RESUMEN
As our ongoing searching for the bioactive natural terpenoids, nine ent-kauranoids (1-9), including three previously undescribed ones (1, 2, and 9), were isolated from the aerial parts of Isodon amethystoides. Their structures were elucidated on the basis of spectroscopic data analysis, including NMR, MS, and ECD. Compounds 1 and 2 were a pair of tautomeric compounds, which was confirmed by the HPLC analysis and low temperature NMR testing. The underlying mechanism of the tautomer was proposed as an intramolecular SN2 reaction, which was explained by quantum chemical calculation. The HOMO-LUMO gap and the free energy revealed the spontaneous of the tautomeric of the 1 and 2. Additionally, the similar phenomena were also found in the two groups of known compounds 3 and 4 and 6 and 7, respectively. Apart from the tautomer, compounds 3 and 4 can be hydrolyzed into 5 through ester hydrolysis in CDCl3, while compounds 6, 7 can be hydrolyzed into 8 through ester hydrolysis. These phenomena were also confirmed through HPLC analysis and low temperature nuclear magnetic resonance tests and the mechanism was studied using quantum chemical calculation.
Asunto(s)
Antineoplásicos Fitogénicos , Diterpenos de Tipo Kaurano , Isodon , Estructura Molecular , Isodon/química , Componentes Aéreos de las Plantas/química , Ésteres , Ensayos de Selección de Medicamentos AntitumoralesRESUMEN
Few targeted drugs were approved for treatment of colorectal cancer (CRC). Cyclin-dependent kinase 8 played a vital role in regulating transcription and was a key colorectal oncogene associated to colorectal cancer. Here, through de novo drug design and in depth structure-activity relationship analysis, title compound 22, (3-(3-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-N-(4-methyl-3-(trifluoromethyl)phenyl)propenamide), was discovered as a potent type II CDK8 inhibitor, which exhibited potent kinase activity with an IC50 value of 48.6 nM and could significantly inhibit tumor growth in xenografts of CRC in vivo. Further mechanism studies indicated that it could target CDK8 to indirectly inhibit ß-catenin activity, which caused downregulation of the WNT/ß-catenin signal and inducing cell cycle arrest in G2/M and S phases. More importantly, the title compound exhibited low toxicity with good bioavailability (F = 39.8%). These results could provide the reference for design of new type II CDK8 inhibitors against colorectal cancer.
Asunto(s)
Antineoplásicos , Neoplasias Colorrectales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Neoplasias Colorrectales/patología , Quinasa 8 Dependiente de Ciclina , Diseño de Fármacos , Xenoinjertos/química , Xenoinjertos/metabolismo , Humanos , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Piridinas/farmacología , Piridinas/uso terapéutico , Relación Estructura-Actividad , beta Catenina/metabolismoRESUMEN
Increasing the anti-inflammatory cytokine interleukin-10 (IL-10) level is a promising strategy to suppress the progression of pathogenic inflammation including inflammatory bowel disease (IBD). Since cyclin-dependent kinase 8 (CDK8) inhibition can upregulate IL-10 abundance in activated myeloid-derived dendritic cells, it is considered to be an effective target for IBD treatment. Here, the complete discovery process of a novel CDK8 inhibitor as an anti-inflammatory agent was described. Starting with wogonin, structure-based optimization and structure-activity relationship (SAR) study were comprehensively carried out, and then lead compound 85 (N-(2-ethylphenyl)-5-(4-(piperazine-1-carbonyl)phenyl)nicotinamide) was developed as a potent druglike CDK8 inhibitor upregulating IL-10 both in vivo and in vitro. Also, compound 85 (with CDK8 IC50 = 56 nM, IL-10 enhancement rate 88%) exhibited effective anti-inflammatory activity in an animal model of IBD. These results confirmed that certain CDK8 inhibitor could be used as an effective anti-IBD drug.
