuntos
Aminopiridinas , Quinase do Linfoma Anaplásico/antagonistas & inibidores , Crizotinibe/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Inibidores de Proteínas Quinases , Piridonas/química , Aminopiridinas/síntese química , Aminopiridinas/química , Aminopiridinas/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Mutação , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia
10.
J Mol Model ; 25(10): 312, 2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31511986

RESUMO

Perampanel approved by FDA in 2012 is a first-in-class antiepileptic drug which inhibits α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor currents. It is markedly more active than many of its close analogs, and the reasons for this activity difference are not quite clear. Recent crystallographic studies allowed the authors to identify the location of its binding site. Unfortunately, the resolution is low, and the detailed description of perampanel binding mode is still in part speculative. Here we provide a detailed DFT-level conformational analysis of perampanel in a vacuum and in the solvents, mimicking the protein environment, followed by quantum theory of atoms in molecules (QTAIM), non-covalent interactions (NCI), and natural bond orbital (NBO) analyses. The findings indicate the electrostatic nature of the intramolecular interactions which contribute to energy differences of the conformations in a vacuum whereas the increase of dielectric constant leads to the energy equalization of conformations. Based on these results, the docking study was performed to investigate possible binding modes of perampanel and its close analogs in AMPA receptors. The influence of the pyridine nitrogen and cyano group position was explained based on the results of conformational analysis and molecular docking. These findings may contribute to the design of novel antiepileptic drugs and the development of novel approaches to treat neurodegenerative diseases and major depressive disorder.


Assuntos
Teoria da Densidade Funcional , Antagonistas de Aminoácidos Excitatórios/química , Conformação Molecular , Simulação de Acoplamento Molecular , Piridonas/química , Rotação , Eletricidade Estática , Termodinâmica
11.
Molecules ; 24(15)2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31370295

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease with poor prognosis and progression to lung fibrosis related to genetic factors as well as environmental factors. In fact, it was discovered that in South Korea many people who used humidifier disinfectants containing polyhexamethylene guanidine (PHMG), died of lung fibrosis. Currently two anti-fibrotic drugs, pirfenidone and nintedanib, have been approved by the FDA, but unfortunately, do not cure the disease. Since the histone deacetylase (HDAC) activity is associated with progression to chronic diseases and with fibrotic phenomena in the kidney, heart and lung tissues, we investigated the anti-fibrotic effects of CG-745, an HDAC inhibitor. After lung fibrosis was induced in two animal models by bleomycin and PHMG instillation, the regulation of fibrosis and epithelial mesenchymal transition (EMT)-related markers was assessed. CG-745 exhibited potent prevention of collagen production, inflammatory cell accumulation, and cytokines release in both models. Additionally, N-cadherin and vimentin expression were lowered significantly by the treatment of CG-745. The anti-fibrotic effects of CG-745 proven by the EMT regulation may suggest a potential therapeutic effect of CG-745 on lung fibrosis.


Assuntos
Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/efeitos dos fármacos , Fibrose Pulmonar Idiopática/tratamento farmacológico , Pulmão/efeitos dos fármacos , Animais , Biguanidas/toxicidade , Bleomicina/toxicidade , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Inibidores de Histona Desacetilases/química , Histona Desacetilases/química , Humanos , Fibrose Pulmonar Idiopática/induzido quimicamente , Fibrose Pulmonar Idiopática/patologia , Indóis/química , Indóis/uso terapêutico , Pulmão/patologia , Camundongos , Piridonas/química , Piridonas/uso terapêutico , República da Coreia/epidemiologia
12.
J Enzyme Inhib Med Chem ; 34(1): 1489-1497, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31416364

