RESUMEN
Pyrimidine nucleotide biosynthesis is a druggable metabolic dependency of cancer cells, and chemotherapy agents targeting pyrimidine metabolism are the backbone of treatment for many cancers. Dihydroorotate dehydrogenase (DHODH) is an essential enzyme in the de novo pyrimidine biosynthesis pathway that can be targeted by clinically approved inhibitors. However, despite robust preclinical anticancer efficacy, DHODH inhibitors have shown limited single-agent activity in phase 1 and 2 clinical trials. Therefore, novel combination therapy strategies are necessary to realize the potential of these drugs. To search for therapeutic vulnerabilities induced by DHODH inhibition, we examined gene expression changes in cancer cells treated with the potent and selective DHODH inhibitor brequinar (BQ). This revealed that BQ treatment causes upregulation of antigen presentation pathway genes and cell surface MHC class I expression. Mechanistic studies showed that this effect is (1) strictly dependent on pyrimidine nucleotide depletion, (2) independent of canonical antigen presentation pathway transcriptional regulators, and (3) mediated by RNA polymerase II elongation control by positive transcription elongation factor B (P-TEFb). Furthermore, BQ showed impressive single-agent efficacy in the immunocompetent B16F10 melanoma model, and combination treatment with BQ and dual immune checkpoint blockade (anti-CTLA-4 plus anti-PD-1) significantly prolonged mouse survival compared to either therapy alone. Our results have important implications for the clinical development of DHODH inhibitors and provide a rationale for combination therapy with BQ and immune checkpoint blockade.
Asunto(s)
Presentación de Antígeno , Dihidroorotato Deshidrogenasa , Inhibidores de Puntos de Control Inmunológico , Animales , Ratones , Humanos , Presentación de Antígeno/efectos de los fármacos , Línea Celular Tumoral , Inhibidores de Puntos de Control Inmunológico/farmacología , Quinoxalinas/farmacología , Inhibidores Enzimáticos/farmacología , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/antagonistas & inhibidores , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/metabolismo , Ratones Endogámicos C57BL , Melanoma Experimental/tratamiento farmacológico , Melanoma Experimental/inmunología , Compuestos de Bifenilo , QuinaldinasRESUMEN
High-grade B-cell lymphoma (HGBCL), the subtype of non-Hodgkin lymphoma, to be relapsed or refractory in patients after initial therapy or salvage chemotherapy. Dual dysregulation of MYC and BCL2 is one of the important pathogenic mechanisms. Thus, combined targeting of MYC and BCL2 appears to be a promising strategy. Dihydroorotate dehydrogenase (DHODH) is the fourth rate-limiting enzyme for the de novo biosynthesis of pyrimidine. It has been shown to be a potential therapeutic target for multiple diseases. In this study, the DHODH inhibitor brequinar exhibited growth inhibition, cell cycle blockade, and apoptosis promotion in HGBCL cell lines with MYC and BCL2 rearrangements. The combination of brequinar and BCL2 inhibitors venetoclax had a synergistic inhibitory effect on the survival of DHL cells through different pathways. Venetoclax could upregulate MCL-1 and MYC expression, which has been reported as a resistance mechanism of BCL2 inhibitors. Brequinar downregulated MCL-1 and MYC, which could potentially overcome drug resistance to venetoclax in HGBCL cells. Furthermore, brequinar could downregulate a broad range of genes, including ribosome biosynthesis genes, which might contribute to its anti-tumor effects. In vivo studies demonstrated synergetic tumor growth inhibition in xenograft models with brequinar and venetoclax combination treatment. These results provide preliminary evidence for the rational combination of DHODH and BCL2 blockade in HGBCL with abnormal MYC and BCL2.
