排序方式: 共有96条查询结果,搜索用时 62 毫秒
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Daseul Im Joonhong Jun Jihyun Baek Haejin Kim Dahyun Kang Hyunah Bae Hyunwook Cho Jung-Mi Hah 《Journal of enzyme inhibition and medicinal chemistry》2022,37(1):472
Fms-like tyrosine kinase 3 (FLT3) has been verified as a therapeutic target for acute myeloid leukaemia (AML). In this study, we report a series of 2-(1H-indazol-6-yl)-1H-benzo[d]imidazol-5-yl benzamide and phenyl urea derivatives as potent FLT3 inhibitors based on the structural optimisation of previous FLT3 inhibitors. Derivatives were synthesised as benzamide 8a–k, 8n–z, and phenyl urea 8l–m, with various substituents. The most potent inhibitor, 8r, demonstrated strong inhibitory activity against FLT3 and FLT3 mutants with a nanomolar IC50 and high selectivity profiles over 42 protein kinases. In addition, these type II FLT3 inhibitors were more potent against FLT3 mutants correlated with drug resistance. Overall, we provide a theoretical basis for the structural optimisation of novel benzimidazole analogues to develop strong inhibitors against FLT3 mutants for AML therapeutics. 相似文献
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Fei Li Yunjeong Park Jung-Mi Hah Jae-Sang Ryu 《Bioorganic & medicinal chemistry letters》2013,23(4):1083-1086
A series of 1-(6-methylpyridin-2-yl)-5-(quinoxalin-6-yl)-1,2,3-triazoles has been synthesized and evaluated for their ALK5 inhibitory activity. The 1-(6-methylpyridin-2-yl)-1,2,3-triazoles were assembled by Cu(I)-catalyzed azide–alkyne 1,3-dipolar cycloaddition. Following this, quinoxaline was introduced through Pd-catalyzed direct arylation. The synthesized 1-(6-methylpyridin-2-yl)-5-(quinoxalin-6-yl)-1,2,3-triazoles revealed significant selectivity differences with respect to p38α MAP kinase. In particular, 12k showed 80.8% ALK5 inhibitory activity at a concentration of 10 μM and IC50 value of 4.69 μM, but did not show p38α MAP kinase inhibitory activity (?1.94% inhibition at a concentration of 10 μM). 相似文献
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Much data has accumulated supporting a proatherogenic role for oxidized low density lipoprotein (Ox-LDL). Micronutrient antioxidants such as alpha-tocopherol, the principal lipid-soluble antioxidant, assume potential significance because levels can be manipulated by dietary measures without resulting in side effects. Co-incubation of LDL in vitro with alpha-tocopherol inhibits its oxidative modification. Hence the effect of dietary supplementation with alpha-tocopherol on the time course of copper-catalyzed oxidation of LDL was tested in a randomized placebo-controlled single-blind study. Two groups of 12 male subjects were given either placebo or alpha-tocopherol (800 IU/day) for a period of 12 weeks. Alpha-tocopherol therapy did not result in any side effects or exert an adverse effect on the plasma lipid and lipoprotein profile. While the lipid standardized alpha-tocopherol levels were similar at baseline, the supplemented group had 3.3-fold and 4.4-fold higher levels compared to placebo at 6 and 12 weeks, respectively. In the 15 subjects in whom both plasma and LDL alpha-tocopherol levels were quantitated, there was a significant correlation (r = 0.79, P less than 0.0001). At baseline there were no significant differences in the time course curves of thiobarbituric acid-reacting substances (TBARS) activity or conjugated diene formation between the alpha-tocopherol and placebo groups. However, at both 6 and 12 weeks the mean levels of TBARS activity and conjugated diene formation were lower in the alpha-tocopherol group; the most significant differences were manifest at the 3-h time point. Also at both 6 and 12 weeks the mean rate of oxidation was lower in the alpha-tocopherol group.2+_ 相似文献
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Kim YJ Han SH Kang HW Lee JM Kim YS Seo JH Seong YK Ko HJ Choi TH Moon C Kang CY 《Cellular immunology》2011,(2):135-144