RESUMO

MAO-B leads to an increase in the levels of hydrogen peroxide and oxidative free radicals, which contribute to the aetiology of the AD. Thus, both iron ion chelators and MAO-B inhibitors can be used to treat AD. Taking the coumarin derivatives and hydroxypyridinones as the lead compounds, a series of dual-target hybrids were designed and synthesised by Click Chemistry. The compounds were biologically evaluated for their iron ion chelating and MAO-B inhibitory activity. Most of the compounds displayed excellent iron ion chelating activity and moderate to good anti-MAO-B activity. Compounds 27b and 27j exhibited the most potent MAO-B inhibitory activity, with IC50 values of 0.68 and 0.86 µM, respectively. In summary, these dual-target compounds have the potential anti-AD activity.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Cumarínicos/farmacologia , Quelantes de Ferro/farmacologia , Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/metabolismo , Piridonas/farmacologia , Doença de Alzheimer/metabolismo , Cumarínicos/síntese química , Cumarínicos/química , Relação Dose-Resposta a Droga , Humanos , Quelantes de Ferro/síntese química , Quelantes de Ferro/química , Estrutura Molecular , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/química , Piridonas/síntese química , Piridonas/química , Relação Estrutura-Atividade
13.
Environ Sci Pollut Res Int ; 26(30): 30782-30793, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31444723

RESUMO

Reliable estimate of the release of adsorbed pesticide from soil particles is crucial to evaluating the pesticide fate, mobility, efficacy, and remediation. In this study, the dynamics of TCP (3,5,6-trichloro-2-pyridinol) desorption, the main degradation product of chlorpyrifos and triclopyr, is explored quantitatively by the breakthrough curve (BTC) experiment with the tracer of Br- in the loamy farmland purple soil sampled from Sichuan Basin of southwestern China. TCP in the outflow originates from two sources: dissolved TCP in pore water and desorbed TCP from soil particles by infiltrating water. The dissolved TCP is considered proportional to the amount of Br- because both TCP and Br- are dissolved in water uniformly. According to the mass balance equation, the desorbed TCP are estimated and the typical patterns of dynamic TCP desorption are revealed. Characteristics of TCP desorption are compared between packed and undisturbed soil columns as well as between different planting types. The dynamics of the proportion of desorbed TCP during the breakthrough process are characterized. In particular, the high heterogeneity of the undisturbed soil may be responsible for the observed fluctuation of desorbed TCP in the outflow. Additionally, the obtained increase-decrease pattern of the desorbed rate of TCP released from the soil shows that most models proposed to simulate the desorption processes are not appropriate, because these models display a monotone decreasing trend, such as the Noyes-Whitney Rule and other release kinetic models (zero order, first order, Higuchi and Korsmeyer-Peppas model, etc.). After a comparison among linear model, Gamma distribution and Weibull distribution, the CDF of gamma distribution is identified as a better method to describe the proportion of desorbed TCP in outflow. Therefore, this study provides an alternative method to measure the dynamic desorption process of TCP in different environment of the purple soil, and their affecting factors are also identified. These results are useful in quantifying the leaching of the TCP in the field, in support of the prevention of agricultural non-point pollution of pesticides.


Assuntos
Piridonas/química , Poluentes do Solo/química , Adsorção , China , Fazendas , Herbicidas/química , Cinética , Poluentes do Solo/metabolismo
14.
Org Biomol Chem ; 17(28): 6866-6871, 2019 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-31268109

RESUMO

The bifunctional ligand p-SCN-Bn-HOPO, which has four 1,2-hydroxypyridinone groups on a spermine backbone with an isothiocyanate linker, has been shown to be an efficient and stable chelator for Zr(iv) and, more importantly, the radioisotope 89Zr for use in radiolabeling antibodies for positron emission tomography (PET) imaging. Previous studies of 89Zr-HOPO-trastuzumab in mice showed low background, good tumor to organ contrast, and very low bone uptake which show p-SCN-Bn-HOPO to be an important next-generation bifunctional chelator for radioimmunoPET imaging with 89Zr. However, the reported synthesis of p-SCN-Bn-HOPO involves nine steps and multiple HPLC purifications with an overall yield of about 1.4%. Herein we report an improved and efficient synthesis of p-SCN-Bn-HOPO in four steps with 14.3% overall yield which will improve its availability for further biological studies and wider application in PET imaging. The new synthetic route also allows variation in linker length and chemistries which may be helpful in modifying in vivo clearance behaviors of future agents.


