RESUMO
Aberrant activation or mutation of the EGFR-PI3K-Akt-mTOR signaling pathway has been implicated in a wide range of human cancers, especially non-small-cell lung cancer (NSCLC). Thus, dual inhibition of EGFR and PI3K has been investigated as a promising strategy to address acquired drug resistance resulting from the use of tyrosine kinase inhibitors. A series of dual EGFR/PI3Kα inhibitors was synthesized using pharmacophore hybridization of the third-generation EGFR inhibitor olmutinib and the PI3Kα selective inhibitor TAK-117. The optimal compound 30k showed potent kinase inhibitory activities with IC50 values of 3.6 and 30.0 nM against EGFRL858R/T790M and PI3Kα, respectively. Compound 30k exhibited a significant antiproliferative effect in NCI-H1975 cells with a higher selectivity profile than olmutinib. The potential antitumor mechanism, molecular binding modes, and in vitro metabolic stability of compound 30k were also clarified.
RESUMO
The abnormal activation of the mTOR pathway is closely related to the occurrence and progression of cancer, especially colorectal cancer. In this study, a rational virtual screening strategy has been established and MT-5, a novel mTOR inhibitor with a quinoline scaffold, was obtained from the ChemDiv database. MT-5 showed potent kinase inhibitory activity (IC50: 8.90 µM) and antiproliferative effects against various cancer cell lines, especially HCT-116 cells (IC50: 4.61 µM), and this was 2.2-fold more potent than that of the cisplatin control (IC50: 9.99 µM). Western blot, cell migration, cycle arrest, and apoptosis assays were performed with HCT-116 cells to investigate the potential anticancer mechanism of MT-5. Metabolic stability results in vitro indicated that MT-5 exhibited good stability profiles in artificial gastrointestinal fluids, rat plasma, and liver microsomes. In addition, the key contribution of the residues around the binding pocket of MT-5 in binding to the mTOR protein was also investigated from a computational perspective.
Assuntos
Neoplasias Colorretais , Detecção Precoce de Câncer , Humanos , Animais , Ratos , Inibidores de MTOR , Serina-Treonina Quinases TOR , Células HCT116 , Neoplasias Colorretais/tratamento farmacológicoRESUMO
A convenient method was developed for the preparation of thiolated compounds via a DBU-catalyzed aerobic cross-dehydrogenative coupling (CDC) reaction. The established protocol is environmentally friendly and operationally simple. Substrates like (hetero)aryl acetates, (hetero)aryl ketones, and indoles could be transformed into the corresponding thiolated products in moderate to high yields and further applied in the preparation of bioactive compounds in a prefunctionalization-free manner.
Assuntos
Cetonas , Compostos de Sulfidrila , Catálise , Estrutura Molecular , Cetonas/químicaRESUMO
An efficient radical annulation of N-arylacrylamides with disulfides is developed for the synthesis of sulfurated oxindoles. The reaction occurs in a facile manner using CoBr2 as both an initiator and a promoter for the first time and (NH4)2S2O8 as the oxidant. By controlling the CoBr2/(NH4)2S2O8 ratio, a wide range of sulfurated and brominated/sulfurated oxindoles are selectively prepared in good to excellent yields. The present protocol is simple and highly atom economical, and can tolerate a broad range of substrates.
Assuntos
Cobalto , Dissulfetos , Indóis , OxindóisRESUMO
An efficient aerobic iron-catalyzed annulation of unsaturated carboxylic acids with disulfides has been developed. This procedure proceeds using FeCl3 as the catalyst and KI as an iodine source under an air atmosphere, which provides practical access to a wide range of substituted γ-lactone derivatives. The disclosed method is quite simple, highly atom-economic, environmentally friendly, and tolerates a broad substrate scope.
Assuntos
Ferro , Lactonas , Ácidos Carboxílicos , Catálise , DissulfetosRESUMO
Four series of cajanonic acid A (CAA) derivatives have been designed and synthesized. The newly prepared compounds have been screened for glucose consumption activity in HepG2 cell lines and PPARγ antagonistic activity in HEK293 cell lines. Compound 26g bearing a tetrahydroisoquinolinone scaffold showed the most potent PPARγ antagonistic and hypoglycemic activities. An oral glucose tolerance test (OGTT) was performed and the results further confirmed that 26g was a potent hypoglycemic agent. In addition, the possible binding modes for compound 26g in the PPARγ protein have been investigated in this study.