Asunto(s)
Compuestos Bicíclicos Heterocíclicos con Puentes , Dihidroorotato Deshidrogenasa , Sinergismo Farmacológico , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH , Proteínas Proto-Oncogénicas c-bcl-2 , Proteínas Proto-Oncogénicas c-myc , Sulfonamidas , Ensayos Antitumor por Modelo de Xenoinjerto , Humanos , Animales , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Ratones , Sulfonamidas/farmacología , Sulfonamidas/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Proteínas Proto-Oncogénicas c-myc/antagonistas & inhibidores , Línea Celular Tumoral , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/antagonistas & inhibidores , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/genética , Apoptosis/efectos de los fármacos , Linfoma de Células B/tratamiento farmacológico , Linfoma de Células B/genética , Linfoma de Células B/patología , Linfoma de Células B/metabolismo , Reordenamiento Génico , Proliferación Celular/efectos de los fármacos , Compuestos de Bifenilo , QuinaldinasRESUMEN
Mitochondrial therapy is a promising new strategy that offers the potential to achieve precise disease diagnosis or maximum therapeutic response. However, versatile mitochondrial theranostic platforms that integrate biomarker detection and therapy have rarely been exploited. Here, we report a charge-reversal nanomedicine activated by an acidic microenvironment for mitochondrial microRNA (mitomiR) detection and ion-interference therapy. The transporter liposome (DD-DC) was constructed from a pH-responsive polymer and a positively charged phospholipid, encapsulating NaCl nanoparticles with coloading of the aggregation-induced emission (AIE) fluorogens AIEgen-DNA/G-quadruplexes precursor and brequinar (NAB@DD-DC). The negatively charged nanomedicine ensured good blood stability and high tumor accumulation, while the charge-reversal to positive in response to the acidic pH in the tumor microenvironment (TME) and lysosomes enhanced the uptake by tumor cells and lysosome escape, achieving accumulation in mitochondria. The subsequently released Na+ in mitochondria not only contributed to the formation of mitomiR-494 induced G-quadruplexes for AIE imaging diagnosis but also led to an osmolarity surge that was enhanced by brequinar to achieve effective ion-interference therapy.
Asunto(s)
Compuestos de Bifenilo , G-Cuádruplex , MicroARNs , Nanopartículas , Neoplasias , Quinaldinas , Humanos , Cloruro de Sodio , Neoplasias/diagnóstico por imagen , Neoplasias/terapia , Mitocondrias , Concentración de Iones de Hidrógeno , Línea Celular Tumoral , Microambiente TumoralRESUMEN
Proteins play an important role in biological systems and several proteins are used in diagnosis, therapy, food industry etc. Thus, knowledge about the physical properties of the proteins is of utmost importance, which will aid in understanding their function and subsequent applications. The melting temperature (Tm) of a protein is one of the essential parameters which gives information about the stability of a protein under different conditions. In the present study, we have demonstrated a method for determining the Tm of proteins using the supramolecular interaction between Quinaldine Red (QR) and proteins. Using this method, we have determined the Tm of 5 proteins and compared our results with established protocols. Our results showed good agreement with the other methods and published values. The method developed in this study is inexpensive, quick, and devoid of complex instruments and pre/post-treatment of the samples. In addition, this method can be adopted for high throughput in multi-plate mode. Thus, this study projects a new methodology for Tm determination of various proteins with user friendly operation.
