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高等学校化学学报 2008年第12期29卷 2525-2530页

作者：徐崑杨晓达王夔北京大学医学部药学院化学生物学系和天然药物及仿生药物国家重点实验室北京100191

应用固定化钙调蛋白(CaM)亲合色谱法、变性丙烯酰胺电泳(SDS-PAGE)和基质辅助激光解析电离飞行时间质谱(MALDI-TOF-MS)等方法研究了La3+诱导CaM在大鼠脑匀浆液中的钙调蛋白亲合蛋白(CaMBP)谱以及CaM-CaMBP在模拟细胞环境下结合作用的La3... 详细信息

应用固定化钙调蛋白(CaM)亲合色谱法、变性丙烯酰胺电泳(SDS-PAGE)和基质辅助激光解析电离飞行时间质谱(MALDI-TOF-MS)等方法研究了La3+诱导CaM在大鼠脑匀浆液中的钙调蛋白亲合蛋白(CaMBP)谱以及CaM-CaMBP在模拟细胞环境下结合作用的La3+浓度依赖关系,并与Ca2+的作用进行了比较.实验结果表明,(1)La3+参与的CaMBP物种与Ca2+的基本相同.鉴定了其中含量高且稳定出现的5种CaMBP分别是参与糖酵解反应的6-磷酸果糖激酶和3-磷酸甘油醛脱氢酶、细胞骨架类的微管蛋白和肌动蛋白以及应激反应相关的71000热休克同源蛋白,表明稀土离子可能参与多种细胞过程;(2)La3+诱导CaM与5种CaMBP结合的浓度依赖曲线因CaMBP物种的不同而存在差别.热休克同源蛋白、肌动蛋白或微管蛋白对La3+相对敏感,La3+在金属-CaM-CaMBP三元体系中与CaM的结合常数K与Ca2+的相近或稍高;而6-磷酸果糖激酶和3-磷酸甘油醛脱氢酶体系对La3+的敏感性明显低于Ca2+.其原因可能在于模拟细胞环境的复杂性以及CaM-CaMBP蛋白质相互作用对金属离子与CaM配位结合的调节.

关键词：钙调蛋白钙调蛋白结合蛋白稀土蛋白组学

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钒配合物的药理作用和理性药物设计

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中国科学：化学 2017年第2期47卷 162-171页

作者：董雅琼牛霞肖茹月张悦夏青杨晓达北京大学天然和仿生药物国家重点实验室及药学院化学生物学系北京大学医学部北京100191

自19世纪90年代以来,钒配合物的药物发现及其基础研究有了很大的进展,但仍然存在很多亟待解决的问题.本文综述了钒配合物的抗肿瘤、抗糖尿病作用和分子机制,及其潜在新作用——抗阿尔茨海默症的作用,也介绍了钒配合物的毒性作用及其机... 详细信息

自19世纪90年代以来,钒配合物的药物发现及其基础研究有了很大的进展,但仍然存在很多亟待解决的问题.本文综述了钒配合物的抗肿瘤、抗糖尿病作用和分子机制,及其潜在新作用——抗阿尔茨海默症的作用,也介绍了钒配合物的毒性作用及其机制研究.另外,本文在阐明其药理作用和毒性作用分子机理的基础上,综述了钒配合物的理性药物设计,包括基于与靶蛋白作用的钒配合物、基于BMOV先导化合物的钒配合物和基于抗氧化策略的钒配合物等.未来抗糖尿病钒配合物的理性药物设计的关键仍是如何平衡其潜在毒性与抗糖尿病药理活性,而通过抗氧化策略的钒配合物设计或许是解决这一关键问题的有效途径.

关键词：钒配合物糖尿病阿尔茨海默症 PPAR Aβ

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Discovery of novel dithiocarbamic acid ester HGWJ-11C with significant anticancer action

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Journal of Chinese Pharmaceutical Sciences 2014年第10期23卷 681-687页

作者：刘彬卫军王一强葛泽梅李润涛北京大学医学部天然药物及仿生药物国家重点实验室药学院化学生物学系北京100191

To find novel lead compound, seventy-four compound libraries were built through two rounds by a solution-phase CC on the basis of our developed method for the synthesis of dithiocarbamic acid ester. After evaluation for the antitumor activities of libraries, six compounds were selected to be synthesized and examined their antitumor activities. It was found that compound 13 （HGWJ-11 C） with novel structure exhibited significant antitumor activities and the scaffold of dithiocarbamic acid was very crucial for the antitumor activity. The compound 13 is worth studying deeply as a potent hit compound.