We had previously shown that activated NKT cells licensed B cells to be immunogenic antigen-presenting cells and helped to elicit a wide spectrum of cancer targeted immune responses. In the current study, we sought to verify the safety of αGalCer-loaded, and adenovirus-transduced B cell-based vaccines, together with mechanism of action. Intravenously injected αGalCer-loaded, antigen-expressing B cells rapidly localized in the spleen and directly primed CD8+ T cells in an antigen-specific manner. The transferred antigen was sustained for at least 30 days. While some injected B cells produced nonspecific IgG, the antigen-specific IgG response was completely dependent on endogenous B cells. The liver was one of the main tissues where injected B cells were retained; however, we could not find the signs of liver toxicity. Our results demonstrate that αGalCer-loaded, antigen-expressing B cells behave as “antigen-presenting” cells that stimulate endogenous antigen-specific T cells and B cells in vivo without significant toxicity. 相似文献
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Jung-Mi Kang Thanavel Rajangam Jong-Won Rhie Sang-Heon Kim 《Journal of cellular physiology》2020,235(10):6915-6928
It is essential to characterize the cellular properties of mesenchymal stem cell populations to maintain quality specifications and control in regenerative medicine. Biofunctional materials have been designed as artificial matrices for the stimulation of cell adhesion and specific cellular functions. We have developed recombinant maltose-binding protein (MBP)-fused proteins as artificial adhesion matrices to control human mesenchymal stem cell (hMSC) fate by using an integrin-independent heparin sulfate proteoglycans-mediated cell adhesion. In this study, we characterize cell adhesion-dependent cellular behaviors of human adipose-derived stem cells (hASCs) and human bone marrow stem cells (hBMSCs). We used an MBP-fused basic fibroblast growth factor (MF)-coated surface and fibronectin (FN)-coated surface to restrict and support, respectively, integrin-mediated adhesion. The cells adhered to MF exhibited restricted actin cytoskeleton organization and focal adhesion kinase phosphorylation. The hASCs and hBMSCs exhibited different cytoplasmic projection morphologies on MF. Both hASCs and hBMSCs differentiated more dominantly into osteogenic cells on FN than on MF. In contrast, hASCs differentiated more dominantly into adipogenic cells on MF than on FN, whereas hBMSCs differentiated predominantly into adipogenic cells on FN. The results indicate that hASCs exhibit a competitive differentiation potential (osteogenesis vs. adipogenesis) that depends on the cell adhesion matrix, whereas hBMSCs exhibit both adipogenesis and osteogenesis in integrin-mediated adhesion and thus hBMSCs have noncompetitive differentiation potential. We suggest that comparing differentiation behaviors of hMSCs with the diversity of cell adhesion is an important way to characterize hMSCs for regenerative medicine. 相似文献
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The ERK pathway is a well-known therapeutic target of cancer treatment with great advantage of selectivity between normal cells and cancer cells, and the number of direct ERK kinase inhibitors is quite limited considering large number of available ERK structure from PDB. Therefore, we tried to combine 3D-QSAR with side-chain hopping in an attempt to produce novel structures as ERK inhibitors. The predictive models with q(2) value of 0.867, r(2) value of 0.991 in CoMFA and q(2) value of 0.628, r(2) value of 0.950 in CoMSIA were used to select effective compounds from new library generated from side-chain hopping by CombiGlide. 相似文献
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The synthesis of a novel series of N-(5-amino-1-(4-methoxybenzyl)-1H-pyrazol-4-yl amide derivatives 6a-o, 7a-s and their antiproliferative activities against A375P melanoma cell line were described. Most compounds showed competitive antiproliferative activities to sorafenib, the reference standard. Among them, N-(5-amino-1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-5-(3-(4-chloro-3-(trifluoromethyl)phenyl) ureido)-2-methylbenzamide 7c exhibited potent activities (GI(50)=0.27 μM). Especially, 7c was found to be a potent and selective B-Raf V600E and C-Raf inhibitor (IC(50)=0.26 μM, IC(50)=0.11 μM, respectively), showing a possibility as melanoma therapeutics. 相似文献