Assuntos
PPAR gama/antagonistas & inibidores , Extratos Vegetais/farmacologia , Estilbenos/farmacologia , Cajanus/química , Linhagem Celular , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , PPAR gama/metabolismo , Extratos Vegetais/síntese química , Extratos Vegetais/química , Estilbenos/síntese química , Estilbenos/química , Relação Estrutura-AtividadeRESUMO
LC-MS guided chemical investigation of the periploside-rich extract of the root barks of Periploca sepium afforded six new minor pregnane glycosides, named periplosides A1-A6 (1-6). Their structures were characterized on the basis of extensive spectroscopic analysis. Compounds 1-6 were evaluated for their inhibitory activities against the proliferation of T and B lymphocytes in vitro, among them, compound 5 exhibited significant inhibitory activities and the most favorite selective index (SI) values against the proliferation of T lymphocyte (IC50 = 0.30 µM, SI = 176) and B lymphocyte (IC50 = 0.55 µM, SI = 97).
Assuntos
Linfócitos B/efeitos dos fármacos , Glicosídeos/farmacologia , Periploca/química , Raízes de Plantas/química , Pregnanos/farmacologia , Linfócitos T/efeitos dos fármacos , Animais , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Glicosídeos/química , Glicosídeos/isolamento & purificação , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Pregnanos/química , Pregnanos/isolamento & purificação , Relação Estrutura-AtividadeRESUMO
Two series of tetrahydrocarbazole derivatives have been designed and synthesized based on ZG02, a promising candidate developed in our previous studies. The newly prepared compounds were screened for glucose consumption activity in HepG2 cell lines. Aza-tetrahydrocarbazole compound 12b showed the most potent hypoglycemic activity with a 45% increase in glucose consumption when compared to the solvent control, which had approximately 1.2-fold higher activity than the positive control compounds (metformin and ZG02). An investigation of the potential mechanism indicated that 12b may exhibit hypoglycemic activity via activation of the AMPK pathway. Metabolic stability assays revealed that 12b showed good stability profiles in both artificial gastrointestinal fluids and blood plasma from SD rats. An oral glucose tolerance test (OGTT) was performed and the results further confirmed that 12b was a potent hypoglycemic agent.
Assuntos
Carbazóis/química , Desenho de Fármacos , Hipoglicemiantes/síntese química , Proteínas Quinases Ativadas por AMP/química , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Sítios de Ligação , Carbazóis/farmacologia , Carbazóis/uso terapêutico , Estabilidade de Medicamentos , Glucose/metabolismo , Teste de Tolerância a Glucose , Meia-Vida , Células Hep G2 , Hepatócitos/citologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Simulação de Dinâmica Molecular , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
Four series of berberine derivatives were designed and synthesized. All the synthetic compounds were screened for in vitro glucose consumption activity in HepG2 cell lines. The results showed that most of the tested compounds exhibited potent hypoglycemic activity, and the most potent compound 20b exhibited its potency by 3.23-fold of berberine, 1.39-fold of metformin and 1.20-fold of rosiglitazone, respectively. Western blot assay indicated these novel berberine-based derivatives executed their glucose-decreasing activity via the activation of AMPK pathway.