Asunto(s)
Quinasa 8 Dependiente de Ciclina , Enfermedades Inflamatorias del Intestino , Animales , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Interleucina-10 , Estructura Molecular , Inhibidores de Proteínas Quinasas/farmacología , Regulación hacia ArribaRESUMEN
T-LAK-cell-originated protein kinase (TOPK), a novel member of the mitogen-activated protein kinase family, is considered an effective therapeutic target for skin inflammation. In this study, a series (A - D) of paeonol derivatives was designed and synthesised using a fragment growing approach, and their anti-inflammatory activities against lipopolysaccharide (LPS)-induced nitric oxide production in RAW264.7 cells were tested. Among them, compound B12 yielded the best results (IC50 = 2.14 µM) with low toxicity (IC50 > 50 µM). Preliminary mechanistic studies indicated that this compound could inhibit the TOPK-p38/JNK signalling pathway and phosphorylate downstream related proteins. A murine psoriasis-like skin inflammation model was used to determine its therapeutic effect.
Asunto(s)
Acetofenonas/farmacología , Antiinflamatorios no Esteroideos/farmacología , Descubrimiento de Drogas , Inflamación/tratamiento farmacológico , Piel/efectos de los fármacos , Acetofenonas/síntesis química , Acetofenonas/química , Animales , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/química , Línea Celular , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Inflamación/metabolismo , Proteínas Quinasas JNK Activadas por Mitógenos/antagonistas & inhibidores , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Lipopolisacáridos/antagonistas & inhibidores , Lipopolisacáridos/farmacología , Ratones , Ratones Endogámicos BALB C , Microsomas Hepáticos/química , Microsomas Hepáticos/metabolismo , Quinasas de Proteína Quinasa Activadas por Mitógenos/antagonistas & inhibidores , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Estructura Molecular , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico/biosíntesis , Transducción de Señal/efectos de los fármacos , Piel/metabolismo , Relación Estructura-Actividad , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Hybridization of nitric oxide (NO) donors with known anti-cancer agents have been emerged as a strategy to achieve improved therapeutic effect and to overcome chemo-resistance in cancer therapy. In this study, furoxan moiety as an efficient NO donor was introduced to phenstatin, a microtubule-interfering agent (MIA), leading to the design and synthesis of a series of furoxan-based NO-releasing arylphenones derivatives. In biological evaluation, the synthesized compounds showed moderate to potent anti-tumor activities against several human cancer cell lines. Among them, compound 15h showed the most potent activities against both chemo-sensitive and resistant cancer cell lines with IC50 values ranging from 0.008 to 0.021 µM. Further mechanistic studies revealed that 15h worked as a bifunctional agent exhibiting both tubulin polymerized inhibition and NO-releasing activities, resulting in potent anti-angiogenesis, colony formation inhibition, cell cycle arrest and apoptosis induction effects. In the nude mice xenograft model, 15h significantly inhibited the paclitaxel-resistant tumor growth with low toxicity, demonstrating the promising potential for further preclinical evaluation as a therapeutic agent, particularly for the treatment of chemo-resistant cancers.
Asunto(s)
Antineoplásicos , Animales , Antineoplásicos/farmacología , Apoptosis , Benzofenonas , Línea Celular Tumoral , Proliferación Celular , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Ratones , Ratones Desnudos , Oxadiazoles , Relación Estructura-ActividadRESUMEN
Cathepsin C (Cat C) participates in inflammation and immune regulation by affecting the activation of neutrophil serine proteases (NSPs). Therefore, cathepsin C is an attractive target for treatment of NSP-related inflammatory diseases. Here, the complete discovery process of the first potent "non-peptidyl non-covalent cathepsin C inhibitor" was described with hit finding, structure optimization, and lead discovery. Starting with hit 14, structure-based optimization and structure-activity relationship study were comprehensively carried out, and lead compound 54 was discovered as a potent drug-like cathepsin C inhibitor both in vivo and in vitro. Also, compound 54 (with cathepsin C Enz IC50 = 57.4 nM) exhibited effective anti-inflammatory activity in an animal model of chronic obstructive pulmonary disease. These results confirmed that the non-peptidyl and non-covalent derivative could be used as an effective cathepsin C inhibitor and encouraged us to continue further drug discovery on the basis of this finding.