Asunto(s)
Colorantes Fluorescentes , Quinaldinas , Temperatura , ProteínasRESUMEN
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19) and the associated global pandemic resulting in >400 million infections worldwide and several million deaths. The continued evolution of SARS-CoV-2 to potentially evade vaccines and monoclonal antibody (mAb)-based therapies and the limited number of authorized small-molecule antivirals necessitates the need for development of new drug treatments. There remains an unmet medical need for effective and convenient treatment options for SARS-CoV-2 infection. SARS-CoV-2 is an RNA virus that depends on host intracellular ribonucleotide pools for its replication. Dihydroorotate dehydrogenase (DHODH) is a ubiquitous host enzyme that is required for de novo pyrimidine synthesis. The inhibition of DHODH leads to a depletion of intracellular pyrimidines, thereby impacting viral replication in vitro. Brequinar (BRQ) is an orally available, selective, and potent low nanomolar inhibitor of human DHODH that has been shown to exhibit broad spectrum inhibition of RNA virus replication. However, host cell nucleotide salvage pathways can maintain intracellular pyrimidine levels and compensate for BRQ-mediated DHODH inhibition. In this report, we show that the combination of BRQ and the salvage pathway inhibitor dipyridamole (DPY) exhibits strong synergistic antiviral activity in vitro against SARS-CoV-2 by enhanced depletion of the cellular pyrimidine nucleotide pool. The combination of BRQ and DPY showed antiviral activity against the prototype SARS-CoV-2 as well as the Beta (B.1.351) and Delta (B.1.617.2) variants. These data support the continued evaluation of the combination of BRQ and DPY as a broad-spectrum, host-acting antiviral strategy to treat SARS-CoV-2 and potentially other RNA virus infections.
Asunto(s)
Tratamiento Farmacológico de COVID-19 , Virus ARN , Antivirales/farmacología , Antivirales/uso terapéutico , Compuestos de Bifenilo , Dipiridamol/farmacología , Humanos , Quinaldinas , SARS-CoV-2 , Replicación ViralRESUMEN
African swine fever virus (ASFV) is a double-stranded DNA virus that causes an acute and hemorrhagic disease in domestic swine, resulting in significant economic losses to the global porcine industry. The lack of vaccines and antiviral drugs highlights the urgent need for antiviral studies against ASFV. Here, we report that brequinar (BQR), which is a specific inhibitor of dihydroorotate dehydrogenase, robustly inhibits ASFV replication in Vero cells, as well as in porcine macrophages. We demonstrate that BQR exerts its antiviral activity in a dose-dependent manner through the depletion of pyrimidine pool. Although BQR does not affect the synthesis of an early viral protein, pI215L, the synthesis of late viral proteins, p17 and p72, is suppressed in the presence of BQR. We also show that BQR is able to induce cellular antiviral response in ASFV-infected macrophages by enhancing the expression of interferon-stimulated genes. Taken together, our study reveals that targeting nucleotide biosynthesis represents a promising strategy for developing antiviral agents against ASFV.
Asunto(s)
Virus de la Fiebre Porcina Africana , Fiebre Porcina Africana , Virus de la Fiebre Porcina Africana/fisiología , Animales , Antivirales/farmacología , Compuestos de Bifenilo , Chlorocebus aethiops , Quinaldinas , Porcinos , Células Vero , Proteínas Virales/farmacología , Replicación ViralRESUMEN
Tuberculosis (TB) has been described as a global health crisis since the second half of the 1990s. Mycobacterium tuberculosis (Mtb), the etiologic agent of TB in humans, is a very successful pathogen, being the main cause of death in the population among infectious agents. In 2019, it was estimated that around 10 million individuals were contaminated by this bacillus and about 1.2 million succumbed to the disease. In recent years, our research group has reported the design and synthesis of quinoline derivatives as drug candidates for the treatment of TB. These compounds have demonstrated potent and selective growth inhibition of drug-susceptible and drug-resistant Mtb strains. Herein, a new synthetic approach was established providing efficient and rapid access (15 min) to a series of 4-alkoxy-6-methoxy-2-methylquinolines using ultrasound energy. The new synthetic protocol provides a simple procedure utilizing an open vessel system that affords the target products at satisfactory yields (45-84%) and elevated purities (≥95%). The methodology allows the evaluation of a larger number of molecules in assays against the bacillus, facilitating the determination of the structure-activity relationship with a reduced environmental cost.