Assuntos
Quelantes/síntese química , Piridonas/química , Espermina/química , Quelantes/química , Estrutura Molecular , Tomografia por Emissão de Pósitrons
15.
Mar Drugs ; 17(7)2019 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-31277263

RESUMO

Four phenylfuropyridone racemates, (±)-tersones A-C and E (1-3, 5), one phenylpyridone racemate, (±)-tersone D (4), one new pyridine alkaloid, tersone F (6), single new phenylfuropyridone, tersone G (7) and two known analogs 8 and 9 were isolated from the deep-sea fungus Phomopsis tersa. Their structures and absolute configurations were characterized on the basis of comprehensive spectroscopic analyses, single-crystal X-ray diffraction experiments, and electronic circular dichroism (ECD) calculations. Moreover, compounds 1-9 were evaluated for in vitro antimicrobial and cytotoxic activity. Compounds 5b and 8b exhibited antibacterial activity against S. aureus with the MIC value of 31.5 µg/mL, while compound 5b showed cytoxic activities against SF-268, MCF-7, HepG-2 and A549 cell lines with IC50 values of 32.0, 29.5, 39.5 and 33.2 µM, respectively.


Assuntos
Alcaloides/química , Organismos Aquáticos/química , Fungos/química , Piridonas/química , Células A549 , Alcaloides/farmacologia , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Linhagem Celular Tumoral , Células Hep G2 , Humanos , Células MCF-7 , Testes de Sensibilidade Microbiana/métodos , Piridonas/farmacologia , Staphylococcus aureus/efeitos dos fármacos
16.
Nat Commun ; 10(1): 2570, 2019 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-31239437

RESUMO

Searching for actinide decorporation agents with advantages of high decorporation efficiency, minimal biological toxicity, and high oral efficiency is crucial for nuclear safety and the sustainable development of nuclear energy. Removing actinides deposited in bones after intake is one of the most significant challenges remaining in this field because of the instantaneous formation of highly stable actinide phosphate complexes upon contact with hydroxyapatite. Here we report a hydroxypyridinone-based ligand (5LIO-1-Cm-3,2-HOPO) exhibiting stronger affinity for U(VI) compared with the reported tetradentate hydroxypyridinone ligands. This is further revealed by the first principles calculation analysis on bonding between the ligand and uranium. Both in vitro uranium removal assay and in vivo decorporation experiments with mice show that 5LIO-1-Cm-3,2-HOPO can remove uranium from kidneys and bones with high efficiencies, while the decorporation efficiency is nearly independent of the treatment time. Moreover, this ligand shows a high oral decorporation efficiency, making it attractive for practical applications.


Assuntos
Osso e Ossos/química , Quelantes/administração & dosagem , Piridonas/administração & dosagem , Lesões por Radiação/terapia , Urânio/toxicidade , Adsorção , Animais , Osso e Ossos/metabolismo , Quelantes/química , Feminino , Humanos , Rim/química , Rim/metabolismo , Ligantes , Camundongos , Piridonas/química , Lesões por Radiação/induzido quimicamente , Lesões por Radiação/metabolismo , Urânio/química , Urânio/metabolismo
17.
Biomed Chromatogr ; 33(10): e4620, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31215048