Asunto(s)
Antiinflamatorios/uso terapéutico , Catepsina C/antagonistas & inhibidores , Inflamación/tratamiento farmacológico , Inhibidores de Proteasas/uso terapéutico , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Pirimidinas/uso terapéutico , Animales , Antiinflamatorios/síntesis química , Antiinflamatorios/metabolismo , Antiinflamatorios/toxicidad , Catepsina C/metabolismo , Línea Celular Tumoral , Descubrimiento de Drogas , Humanos , Inflamación/etiología , Inflamación/patología , Pulmón/efectos de los fármacos , Pulmón/patología , Masculino , Ratones Endogámicos ICR , Microsomas Hepáticos/metabolismo , Simulación del Acoplamiento Molecular , Estructura Molecular , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/metabolismo , Inhibidores de Proteasas/toxicidad , Unión Proteica , Enfermedad Pulmonar Obstructiva Crónica/complicaciones , Enfermedad Pulmonar Obstructiva Crónica/patología , Pirimidinas/síntesis química , Pirimidinas/metabolismo , Pirimidinas/toxicidad , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
Uncaging chemistry catalyzed by transition metals is developed from deprotection reactions and metal-organic catalytic reactions. Also, it has the characteristics of high efficiency, simplicity and rapidity in the living biological system. In the past decade, metal encapsulation systems (such as nanoparticles) and metal complexes have been developed to reveal the reactivity of transition metals (including palladium, ruthenium, and gold) in biological systems. Metal nanostructures provide huge possibilities for targeted drug delivery, detection, diagnosis and imaging. So far, palladium, ruthenium and gold nano-architectures have dominated the field, but there are some problems that hinder their wide application in clinical practice. In this review, based on palladium, ruthenium, gold and their complexes, the application of prodrug design through uncaging reaction has been widely discussed.
Asunto(s)
Diseño de Fármacos , Oro/química , Paladio/química , Profármacos/química , Rutenio/química , Animales , Humanos , Profármacos/síntesis químicaRESUMEN
In order to discover and develop drug-like anti-inflammatory agents against arthritis, based on "Hit" we found earlier and to overcome drawbacks of toxicity, twelve series of total 89 novel pyrimidine, pyrazolo[4,3-d]pyrimidine and thieno[3,2-d]pyrimidine derivatives were designed, synthesized and screened for their anti-inflammatory activity against NO and toxicity for normal liver cells (LO2). Relationships of balance toxicity and activity have been summarized through multi-steps, and title compounds 22o, 22l were found to show lower toxicity (against LO2: IC50 = 2934, 2301 µM, respectively) and potent effect against NO release (IR = 98.3, 97.67%, at 10 µM, respectively). Furthermore, compound 22o showed potent iNOS inhibitory activity with value of IC50 is 0.96 µM and could interfere stability and formation of the active dimeric iNOS. It's anti-inflammatory activity in vivo was assessed by AIA rat model. Furthermore, the results of metabolic stability, CYP, PK study in vivo, acute toxicity study and subacute toxicity assessment indicated this compound had good drug-like properties for treatment.
Asunto(s)
Artritis/tratamiento farmacológico , Desarrollo de Medicamentos , Inhibidores Enzimáticos/farmacología , Óxido Nítrico Sintasa de Tipo II/antagonistas & inhibidores , Pirazoles/farmacología , Pirimidinas/farmacología , Administración Oral , Animales , Artritis/metabolismo , Células Cultivadas , Dimerización , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/química , Adyuvante de Freund , Humanos , Lipopolisacáridos/antagonistas & inhibidores , Lipopolisacáridos/farmacología , Masculino , Ratones , Estructura Molecular , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico/biosíntesis , Óxido Nítrico Sintasa de Tipo II/metabolismo , Pirazoles/administración & dosificación , Pirazoles/química , Pirimidinas/administración & dosificación , Pirimidinas/química , Células RAW 264.7 , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
Paeonol has been proved to have potential anti-inflammatory activity, but its clinical application is not extensive due to the poor anti-inflammatory activity (14.74% inhibitory activity at 20 µM). In order to discover novel lead compound with high anti-inflammatory activity, series of paeonol derivatives were designed and synthesized, their anti-inflammatory activities were screened in vitro and in vivo. Structure-activity relationships (SARs) have been fully concluded, and finally (E)-N-(4-(2-acetyl-5-methoxyphenoxy)phenyl)-3-(3,4,5-trimet-hoxyphenyl)acrylamide (compound 11a) was found to be the best active compound with low toxicity, which showed 96.32% inhibitory activity at 20 µM and IC50 value of 6.96 µM against LPS-induced over expression of nitric oxide (NO) in RAW 264.7 macrophages. Preliminary mechanism studies indicated that it could inhibit the expression of TLR4, resulting in inhibiting of NF-κB and MAPK pathways. Further studies have shown that compound 11a has obvious therapeutic effect against the adjuvant-induced rat arthritis model.