Assuntos
Berberina/uso terapêutico , Hipoglicemiantes/uso terapêutico , Berberina/análogos & derivados , Berberina/farmacologia , Humanos , Hipoglicemiantes/farmacologiaRESUMO
Rhodojaponin III is a bioactive diterpenoid isolated from the medicinal plant Rhododendron molle G. Don. Quantitative analysis of rhodojaponin III was challenging and the pharmacokinetics of oral rhodojaponin III remained to be investigated. Here, a rapid and sensitive liquid chromatography tandem mass spectrometric (LC-MS/MS) method was developed and validated. The calibration curve was linear over the concentration range of 1-200 ng/mL (r = 0.992). The method was further validated following internationally approved guidelines and all the issues including intra- and inter-day precision, accuracy, carryover, extraction recovery, matrix effects and stability met the recommended limits. The method was then applied to study the pharmacokinetics of rhodojaponin III in mice after intravenous (0.06 mg/kg) or oral (0.24 mg/kg) administration. The results showed that rhodojaponin III had fast oral absorption (time to peak concentration, 0.08 h) and good oral bioavailability (73.6%). In addition, rhodojaponin III was quickly eliminated after it was intravenously or orally administered, with half-life values of 0.19 and 0.76 h, respectively. After oral administration, it was widely distributed in tissues including kidney, lung, heart, spleen and thymus, but had extremely low concentrations in liver and brain. The data presented in this study is beneficial for the further study of rhodojaponin III.
Assuntos
Diterpenos , Administração Oral , Animais , Disponibilidade Biológica , Cromatografia Líquida/métodos , Diterpenos/administração & dosagem , Diterpenos/análise , Diterpenos/farmacocinética , Feminino , Injeções Intravenosas , Limite de Detecção , Modelos Lineares , Masculino , Camundongos , Camundongos Endogâmicos ICR , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem/métodos , Distribuição TecidualRESUMO
After administration, drug molecules usually enter target cells to access their intracellular targets. In eukaryotic cells, these targets are often located in organelles, including the nucleus, endoplasmic reticulum, mitochondria, lysosomes, Golgi apparatus, and peroxisomes. Each organelle type possesses unique biological features. For example, mitochondria possess a negative transmembrane potential, while lysosomes have an intraluminal delta pH. Other properties are common to several organelle types, such as the presence of ATP-binding cassette (ABC) or solute carrier-type (SLC) transporters that sequester or pump out xenobiotic drugs. Studies on subcellular drug distribution are critical to understand the efficacy and toxicity of drugs along with the body's resistance to them and to potentially offer hints for targeted subcellular drug delivery. This review summarizes the results of studies from 1990 to 2017 that examined the subcellular distribution of small molecular drugs. We hope this review will aid in the understanding of drug distribution within cells.
Assuntos
Sistemas de Liberação de Medicamentos , Resistência a Medicamentos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Organelas/metabolismo , Preparações Farmacêuticas/metabolismo , Animais , Células Eucarióticas/metabolismo , Humanos , Preparações Farmacêuticas/administração & dosagem , Distribuição TecidualRESUMO
Pharmacokinetic studies are crucial for elucidating the effective constituents and formula compatibility of traditional Chinese medicines (TCMs). However, studies have usually been limited to single dosages and detection of systemic blood concentrations. To obtain comprehensive pharmacokinetic information, here we propose a multi-dosage and multi-sampling (blood from portal vein or systemic circulation, and liver) strategy to comparatively study the pharmacokinetics of multi-form TCMs, i.e., pure constituents, TCMs, or TCM formula extracts. Based on this strategy, we studied the pharmacokinetics of pure berberine, berberine in CoptidisRhizoma (CRE), and berberine in CoptidisRhizoma-GlycyrrhizaeRadix etRhizoma extracts (CR-GRE). After simple calculation and comparison of the obtained area under the curve (AUC) values, the results revealed the drastically different pharmacokinetic properties of pure berberine compared to CRE and CR-GRE. The results contribute to explaining the pharmacological loss of berberine activity after purification and the compatibility of the CR-GR drug pair. The results also innovatively showed that it was intestinal absorption that differentiated the pharmacokinetics of CRE and pure berberine, and CRE and CR-GRE. In conclusion, we propose a composite strategy to comparatively study the pharmacokinetics of TCMs, which could provide sufficient information to obtain a comprehensive view, before follow-up mechanism-of-action studies.