关键词： Libraries Solution-phase CC Dithiocarbamic acid ester Antitumor

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Different responses of HepG2 subclones to low dose ethaselen

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Journal of Chinese Pharmaceutical Sciences 2016年第4期25卷 302-309页

作者：张国州熊堃马薇薇徐伟曾慧慧北京大学医学部药学院化学生物学系天然药物及仿生药物国家重点实验室北京100191

As a synthesized antineoplastic organoselenium compound, ethaselen is known to induce apoptosis in tumor cells via dose-dependent thioredoxin reductase （TrxR） inhibition. Thioredoxin, the multifunctional biological substrate of TrxR, is then left in the oxidized state, which subsequently leads to intracellular accumulation of reactive oxygen species （ROS）, cell cycle arrest and/or apoptosis. However, the low dose effect of ethaselen remains largely unknown. Several subclones have been derived from HepG2 cells by using single cell or colony isolation. The low dose of ethaselen was defined as the drug concentration of retaining 〉90% HepG2 cells alive. The HepG2 cells were used as reference of its subclones （SM01, SM02 and SM03）, and the cell cycle transition, intracellular proteins change, colony formation and sphere growth were assayed in treatment of low dose ethaselen. HepG2 and its subclones differently responded to lethal dose of cisplatin or 5-fluorouracil. Low dose of ethaselen （1 μm） modulated the cell cycle transition at 12 h of treatment, but ceils were partially recovered at 24 h of treatment though some proteins were still affected. Low dose of ethaselen did not inhibit the small colony （diameter 〉 100 μm） formation and sphere growth of HepG2 and SM01. However, low dose of ethaselen could specifically inhibit the survival, large colony （diameter 〉500 μm） formation and sphere growth of SM03, although SM03 could be rapidly recovered from ethaselen-induced cell cycle check. HepG2 and its subclone cells could survive but respond differently to treatment of low dose ethaselen （1 μM）. Low dose of ethaselen could significantly inhibit a HepG2 subclone （SM03） in cell survival and colony growth.

关键词： Low dose Organoselenium Ceil subcloning Heterogeneity Tumor cell

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Scalable synthesis of salidroside

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Journal of Chinese Pharmaceutical Sciences 2014年第7期23卷 446-453页

作者：梁清照李辉张文轩孟祥豹李中军北京大学医学部天然药物及仿生药物国家重点实验室药学院化学生物学系北京100191

By analyzing the key steps that restricted the industrial synthesis of salidroside, selective protection of tyrosol with different acylation reagents was adopted. The strategy facilitated the crystallization of intermediates, which allowed the scalable synthesis of salidroside. It included a reaction of penta-O-acetyl-β-D-glucose with acyl protected tyrosol in the presence of Lewis acid catalyst（ZnCl2）, followed by deacylation under basic condition（NaOMe/MeOH） to give the salidroside. The total yield of this three-step reaction was 47%. Final product and intermediates were purified by recrystallization, which significantly reduced the cost and made the large scale synthesis feasible.

关键词： Salidroside Acylation of tyrosol Crystallization Scale up feasibility Synthesis

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The long-term toxicity and hypoglycemic effect of vanadyl complexes on non-diabetic and type Ⅱ diabetic mice

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Journal of Chinese Pharmaceutical Sciences 2015年第11期24卷 734-743页

作者：王子维王娜黄美玲杨晓达北京大学医学部药学院天然药物及仿生药物国家重点实验室化学生物学系北京100191

Vanadium compounds are promising anti-diabetic agents. However, the concern in the toxicity, especially the long-term renal side effect along with diabetic status, is restricting the further development of this metal drug. Recently, we have prepared a bis（（5-hydroxy-4-oxo-4H-pyran-2-yl） methyl 2-hydroxy-benzoatato） oxovanadium（BSOV）, which exhibited excellent hypoglycemic effect with low acute toxicity. In order to facilitate the development of anti-diabetic vanadium complexes, especially BSOV, we studied the long-term toxicity and hypoglycemic effect of BSOV in comparison with bis（maltolato） oxovanadium（BMOV） on both non-diabetic and type II diabetic mice. The experiments confirmed a stable hypoglycemic effect for both the vanadium complexes over the testing period（6–7 months）. However, the chronic administration of vanadium compounds slightly increased oxidative stress in ICR mice and the induced renal interstitial edema（RIE） in a part of the diabetic animals associated with low levels of serum albumin. The use of an antioxidant dietary supplement（a combination of vitamin C and Zinc gluconate） could prevent vanadium-induced oxidative stress but have marginal effect on RIE. However, BSOV caused much lower incidence of RIE than BMOV did, suggesting that BSOV is an important step towards the successful development of anti-diabetic vanadium drugs.

