RESUMO
Eukaryotic elongation factor 2 kinase (eEF2K), a member of the atypical α-kinase family, is highly expressed in a variety of tumor tissues. Inhibition of eEF2K function can effectively kill cancer cells without affecting the function of normal cells. Therefore, eEF2K is a promising new target for cancer therapy. In this study, a series of benzamide tryptamine derivatives were designed and synthesized as novel eEF2K inhibitors. The druggability properties of the synthesized compounds were predicted in silico and performed well. The MTT assay indicated that most of these compounds displayed good antiproliferative activity against human leukemia CCRF-CEM and K562 cell lines. The structure-activity relationship (SAR) revealed that substituents with different electronic effects on the C5 position of indole ring or C2', C4' positions of benzene ring have a great influence on the anti-proliferative activity. Among them, 5j demonstrated the highest anti-proliferative activity with IC50 value of 1.63-3.54 µM. this compound displayed an effective eEF2K inhibition by down-regulated the level of phosphorylated eEF2 in CCRF-CEM cells. Additionally, the western blot analysis further revealed that 5j also significantly affected eEF2K-related signaling pathways. Anticancer mechanism studies have shown that 5j arrested the cell cycle in G0/G1 and induced CCRF-CEM cells apoptosis. Furthermore, 5j activated cleaved caspase-9, 8, 3 and cleaved PARP in a time-dependent manner, which suggesting that 5j induced cancer cells apoptosis through both intrinsic and extrinsic pathways. In summary, benzamide tryptamine derivative 5j represents a novel and promising lead structure for the development of eEF2K inhibitors in cancer therapy.
Assuntos
Benzamidas , Quinase do Fator 2 de Elongação , Apoptose , Benzamidas/farmacologia , Linhagem Celular Tumoral , Quinase do Fator 2 de Elongação/metabolismo , Humanos , Relação Estrutura-Atividade , Triptaminas/farmacologiaRESUMO
Cancer is one of the leading causes of death in the world, and antineoplastic drug research continues to be a major field in medicine development. The marine milieu has thousands of biological species that are a valuable source of novel functional proteins and peptides, which have been used in the treatment of many diseases, including cancer. In contrast with proteins and polypeptides, small peptides (with a molecular weight of less than 1000 Da) have overwhelming advantages, such as preferential and fast absorption, which can decrease the burden on human gastrointestinal function. Besides, these peptides are only connected by a few peptide bonds, and their small molecular weight makes it easy to modify and synthesize them. Specifically, small peptides can deliver nutrients and drugs to cells and tissues in the body. These characteristics make them stand out in relation to targeted drug therapy. Nowadays, the anticancer mechanisms of the small marine peptides are still largely not well understood; however, several marine peptides have been applied in preclinical treatment. This paper highlights the anticancer linear and cyclic small peptides in marine resources and presents a review of peptides and the derivatives and their mechanisms.
Assuntos
Antineoplásicos/isolamento & purificação , Organismos Aquáticos/química , Peptídeos/isolamento & purificação , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Humanos , Neoplasias/tratamento farmacológico , Peptídeos/química , Peptídeos/farmacologia , Peptídeos Cíclicos/química , Peptídeos Cíclicos/isolamento & purificação , Peptídeos Cíclicos/farmacologiaRESUMO
Useful insight can be gained into the underlying adsorption mechanism by studying the adsorption of nitrogen by primary structure coal with different water content. In this work, a coal-adsorption gas experimental system is used to investigate the adsorption of nitrogen by coal samples containing different amounts of water ( 2.894%, 1.871%, 0.897%, and 0%) and different pressures (0.7, 1.2, 1.7, 2.2, 2.7, 3.2, and 3.7MPa). The adsorption rates under the different conditions were calculated using a volume method, and the adsorption kinetics investigated using a kinetic model. The results show that an adsorption model based on an opposing process characterizes the adsorption behavior better than the pseudo-first order kinetic model and pseudo-second order kinetic model. The adsorption rate constant, k, reflects the rate at which the gas can get into the pores of different sizes in the coal a greater k value, implies a greater increment in the rate. The k value is found to decrease when the initial pressure is increased for the same moisture content. Also, the greater the water content, the smaller the value of k for a given initial pressure. As the moisture content continues to increase, the k value tends to a certain value. The results presented can provide an experimental basis for the study of the mechanism responsible for the adsorption of nitrogen by primary structure coal with different moisture content.
RESUMO
Impatiens uliginosa is a plant of the Impatiens, with peculiar flowers. In this study, we combined morphogenesis and molecular biology to explore its development of flowers. An analysis of basic observational data and paraffin sectioning showed that it took approximately 13 d for the floral organs to differentiate. An analysis of the development of inflorescences and floral organs by scanning electron microscopy showed that the inflorescence of I. uliginosa is a spiral raceme. The floral organs differentiated in the following order: lateral sepals (Ls), posterior sepal (Ps), anterior sepals (As), anterior petal (Ap), lateral petals (Lp), stamens (St) and gynoecium (Gy). I. uliginosa was found to have four sepals, and the connate stamens are caused by the fusion and growth of filament appendages. The results of fluorescence quantification and virus-induced gene silencing showed that I. uliginosa had its own unique model for flower development, and there was functional diversity of IuAP1 and IuDEF. Among them, IuAP1 controls the formation of bract s (Br), regulates the morphogenesis of posterior sepal, controls the anthocyanin precipitation of the anterior petals and the formation of lateral petals. IuDEF regulates the morphogenesis of lateral sepals, the length of development of the spur, and controls the size of yellow flower color plaques of the lateral petals. In this study, the process of flower development and the function of flower development genes of I. uliginosa were preliminarily verified. This study provides basic guidance and new concepts that can be used to study the development of Impatiens flowers.