Asunto(s)
Antituberculosos/farmacología , Mycobacterium tuberculosis/efectos de los fármacos , Quinaldinas/farmacología , Ondas Ultrasónicas , Antituberculosos/síntesis química , Antituberculosos/química , Pruebas de Sensibilidad Microbiana , Quinaldinas/síntesis química , Quinaldinas/químicaRESUMEN
In this report, we describe a near-infrared fluorescent probe called quinaldine red (QR) which lights up the ß-sheet structure of amyloid fibrils. The photochemical and biophysical properties of QR along with other canonical amyloid probes in the presence of protein fibrils were investigated by using fluorescence spectroscopy, confocal fluorescent microscopy and isothermal titration calorimetry. Moreover, the binding sites and interaction mode between QR and insulin fibrils were calculated based on molecule docking. Among these amyloid probes, QR showed several advantages including strong supramolecular force, near-infrared emission, high sensitivity and resistance to bleaching. A linear response of the fluorescence intensity of QR towards fibril samples in the presence of sera was visualized in the range of 1-30 µM, with the limit of detection (LOD) of 2.31 µM. The recovery and relative standard deviation (RSD) of the proposed method for the determination of protein fibrils was 90.4%-99.2% and 3.05%-3.47%, respectively. Finally, QR can be fluorescently lighted up when meeting the aberrant protein aggregates of pathogenic mice. We recommend QR as a novel and excellent alternative tool for monitoring conformational transition of amyloid proteins.
Asunto(s)
Proteínas Amiloidogénicas/aislamiento & purificación , Técnicas Biosensibles , Colorantes Fluorescentes/química , Conformación Proteica en Lámina beta , Proteínas Amiloidogénicas/química , Proteínas Amiloidogénicas/ultraestructura , Animales , Rayos Infrarrojos , Ratones , Quinaldinas/química , Espectrometría de FluorescenciaRESUMEN
The chiral structure of antibiotic vancomycin (Van) was exploited as an innovative coordination sphere for the preparation of an IrCp* based hybrid catalysts. We found that Van is able to coordinate iridium (Ir(III)) and the complexation was demonstrated by several analytical techniques such as MALDI-TOF, UV, Circular dichroism (CD), Raman IR, and NMR. The hybrid system so obtained was employed in the Asymmetric Transfer Hydrogenation (ATH) of cyclic imines allowing to obtain a valuable 61% e.e. (R) in the asymmetric reduction of quinaldine 2. The catalytic system exhibited a saturation kinetics with a calculated efficiency of Kcat/KM = 0.688 h-1mM-1.
Asunto(s)
Antibacterianos/química , Complejos de Coordinación/química , Iminas/química , Iridio/química , Vancomicina/química , Catálisis , Hidrogenación , Cinética , Oxidación-Reducción , Quinaldinas/química , EstereoisomerismoRESUMEN
We report the synthesis and metabolic and biological evaluation of a series of 17 novel heterocyclic derivatives of isocombretastatin-A4 (iso-CA-4) and their structure-activity relationships. Among these derivatives, the most active compound, 4f, inhibited the growth of a panel of seven cancer cell lines with an IC50 in the low nanomolar range. In addition, 4f showed interesting activity against CA-4-resistant colon-carcinoma cells and multidrug-resistant leukemia cells. It also induced G2/M cell-cycle arrest. Structural data indicated binding of 4f to the colchicine site of tubulin, likely preventing the curved-to-straight tubulin structural changes that occur during microtubule assembly. Also, 4f disrupted the blood-vessel-like assembly formed by human umbilical-vein endothelial cells in vitro, suggesting its function as a vascular-disrupting agent. An in vitro metabolism study of 4f showed its high human-microsomal stability in comparison with that of iso-CA-4. The physicochemical properties of 4f may be conducive to CNS permeability, suggesting that this compound may be a possible candidate for the treatment of glioblastoma.