RESUMO

A simple, highly sensitive and rapid method for quantification of olprinone (phosphodiesterase 3 inhibitor) in rabbit plasma using liquid chromatography-tandem mass spectrometry with electrospray was developed. An aliquot of 50 µL of plasma sample was cleaned up and extracted using Ostro™ 96-well plate followed by dilution. Chromatographic separation of olprinone and olprinone-d3 was carried out on a CORTECS® T3 column within 3 min. Detection was achieved using a triple quadrupole mass spectrometer employing electrospray ionization operated in positive ion multiple reaction monitoring mode using the transitions m/z 251.07 → m/z 155.06 and m/z 254.21 → m/z 158.10 for olprinone and olprinone-d3, respectively. The method was validated according to US Food and Drug Administration guideline for bioanalytical methods, and showed excellent linearity in the range 10.0-2000.0 ng/mL with coefficient of determination >0.99. The intra- and inter-day precisions (CV) were <5.1% and the accuracies were within the range 99.7-103.2% at all quality control concentrations. Furthermore, olprinone was stable under various stability conditions. The developed method was used for quantification of olprinone in rabbit plasma after its intravenous administration at the dose of 1 mg/kg in order to better understand the metabolism of olprinone in a rabbit model of lung injury.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Imidazóis/sangue , Piridonas/sangue , Espectrometria de Massas em Tandem/métodos , Animais , Estabilidade de Medicamentos , Imidazóis/química , Imidazóis/farmacocinética , Limite de Detecção , Modelos Lineares , Piridonas/química , Piridonas/farmacocinética , Coelhos , Reprodutibilidade dos Testes
18.
Org Biomol Chem ; 17(25): 6201-6214, 2019 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-31179474

RESUMO

We have recently reported computational models for prediction of cell-based anticancer activity using machine learning methods. Herein, we have developed an integrated strategy to discover new anticancer agents using a cascade of the established screening models. Application of this strategy identified 17 compounds with antitumor activity. Among these compounds, h2 (containing a pyrazolo[3,4-b]pyridin-6-one scaffold) exhibited anticancer activity against six tumor cell lines, including MDA-MB-231, HeLa, MCF-7, HepG2, CNE2 and HCT116, with IC50 values of 13.37, 13.04, 15.45, 7.05, 9.30 and 8.93 µM. Subsequently, a total of 61 h2 analogues were obtained by similarity searching and tested for their anticancer activities. I2 was identified as a novel anticancer agent having activity against MDA-MB-231, HeLa, MCF-7, HepG2, CNE2 and HCT116 tumor cell lines with IC50 values of 3.30, 5.04, 5.08, 3.71, 2.99 and 5.72 µM. I2 also showed potent cytotoxicity against adriamycin-resistant human breast and hepatocarcinoma cells. Further investigation revealed that I2 inhibited the microtubule polymerization by binding to the colchicine site, resulting in inhibition of cell migration, cell cycle arrest in the G2/M phase and apoptosis of cancer cells. Finally, molecular docking and molecular dynamics provided insights into the binding interactions of I2 with tubulin. This study identified I2 as a novel starting point for further development of anticancer agents that target tubulin.


Assuntos
Antineoplásicos/farmacologia , Pirazóis/farmacologia , Piridonas/farmacologia , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Sítios de Ligação , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Descoberta de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Pirazóis/química , Piridonas/química , Relação Estrutura-Atividade , Tubulina (Proteína)/química , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacologia
19.
J Pharmacol Exp Ther ; 370(2): 269-277, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31175220