Asunto(s)
Acetofenonas/farmacología , Antiinflamatorios no Esteroideos/farmacología , Artritis Experimental/tratamiento farmacológico , Diseño de Fármacos , FN-kappa B/antagonistas & inhibidores , Óxido Nítrico/antagonistas & inhibidores , Acetofenonas/síntesis química , Acetofenonas/química , Animales , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/química , Artritis Experimental/inducido químicamente , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Relación Dosis-Respuesta a Droga , Adyuvante de Freund/administración & dosificación , Lipopolisacáridos/antagonistas & inhibidores , Lipopolisacáridos/farmacología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Masculino , Ratones , Estructura Molecular , FN-kappa B/metabolismo , Óxido Nítrico/análisis , Óxido Nítrico/biosíntesis , Células RAW 264.7 , Relación Estructura-ActividadRESUMEN
Telomere and telomerase play important roles in abnormal cell proliferation, metastasis, stem cell maintenance, and immortalization in various cancers. Therefore, designing of drugs targeting telomerase and telomere is of great significance. Over the past two decades, considerable knowledge regarding telomere and telomerase has been accumulated, which provides theoretical support for the design of therapeutic strategies such as telomere elongation. Therefore, the development of telomere-based therapies such as nucleoside analogs, non-nucleoside small molecules, antisense technology, ribozymes, and dominant negative human telomerase reverse transcriptase are being prioritized for eradicating a majority of tumors. While the benefits of telomere-based therapies are obvious, there is a need to address the limitations of various therapeutic strategies to improve the possibility of clinical applications. In this study, current knowledge of telomere and telomerase is discussed, and therapeutic strategies based on recent research are reviewed.
Asunto(s)
Terapia Molecular Dirigida , Neoplasias/tratamiento farmacológico , Neoplasias/enzimología , Telomerasa/antagonistas & inhibidores , Animales , Terapia Genética , Humanos , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología , Telomerasa/química , Telomerasa/metabolismo , Telómero/química , Telómero/metabolismoRESUMEN
In order to discover novel anti-inflammatory agents, total thirty-seven new resveratrol-based flavonol derivatives were designed and synthesized. All compounds have been screened for their anti-inflammatory activity by evaluating their inhibition effect of LPS-induced NO production in RAW 264.7 macrophages. Their toxicity was also assessed in vitro. Structure-activity relationships (SARs) have been concluded, and finally 2-(2,4-dimethoxy-6-(4-methoxystyryl)phenyl)-3-hydroxy-4H-chromen-4-one was found to be the most active scaffold with low toxicity. This compound could significantly decrease productions of NO, IL-6 and TNF-α with IC50 values of 1.35, 1.12 and 1.92⯵M, respectively in RAW 264.7 macrophages. Preliminary mechanism studies indicated that it could inhibit the expression of TLR4 protein, resulting in activation of the NF-ĸB cell signaling pathway. The in vivo anti-inflammatory activity of this compound could reduce pulmonary inflammation by mouse model of LPS-induced acute lung injury (ALI). We believe these findings would further support studies of rational design of more efficient acute lung injury regulatory inhibitors.
Asunto(s)
Antiinflamatorios/síntesis química , Antiinflamatorios/farmacología , Flavonoides/síntesis química , Flavonoides/farmacología , Interleucina-6/antagonistas & inhibidores , Óxido Nítrico/antagonistas & inhibidores , Resveratrol/química , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Animales , Antiinflamatorios/toxicidad , Flavonoides/química , Flavonoides/toxicidad , Técnicas In Vitro , Concentración 50 Inhibidora , Lipopolisacáridos/toxicidad , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Ratones , Simulación del Acoplamiento Molecular , FN-kappa B/metabolismo , Células RAW 264.7 , Relación Estructura-Actividad , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Four series of total 35 new pyrazolo[4,3-d]pyrimidine compounds were designed, synthesized and evaluated for their inhibitory activity against LPS-induced NO production in RAW264.7 macrophages. Among them, compound 4e was found to be the most potent inhibitor, which decreased the production of cytokines in vitro, such as NO, IL-6 and TNF-α, with IC50 values of 2.64, 4.38 and 5.63 µM, respectively. Further studies showed that compound 4e inhibited cytokines secretion of macrophages through suppressing TLR4/p38 signaling pathway. Additionally, compound 4e showed in vivo anti-inflammatory activity in LPS-induced model of acute lung injury. These data suggested that compound 4e may be a promising lead structure for the treatment of ALI.