Assuntos
Berberina/química , Berberina/farmacocinética , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacocinética , Animais , Antioxidantes/química , Antioxidantes/farmacocinética , Área Sob a Curva , Química Farmacêutica , Relação Dose-Resposta a Droga , Feminino , Humanos , Absorção Intestinal/fisiologia , Masculino , Medicina Tradicional Chinesa , Camundongos , Estrutura Molecular , Terpenos/farmacologiaRESUMO
Grassland fire disaster is an important influence factor to grassland ecological system in China. Therefore, it is crucial to study on the monitoring, prediction and management of grassland fire. Remote Sensing (RS) provides detailed data and saves a lot of manpower, material resources and financial resources on the research of grassland fire. However, it is difficult to identify the grassland fuel and soil with Remote Sensing. In this paper, we introduced fractal into the spectral analyses of the field-derived spectra (FDS) of grassland fuel and soil to solve the problem above. The study area laid on the Westward of Changling, Jinlin province, China. Study subjects included soil and dominant species: Leymus chinensis, Reed, Chloris virgate, Kalimeris integrifolia and Artemisia mongolica. FDS of study subjects were measured with ASD FS3 and continuums of FDS were calculated by Matlab 2010. Meanwhile, Box-counting values of FDS and continuums were calculated by Matlab 2010. According to the spectral and continuum analysis, it is difficult to identify soil, Leymus chinensis, Reed, Chloris virgate, and Artemisia mongolica because of the similar spectral curves. However, the Artemisia mongolica can be identified for the strong reflection. For typical fractal characteristics of FDS and continuum, clustering analyses of study subjects were done according to box-counting values of FDS and continuum. The results of clustering analyses show that Box-counting values of FDS and continuum are important indexes to identify the study subjects. This study provides a new thought to identity the grassland combustibles and soil with Remote Sensing.
RESUMO
Using N'-aryl acylhydrazines as aryl donors, a novel copper(ii)-catalyzed homo-coupling reaction of N'-aryl acylhydrazines has been developed for the synthesis of N',N'-diaryl acylhydrazines. We also provided a complementary procedure for the preparation of unsymmetrical diaryl acylhydrazines via cross-coupling reaction. These protocols featured mild reaction conditions, wide functional group tolerance and highly regioselective products. Control experiments indicated that this kind of coupling reaction might undergo a transient acyl diazene intermediate.
Assuntos
Cobre/química , Hidrazinas/síntese química , Catálise , Hidrazinas/química , Estrutura Molecular , EstereoisomerismoRESUMO
The aberrant activation of the PI3K/mTOR signaling pathway is implicated in various human cancers. Thus, the development of inhibitors targeting mTOR has attracted considerable attention. In this study, we used a structure-based drug design strategy to discover a highly potent and kinase-selective mTOR inhibitor 24 (PT-88), which demonstrated an mTOR inhibitory IC50 value of 1.2 nM without obvious inhibition against another 195 kinases from the kinase profiling screening. PT-88 displayed selective inhibition against MCF-7 cells (IC50: 0.74 µM) with high biosafety against normal cells, in which autophagy induced by mTOR inhibition was implicated. After successful encapsulation in a lipodisc formulation, PT-88 demonstrated favorable pharmacokinetic and biosafety profiles and exerted a large antitumor effect in an MCF-7 subcutaneous bearing nude mice model. Our study shows the discovery of a highly selective mTOR inhibitor using a structure-based drug discovery strategy and provides a promising antitumor candidate for future study and development.
Assuntos
Antineoplásicos , Neoplasias da Mama , Desenho de Fármacos , Inibidores de MTOR , Camundongos Nus , Serina-Treonina Quinases TOR , Triazinas , Humanos , Animais , Triazinas/síntese química , Triazinas/farmacologia , Triazinas/química , Triazinas/farmacocinética , Triazinas/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Feminino , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Camundongos , Inibidores de MTOR/farmacologia , Inibidores de MTOR/síntese química , Inibidores de MTOR/uso terapêutico , Inibidores de MTOR/química , Relação Estrutura-Atividade , Células MCF-7 , Proliferação de Células/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacocinética , Camundongos Endogâmicos BALB C , Autofagia/efeitos dos fármacosRESUMO
The corn in the grain filling stage fell over in the central region of Jilin province by the Typhoon Bolaven influence. In order to determine the impact of falling over corn canopy on the reflected information, the hyperspectral reflectance was detected at different viewing zenith angles, at the same time, the polarized reflection was also measured. The results from the analysis by combining the reflection and polarization from corn canopy showed that the reflection of falling over corn is low in visible, while increases in the near infrared wavelength. The reflection from falling over corn canopy was more anisotropic than stand-up corn canopy. The reflected light was highly polarized, the polarization of corn canopy provided the probability for distinguishing between falling over corn and stand-up corn. This research provides a basis for estimating the disaster area and lost units.