Asunto(s)
Carbazoles/farmacología , Quinaldinas/farmacología , Moduladores de Tubulina/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/metabolismo , Antineoplásicos/farmacología , Carbazoles/síntesis química , Carbazoles/metabolismo , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana , Humanos , Microsomas Hepáticos/metabolismo , Estructura Molecular , Polimerizacion/efectos de los fármacos , Unión Proteica , Quinaldinas/síntesis química , Quinaldinas/metabolismo , Ratas , Relación Estructura-Actividad , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/síntesis química , Moduladores de Tubulina/metabolismoRESUMEN
In continuation of our research aimed at discovery and development of new pesticidal agents, a series of new 8-hydroxyquinaldine derivatives containing a N-phenylpyrazole moiety were prepared and their structures were characterized by 1H NMR, IR, ESI-MS and mp. Meanwhile, an efficient way of using iodine-mediated oxidative cyclization for one pot synthesis of these 8-hydroxyquinaldine derivatives containing a N-phenylpyrazole moiety was developed. The bioassay showed that compounds 8g and 9f exhibited potent pesticidal activities against both Mythimna separata Walker and Plutella xylostella Linnaeus. The structure-activity relationships were also discussed.
Asunto(s)
Insecticidas/toxicidad , Yodo/química , Pirazoles/toxicidad , Quinaldinas/toxicidad , Animales , Ciclización , Insecticidas/síntesis química , Insecticidas/química , Estructura Molecular , Mariposas Nocturnas/efectos de los fármacos , Oxidación-Reducción , Pirazoles/síntesis química , Pirazoles/química , Quinaldinas/síntesis química , Quinaldinas/química , Relación Estructura-ActividadRESUMEN
There is an urgent need for the discovery of new antileishmanial drugs with a new mechanism of action. Type 2 NADH dehydrogenase from Leishmania infantum (LiNDH2) is an enzyme of the parasite's respiratory system, which catalyzes the electron transfer from NADH to ubiquinone without coupled proton pumping. In previous studies of the related NADH: ubiquinone oxidoreductase crystal structure from Saccharomyces cerevisiae, two ubiquinone-binding sites (UQI and UQII) were identified and shown to play an important role in the NDH-2-catalyzed oxidoreduction reaction. Based on the available structural data, we developed a three-dimensional structural model of LiNDH2 using homology detection methods and performed an in silico virtual screening campaign to search for potential inhibitors targeting the LiNDH2 ubiquinone-binding site 1-UQI. Selected compounds displaying favorable properties in the computational screening experiments were assayed for inhibitory activity in the structurally similar recombinant NDH-2 from S. aureus and leishmanicidal activity was determined in the wild-type axenic amastigotes and promastigotes of L. infantum. The identified compound, a substituted 6-methoxy-quinalidine, showed promising nanomolar leishmanicidal activity on wild-type axenic promastigotes and amastigotes of L. infantum and the potential for further development.
Asunto(s)
Antiprotozoarios/química , Leishmania infantum/enzimología , NADH Deshidrogenasa/metabolismo , Quinaldinas/química , Antiprotozoarios/farmacología , Dominio Catalítico/efectos de los fármacos , Simulación por Computador , Evaluación Preclínica de Medicamentos , Leishmania infantum/efectos de los fármacos , Modelos Moleculares , NADH Deshidrogenasa/química , Proteínas Protozoarias/química , Proteínas Protozoarias/metabolismo , Quinaldinas/farmacología , Homología Estructural de Proteína , Relación Estructura-ActividadRESUMEN
The study aims to establish a preliminary environmental assessment of a quinaldine-based LOHC system composed of hydrogen-lean, partially hydrogenated, and fully hydrogenated forms. We examined their toxicity toward the soil bacteria Arthrobacter globiformis and the Collembola Folsomia candida in two exposure scenarios, with and without soil, to address differences in the bioavailability of the compounds. In both scenarios, no or only slight toxicity toward soil bacteria was observed at the highest test concentration (EC50 > 3397 µmol L-1 and >4892 µmol kg-1 dry weight soil). The effects of the three quinaldines on F. candida in soil were similar, with EC50 values ranging from 2119 to 2559 µmol kg-1 dry weight soil based on nominal concentrations. Additionally, corrected pore-water-concentration-based EC50 values were calculated by equilibrium partitioning using soil/pore-water distribution coefficients. The tests without soil (simulating pore-water exposure) revealed higher toxicity, with LC50 values between 78.3 and 161.6 µmol L-1 and deformation of the protective cuticle. These results assign the compounds to the category "harmful to soil organisms". Potential risks toward the soil environment of the test compounds are discussed on the basis of predicted no-effect concentrations.