Asunto(s)
Lesión Pulmonar Aguda/tratamiento farmacológico , Diseño de Fármacos , Pirazoles/farmacología , Pirimidinas/farmacología , Lesión Pulmonar Aguda/metabolismo , Lesión Pulmonar Aguda/patología , Animales , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Citocinas/antagonistas & inhibidores , Citocinas/metabolismo , Relación Dosis-Respuesta a Droga , Lipopolisacáridos/antagonistas & inhibidores , Lipopolisacáridos/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico/metabolismo , Pirazoles/síntesis química , Pirazoles/química , Pirimidinas/síntesis química , Pirimidinas/química , Células RAW 264.7 , Transducción de Señal/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
In order to discover novel anti-inflammatory agents for treatment of arthritis and based on preliminary structure-activity relationships, four series (A-D) of total 90 new pyrazolo[4,3- d]pyrimidine compounds were designed and synthesized. All the compounds have been tested for their anti-inflammatory activities by inhibiting of LPS-induced NO production. A clear structure-activity relationship has been concluded step by step, and finally 3,4,5-trimethoxystyryl-1 H-pyrazolo[4,3- d]pyrimidine was found to be the most active scaffold. Among them, compound D27 was discovered as the most potent anti-inflammatory agent (IC50 = 3.17 µM) with low toxicity and strong inhibitory of NO release (IR = 90.4% at 10 µM). This compound also showed potent inhibition of iNOS with IC50 value of 1.12 µM. Preliminary mechanism studies indicated that it could interfere with the stability and formation of active dimeric iNOS. The anti-inflammatory effect of this compound was determined by adjuvant-induced arthritis in rat model. We believe these findings would further support the study of rational design of more efficient iNOS inhibitors in the future.
Asunto(s)
Antiinflamatorios/uso terapéutico , Artritis Experimental/tratamiento farmacológico , Inhibidores Enzimáticos/química , Óxido Nítrico Sintasa de Tipo II/antagonistas & inhibidores , Pirazoles/química , Piridinas/química , Animales , Antiinflamatorios/química , Antiinflamatorios/metabolismo , Antiinflamatorios/farmacología , Artritis Experimental/patología , Cristalografía por Rayos X , Dimerización , Modelos Animales de Enfermedad , Diseño de Fármacos , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Interleucina-1beta/metabolismo , Lipopolisacáridos/toxicidad , Macrófagos/citología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ratones , Conformación Molecular , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Pirazoles/metabolismo , Pirazoles/farmacología , Pirazoles/uso terapéutico , Piridinas/metabolismo , Piridinas/farmacología , Piridinas/uso terapéutico , Células RAW 264.7 , Ratas , Relación Estructura-ActividadRESUMEN
In this study, twenty curcumin analogue hybrids as potential anticancer agents through regulation protein of TrxR were designed and synthesized. Results of anticancer activity showed that 5,7-dimethoxy-3-(3-(2-((1E, 4E)-3-oxo-5-(pyridin-2-yl)penta-1,4-dien-1- yl)phenoxy)propoxy)-2-(3,4,5-trimethoxyphenyl)-4H-chromen-4-one (compound 7d) could induce gastric cancer cells apoptosis by arresting cell cycle, break mitochondria function and inhibit TrxR activity. Meanwhile, western blot revealed that this compound could dramatically up expression of Bax/Bcl-2 ratio and high expression of TrxR oxidation. These results preliminarily show that the important role of ROS mediated activation of ASK1/MAPK signaling pathways by this title compound.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Curcumina/análogos & derivados , Curcumina/farmacología , Neoplasias/tratamiento farmacológico , Antineoplásicos/síntesis química , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Curcumina/síntesis química , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Neoplasias/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacos , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/metabolismo , Tiorredoxina Reductasa 1/antagonistas & inhibidores , Tiorredoxina Reductasa 1/metabolismoRESUMEN
BuChE inhibitors play important roles in treatment of patients with advanced Alzheimer's disease (AD). A series of tricyclic pyrazolo[1,5-d][1,4]benzoxazepin-5(6H)-one derivatives were synthesized and evaluated as acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitors. Some derivatives showed selective BuChE inhibitory activity, which was influenced by the volumes of the substituted groups at the C6 position and halogen substituents at the benzene ring of tricyclic scaffold. Among them, compounds 3f and 3o with dihalogen and 6-ethyl substituent showed the most potent activity (IC50â¯=â¯2.95, 2.04⯵M, and mixed-type, non-competitive inhibition against BuChE, respectively). Eutomer (6R)-3o exhibited better BuChE inhibitory activity than (6S)-3o. Compound 3o exhibited nontoxic, good ADMET properties, and remarkable neuroprotective activity. Docking studies revealed the same binding orientation within the active site of target enzyme. Compound 3o was nicely bound to BuChE via three hydrogen bonds, one Alkyl interaction and three Pi-Alkyl interactions. The selective BuChE inhibitors had a potential use in progressive neurodegenerative disorder.