Assuntos
Biomassa , Produtos Agrícolas/crescimento & desenvolvimento , Refratometria/métodos , Análise Espectral/métodos , Vento , China , Produtos Agrícolas/química , Desastres , Previsões , Tecnologia de Sensoriamento Remoto/métodosRESUMO
Depression is a grievous mental disease with an increasing high morbidity year by year and a serious social harm. The pathogenesises of depression is complicated and involves with multi-mechanisms and multi-organs. Recent studies demondtrate that in the nerval system and endocrine system there are many types of neurotransmitters and hormones, as well as their receptors, involved in depression. This paper reviews the research progress of depression in recent years.
Assuntos
Depressão/fisiopatologia , Sistema Endócrino , Hormônios/fisiologia , Humanos , Neurotransmissores/fisiologia , Receptores de Neurotransmissores/fisiologiaRESUMO
Protoporphyrinogen oxidase (PPO) is a key enzyme in chlorophyll and heme biosynthesis, and the development of its inhibitors is of great importance both in the pharmaceutical and pesticide industries. However, the currently developed PPO inhibitors have insignificant bio-selectivity and have a serious impact on non-target organisms. In this study, a docking-based virtual screening approach combined with bio-activity testing was used to obtain novel selective inhibitors of PPO. The results of the bio-activity test showed that thirteen compounds showed 10-fold selectivity over human PPO. And the best selective compound, ZINC70338, has a K i value of 2.21 µM for Nicotiana tabacum PPO and >113-fold selectivity for human PPO. The selectivity mechanism of ZINC70338 in different species of PPO was then analyzed by molecular dynamics simulations to provide a design basis and theoretical guidance for the design of novel selective inhibitors.
RESUMO
The dysregulation of the phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin signaling pathway has been implicated in various human cancers, and isoform-selective inhibitors targeting PI3Kα have received significant interest in recent years. In this study, we have designed and synthesized three series of substituted benzoxazole derivatives based on the clinical candidate TAK-117 (8a). A detailed structure-activity relationship (SAR) study has identified the optimal compound 18a bearing a quinoxaline scaffold. Compared to the control 8a, 18a exhibited 4.4-fold more potent inhibitory activity against PI3Kα (IC50: 2.5 vs 11 nM) and better isoform-selective profiles over other PI3Ks. In addition, 18a showed a 1.5-fold more potent antiproliferative effect against HCT-116 cell lines (IC50: 3.79 vs 5.80 µM) and a better selectivity over the normal tissue cells. The potential antitumor mechanism and in vitro metabolic stability of 18a were also investigated. Notably, pharmacokinetic assays indicated that 18a had a higher plasma exposure, a higher maximum concentration and shorter elimination time compared to 8a.
Assuntos
Neoplasias Colorretais , Fosfatidilinositol 3-Quinases , Humanos , Células HCT116 , Quinoxalinas/farmacologia , Transdução de Sinais , Neoplasias Colorretais/tratamento farmacológicoRESUMO
The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway is one of the most important intracellular pathways involved in cell proliferation, growth, differentiation, and survival. Therefore, this route is a prospective biological target for treating various human diseases, such as tumors, neurodegenerative diseases, pulmonary fibrosis, and diabetes. An increasing number of clinical studies emphasize the necessity of developing novel molecules targeting the PI3K/AKT/mTOR pathway. This review focuses on recent advances in ATP-competitive inhibitors, allosteric inhibitors, covalent inhibitors, and proteolysis-targeting chimeras against the PI3K/AKT/mTOR pathway, and highlights possible solutions for overcoming the toxicities and acquired drug resistance of currently available drugs. We also provide recommendations for the future design and development of promising drugs targeting this pathway.