Asunto(s)
Arthrobacter , Artrópodos , Quinaldinas , Contaminantes del Suelo , Animales , Hidrógeno , Reproducción , SueloRESUMEN
A quinaldine functionalized probe QP has been designed and synthesized. It exhibited selective turn-off fluorescence response toward Cu2+ ion over most of the biologically important ions at physiological pH. The binding ratio of the probe QP and Cu2+ ion was determined to be 1:1 through fluorescence titration, Job's plot and ESI-MS. The binding constant (K) of Cu2+ to probe QP was found to be 2.12×104M-1. Further, the Cu2+ ensemble of probe QP was found to respond H2PO4- and HPO42- among other important biological anions via fluorescence turn-on response at physiological pH. Fluorescence microscopy imaging using living Hela cells showed that probe QP could be used as an effective fluorescent probe for detecting Cu2+ cation and H2PO4- and HPO42- anions in living cells.
Asunto(s)
Cobre/química , Colorantes Fluorescentes/química , Fosfatos/análisis , Quinaldinas/química , Espectrometría de Fluorescencia/métodos , Técnicas Citológicas/métodos , Colorantes Fluorescentes/análisis , Células HeLa , Humanos , Iones/análisis , Iones/química , Microscopía Fluorescente , Quinaldinas/análisisRESUMEN
BmrR is a multidrug resistance (MDR) regulator that responds to diverse ligands. To obtain insight into signal recognition, allosteric control, and cooperativity, we used a quantitative inâ vitro transcription assay to determine the ligand-dependent activation profiles for a diverse set of cations, zwitterions, and uncharged ligands. As for many other biological switch systems, the data are well described by a modified Hill equation. Parameters extracted from curve fits to the data include L50 , RMAX and N. We found that L50 values correlate directly with ΔGBIND values, suggesting that the parameter reflects binding, whereas RMAX and N reflect allosteric control and cooperativity, respectively. Our results suggest unconventional coupling between ligand binding and allosteric control, with weakly interacting ligands exhibiting the highest levels of activation. Such properties are in stark contrast to those often exhibited by biological switch proteins, whereby ligand binding and allostery are tightly coupled, yielding both high selectivity and ultrasensitivity. We propose that weakened coupling, as observed for BmrR, may be important for providing robust activation responses to unrelated ligands. We also propose that other MDR proteins and other polyspecific switch systems will show similar features.
Asunto(s)
Proteínas Bacterianas/metabolismo , Ligandos , Transactivadores/metabolismo , Regulación Alostérica , Aminoquinolinas/química , Aminoquinolinas/farmacología , Bacillus subtilis/metabolismo , Proteínas Bacterianas/química , Proteínas Bacterianas/genética , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Regiones Promotoras Genéticas , Quinaldinas/química , Quinaldinas/farmacología , Termodinámica , Transactivadores/química , Transactivadores/genética , Activación Transcripcional/efectos de los fármacosRESUMEN
Human liver cancer is one of the most frequently diagnosed cancers worldwide. The development of resistance to therapy limits the application against the disease. To improve treatment, new effective anticancer agents are constantly pursued. Previously, we reported that an indolylquinoline, 3-((7-ethyl-1H-indol-3-yl)-methyl)-2-methylquinoline (EMMQ), is effective in suppressing the growth of human lung cancer by impairing mitochondria functions. The present study revealed that EMMQ inhibited cell growth and induced apoptosis in liver cancer cells, but not in normal cells. This study demonstrated that EMMQ induced DNA damage by activating p53 and γ-H2AX and cell arrest by suppressing cyclin D1 and CDK2. Damaged DNA injured mitochondrial functions by lowering the membrane potential and producing reactive oxygen species. The subsequent mitochondrial cytochrome c release attenuated pro-survival signals and increased apoptotic characteristics. Introduction of p53 shRNA abrogated drug effects by reducing DNA damage while maintaining mitochondria integrity. In brief, the study demonstrates that the effectiveness of EMMQ accentuated apoptosis of hepatocarcinoma cells by activating p53. Based on these collective findings, the study offered a new perspective of EMMQ that was shown to be a promising candidate to treat liver cancer.