Asunto(s)
Benzazepinas/farmacología , Butirilcolinesterasa/metabolismo , Inhibidores de la Colinesterasa/farmacología , Fármacos Neuroprotectores/farmacología , Acetilcolinesterasa/metabolismo , Animales , Benzazepinas/síntesis química , Benzazepinas/química , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/química , Relación Dosis-Respuesta a Droga , Electrophorus , Caballos , Simulación del Acoplamiento Molecular , Estructura Molecular , Fármacos Neuroprotectores/síntesis química , Fármacos Neuroprotectores/química , Células PC12 , Ratas , Relación Estructura-ActividadRESUMEN
Dominant-negative mutants of telomerase hTERT were demonstrated to have selective effects in tumor cells. However, no any effective and highly selective hTERT inhibitor has been developed so far. We focused on developing new hTERT modulators and synthesized a small molecular compound, named (4-bromophenyl)(3-hydroxy-4-methoxyphenyl)methanone. Our in vitro studies found that title compound showed high inhibitory activity against telomerase, had high antiproliferative capacity on SMMC-7721 cells with IC50 value 88 nm, and had no obvious toxic effect on human normal hepatocyte cells with IC50 value 10 µM. Our in vivo studies showed that this compound significantly inhibited tumor growth in xenograft tumor models. The further molecular mechanisms of title compound inhibition SMMC-7721 cell proliferation by modulating hTERT were explored; the results showed that endoplasmic reticulum stress (ERS) through ER over response (EOR) activates the expression of hTERT, and then induces ERS, which is believed to be intricately associated with oxidative stress and mitochondrial dysfunction, resulting in apoptotic cell death, thereby modulating the expression of downstream signaling molecules including CHOP (CAAT/enhancer-binding protein homologous protein)) and mitochondrion pathway of apoptosis, leading to inhibition of cell proliferation.