RESUMO

Cabotegravir, a novel integrase inhibitor under development for treatment and prevention of HIV, is primarily metabolized by UDP-glucuronosyltransferase (UGT)1A1 and UGT1A9 to a direct ether glucuronide metabolite. The aim of these studies was to elucidate the mechanistic basis of cabotegravir-glucuronide disposition in humans. Cabotegravir glucuronidation was predominantly hepatic (>95%) with minimal intestinal and renal contribution. Rat liver perfusions demonstrated that cabotegravir-glucuronide formed in the liver undergoes comparable biliary and sinusoidal excretion, consistent with high concentrations of the glucuronide in human bile and urine. Cabotegravir-glucuronide biliary excretion was mediated by multidrug resistance-associated protein (MRP)2 (not transported by breast cancer resistance protein or P-glycoprotein), whereas hepatic basolateral excretion into sinusoidal blood was via both MRP3 [fraction transport (Ft) = 0.81] and MRP4 (Ft = 0.19). Surprisingly, despite high urinary recovery of hepatically-formed cabotegravir-glucuronide, metabolite levels in circulation were negligible, a phenomenon consistent with rapid metabolite clearance. Cabotegravir-glucuronide was transported by hepatic uptake transporters organic anion-transporting (OAT) polypeptide (OATP)1B1 and OATP1B3; however, metabolite clearance by hepatic uptake from circulation was low (2.7% of hepatic blood flow) and unable to explain the minimal systemic exposure. Instead, circulating cabotegravir-glucuronide undergoes efficient renal clearance, where uptake into the proximal tubule would be mediated by OAT3 (not transported by OAT1), and subsequent secretion into urine by MRP2 (Ft = 0.66) and MRP4 (Ft = 0.34). These studies provide mechanistic insight into the disposition of cabotegravir-glucuronide, a hepatically-formed metabolite with appreciable urinary recovery and minimal systemic exposure, including fractional contribution of redundant transporters to any given process based on quantitative proteomics. SIGNIFICANCE STATEMENT: The role of membrane transporters in metabolite disposition, especially glucuronides, and as sites of unexpected drug-drug interactions, which alter drug efficacy and safety, has been established. Cabotegravir-glucuronide, formed predominantly by direct glucuronidation of parent drug in liver, was the major metabolite recovered in human urine (27% of oral dose) but was surprisingly not detected in systemic circulation. To our knowledge, this is the first mechanistic description of this phenomenon for a major hepatically-formed metabolite to be excreted in the urine to a large extent, but not circulate at detectable levels. The present study elucidates the mechanistic basis of cabotegravir-glucuronide disposition in humans. Specific hepatic and renal transporters involved in the disposition of cabotegravir-glucuronide, with their fractional contribution, have been provided.


Assuntos
Glucuronídeos/química , Inibidores de Integrase/química , Inibidores de Integrase/metabolismo , Piridonas/química , Piridonas/metabolismo , Animais , Transporte Biológico , Células HEK293 , Hepatócitos/metabolismo , Humanos , Fígado/citologia , Fígado/metabolismo , Microssomos/metabolismo , Ratos
20.
Sensors (Basel) ; 19(9)2019 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-31052519

RESUMO

A small extent of endogenous labile zinc is involved in many vital physiological roles in living systems. However, its detailed functions have not been fully elucidated. In this study, we developed a novel biheteroaryl-based low molecular weight fluorescent sensor, 3-(phenylsulfonyl)-pyrazine-pyridone (5b), and applied it for the detection of endogenous labile zinc ions from lung cancer cells during apoptosis. The electron-withdrawing property of the sulfonyl group between the phenyl ring as an electron donor and the pyridone ring as a fluorophore inhibited the intramolecular charge transfer state, and the background fluorescence of the sensor was decreased in aqueous media. From the structure-fluorescence relationship analysis of the substituent effects with/without Zn2+, compound 5b acting as a sensor possessed favorable properties, including a longer emission wavelength, a large Stokes shift (over 100 nm), a large fluorescence enhancement in response to Zn2+ under physical conditions, and good cell membrane permeability in living cells. Fluorescence imaging studies of human lung adenocarcinoma cells (A549) undergoing apoptosis revealed that compound 5b could detect endogenous labile zinc ions. These experiments suggested that the low molecular weight compound 5b is a potential fluorescence sensor for Zn2+ toward understanding its functions in living systems.


Assuntos
Técnicas Biossensoriais , Íons/isolamento & purificação , Neoplasias Pulmonares/química , Zinco/isolamento & purificação , Humanos , Íons/química , Neoplasias Pulmonares/diagnóstico , Imagem Óptica , Pirazinas/síntese química , Pirazinas/química , Piridonas/síntese química , Piridonas/química , Água/química , Zinco/química
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