Asunto(s)
Apoptosis/efectos de los fármacos , Carcinoma Hepatocelular/patología , Daño del ADN/efectos de los fármacos , Indoles/farmacología , Neoplasias Hepáticas/patología , Hígado/patología , Quinaldinas/farmacología , Quinolinas/farmacología , Proteína p53 Supresora de Tumor/genética , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ciclina D1/antagonistas & inhibidores , Quinasa 2 Dependiente de la Ciclina/antagonistas & inhibidores , Citocromos c/metabolismo , Activación Enzimática/efectos de los fármacos , Puntos de Control de la Fase G1 del Ciclo Celular/efectos de los fármacos , Células Hep G2 , Histonas/metabolismo , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Mitocondrias/genética , Quinaldinas/química , Interferencia de ARN , ARN Interferente Pequeño/genética , Especies Reactivas de Oxígeno/metabolismo , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
A metal-free, mild and efficient method for the synthesis of 2-methylquinolines was successfully developed by condensation of anilines with vinyl ethers in the presence of catalytic amount of iodine. Modification of both pyridine and benzene moieties was easily achieved by changing only the vinyl ether and aniline. In this reaction, the iodine species was revealed to show dual behavior; molecular iodine serves as an oxidant, while its reduced form, hydrogen iodide, activates the vinyl ether. The redox reaction between these iodine species enables the use of a catalytic amount of iodine in this synthetic method.
Asunto(s)
Compuestos de Anilina/química , Yodo/química , Quinaldinas/química , Compuestos de Vinilo/química , Catálisis , Espectroscopía de Resonancia Magnética , Estructura Molecular , Oxidación-Reducción , Quinaldinas/síntesis químicaRESUMEN
A novel Cu-catalyzed direct amidation of 2-methylquinolines with amines is described. This method afforded an efficient approach for the synthesis of biologically important aromatic amides from readily available coupling partners using molecular oxygen as the oxidant.
Asunto(s)
Amidas/síntesis química , Aminas/química , Cobre/química , Hidrocarburos Aromáticos/síntesis química , Quinaldinas/química , Amidas/química , Aminas/síntesis química , Catálisis , Hidrocarburos Aromáticos/química , Oxidantes/química , Oxidación-Reducción , Oxígeno/química , Quinaldinas/síntesis químicaRESUMEN
An efficient procedure for 2-sulfolmethyl quinoline preparation from 2-methylquinolines and sodium sulfinates under transition-metal free conditions is described. Halogen functional groups were well tolerated to give the corresponding products in good to high yields.
Asunto(s)
Quinaldinas/síntesis química , Ácidos Sulfínicos/química , Compuestos de Azufre/síntesis química , Halógenos/química , Quinaldinas/química , Sodio/química , Compuestos de Azufre/químicaRESUMEN
A series of 5-[1-(arylimino)methyl]quinaldine-8-ol derivatives L1-L5 and their trinuclear zinc(II) complexes (C1-C5) were synthesized. The compounds L1-L5 were fully characterized by the FT-IR spectra, NMR measurement and elemental analysis, meanwhile the zinc complexes C1-C5 were characterized by the FT-IR spectra and elemental analysis as well as the single crystal X-ray diffraction of a representative complex C3, which revealed a trinuclear zinc complex bearing six organic ligands. The fluorescent properties of both organic compounds and the zinc complexes have been carefully investigated by the UV-Vis absorption in various solvents, indicating the significant influences of the solvents and also double exponential decays.