Asunto(s)
Estrés del Retículo Endoplásmico/efectos de los fármacos , Indoles/uso terapéutico , Telomerasa/metabolismo , Apoptosis , Línea Celular Tumoral , Proliferación Celular , Humanos , Indoles/farmacología , Regulación hacia ArribaRESUMEN
To develop novel anti-inflammatory agents, a series of unsaturated glycyrrhetic acids were designed, synthesized and evaluated for anti-inflammatory activity using RAW264.7 cells. The structure-activity relationship (SAR) of NO inhibitory activity was analyzed. α,ß-Unsaturated glycyrrhetic acids showed better activity, among them, compounds 6k and 6l with piperazine unit exhibited the most potent nitric oxide (NO) and interleukin-6 (IL-6) inhibitory activity (IC50 = 13.3 and 15.5 µM respectively). Furthermore, compound 6k could also significantly suppress LPS-induced iNOS and COX-2 expression and IL-6 production through MAPKs and NF-kB signaling pathway.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Diseño de Fármacos , Ácido Glicirretínico/farmacología , Interleucina-6/antagonistas & inhibidores , Óxido Nítrico/antagonistas & inhibidores , Animales , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/química , Supervivencia Celular/efectos de los fármacos , Ciclooxigenasa 2/metabolismo , Relación Dosis-Respuesta a Droga , Ácido Glicirretínico/síntesis química , Ácido Glicirretínico/química , Interleucina-6/biosíntesis , Lipopolisacáridos/antagonistas & inhibidores , Lipopolisacáridos/farmacología , Ratones , Estructura Molecular , Óxido Nítrico/biosíntesis , Óxido Nítrico Sintasa de Tipo II/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo II/metabolismo , Células RAW 264.7 , Relación Estructura-ActividadRESUMEN
To develop new anti-inflammatory agents with improved pharmaceutical profiles, a series of new phenyl-pyrazoline-coumarin derivatives (4aâ¼4m) were designed and synthesized. Compounds 4a and 4b were determined by X-ray crystallography. All of the compounds have been screened for their anti-inflammatory activity characterized by evaluating their inhibition against LPS-induced IL-6 release. Among them, compound 4m showed the highest anti-inflammatory activity with inhibiting IL-6, TNF-α and nitric oxide (NO) production lipopolysaccharide (LPS)-stimulated. The further study showed that title compound 4m could significantly suppress expressions of nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) and the productions of IL-6, TNF-α, NO through NF-κB/MAPK signaling pathway. The anti-inflammatory activity of compound 4m was determined by carrageenan induced paw edema. Furthermore in vivo evaluation results indicated that compound 4m could inhibit AA-induced rat ankle joints.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Cumarinas/farmacología , Interleucina-6/antagonistas & inhibidores , Óxido Nítrico/antagonistas & inhibidores , Pirazoles/farmacología , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Animales , Articulación del Tobillo/efectos de los fármacos , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/química , Carragenina , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Cumarinas/química , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Edema/inducido químicamente , Edema/tratamiento farmacológico , Interleucina-6/biosíntesis , Lipopolisacáridos/antagonistas & inhibidores , Lipopolisacáridos/farmacología , Masculino , Ratones , Modelos Moleculares , Estructura Molecular , Óxido Nítrico/biosíntesis , Pirazoles/química , Células RAW 264.7 , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
Based on telomerase, thirteen novel phenstatin moiety linked stavudine derivatives (8aâ¼8e and 11aâ¼11f) were synthesized. The structures were determined by NMR and TOF-HRMS. The screening results showed that some compounds had better anti-cancer activity in vivo and in vitro. Among them, Compound 8d showed high inhibitory activity against telomerase and showed good antiproliferative activity against SGC-7901 cell with IC50 value 0.77 µM by inducing cell cycle arrest at G2 phase. It also could improve SGC-7901 cell apoptosis, mitochondrial membrane potential assay indicated that the dissipation of MMP might participate in apoptosis induced by title compound. In vivo studies showed that compound 8d displayed potent anticancer activity with inhibition tumor growth.
Asunto(s)
Benzofenonas/síntesis química , Diseño de Fármacos , Nucleósidos/síntesis química , Telomerasa/antagonistas & inhibidores , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Benzofenonas/química , Benzofenonas/farmacología , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Células HeLa , Humanos , Concentración 50 Inhibidora , Espectroscopía de Resonancia Magnética , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Estructura Molecular , Nucleósidos/química , Nucleósidos/farmacologíaRESUMEN
It is of our interest to generate and identify novel compounds with regulation telomerase for cancer therapy. In order to carry out more rational design, based on structure-based drug design, several series of N-substituted-dihydropyrazole derivatives, totally 78 compounds as potential human telomerase inhibitors were designed and synthesized. The results demonstrated that some compounds had potent anticancer activity against four tumor cell lines, and showed good selectivity on tumor cells over somatic cells. By the modified TRAP assay, compound 13i exhibited the most potent inhibitory activity against telomerase with an IC50 value of 0.98 µM. In vivo evaluation results indicated that compound 13i could inhibit growth of S180 and HepG2 tumor-bearing mice, and it also significantly enhanced the survival rate of EAC tumor-bearing mice. The further results in vivo confirmed that it could significantly improve pathological changes of N,N-diethylnitrosamine (DEN)-induced rat hepatic tumor. These data support further studies to assess rational design of more efficient telomerase inhibitors in the future.