关键词： Bis((5-hydroxy-4-oxo-4H-pyran-2-yl) methyl 2-hydroxy-benzoatato) oxovanadium Vanadium Diabetes Long-term toxicity

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Vanadium regulates HSP60-induced IL-6 release from RAW264.7 cells in a dose-dependent manner

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Journal of Chinese Pharmaceutical Sciences 2015年第1期24卷 28-33页

作者：郭巍杨晓达北京大学医学部药学院化学生物学系天然药物及仿生药物国家重点实验室北京100191

Vanadium compounds are promising anti-diabetic agents. However, the underlying mechanisms have not been fully elucidated. Inflammation and auto-immune disorders play important roles in the progresses of both type Ⅰ and type Ⅱ diabetes, in which heat shock protein 60 （HSP60） is an important endogenous inflammatory mediator. In the present work, we investigated the effects of vanadium compounds （vanadyl sulfate and sodium metavanadate） on the IL-6 production in RAW264.7 cells upon HSP60 stimulation. Our data revealed that both vanadyl ions regulated the IL-6 expression in a concentration-dependent manner. However, the two common NF-κB and PPAR-γ, signal pathways were not involved in this process. Further works are needed to elucidate the underlying mechanism and significance of the immuno-modification actions for the pharmacological applications of anti-diabetic vanadium compounds.

关键词： Vanadyl ions Heat shock protein 60 Interleukin-6

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Design,synthesis and anti-tumor activities of cyclic phosphoramidate mustard-quinazoline conjugates

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Journal of Chinese Pharmaceutical Sciences 2017年第10期26卷 727-736页

作者：陈加贝郑育奋孔维崎李鑫罗来春韩彦君林松文孙崎葛泽梅李润涛北京大学医学部药学院化学生物学系天然药物及仿生药物国家重点实验室北京100191

A series of new cyclic phosphoramidate mustard-quinazoline conjugates were designed and synthesized based on the drug candidate EMB-3, a multi-target-directed ligand against tumor cells, and their anti-tumor activities were evaluated on breast cancer and lung cancer cells. Compound 6d exhibited the best anti-tumor performance with IC5o = 0.6 pM （8-fold of EMB-3） on BT474 breast tumor cells. Compound 6d inhibited epidermal growth factor receptor （EGFIL biomarker for NSCLC） and human epidermal growth factor 2 （HER2, biomarker for breast cancer） with IC50 of 18 nM and 78 nM, respectively. The preliminary pharmacokinetic study revealed that 6d was more stable than EMB-3 during the in vivo metabolism. A single dose per os （PO） administration of 6d in rat model （10 mg/kg） resulted in a moderate tl/2 of 1.7 h. These results indicated that compound 6d was a potential lead compound for the treatment of breast cancer.

关键词： Phosphoramidate mustard conjugate Anti-tumor Breast cancer EGFR/HER2

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Butaselen and cisplatin synergistically inhibit human cancer cells proliferation

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Journal of Chinese Pharmaceutical Sciences 2017年第8期26卷 595-604页

作者：邹乔陈伊凡郑小青徐彬瑗刘禹锡曾慧慧北京大学医学部药学院天然药物及仿生药物国家重点实验室北京100191 北京大学医学部药学院化学生物学系北京100191

Cisplatin （CDDP）, a platinum-containing drug, has been widely used in the therapy of many types of cancers today. However, the side effects of CDDP have limited its clinical application. Butaselen （BS）, a TrxR inhibitor designed by our group, has shown anti-tumor effects in vivo and in vitro. In this study, we investigated the combinatory effects of BS and CDDP on BEL-7402 cells, LoVo cells, HeLa cells and A549 cells. We observed synergistic effects when BS and CDDP were used in combination, especially in BEL-7402 cells. Apoptosis analysis also revealed that the combination treatment of BS and CDDP （1：1） for 48 h induced higher apoptotic effects in BEL-7402 cells. A further study in BEL-7402 cells showed that the synergistic effect might be mediated by the sharp reduction of ratio of Bcl-2/Bax protein. Taken together, the combination of CDDP and BS might be of great potential for chemotherapy.

关键词： Butaselen Cisplatin Synergistic effect Bcl-2 Bax

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A new proteasome inhibitor YSY-01A induced autophagy in PC-3M cells

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Journal of Chinese Pharmaceutical Sciences 2014年第8期23卷 565-571页

作者：王喆袁霞葛泽梅冉福香吴军李润涛崔景荣北京大学医学部天然药物及仿生药物国家重点实验室北京100191 北京大学医学部药学院化学生物学系北京100191

YSY-01A has shown proliferation inhibitory activity to certain types of tumor cells by inhibiting proteasome. How- ever, its effect on autophagy, which is related with the ubiquitin proteasome pathway （UPP）, remains unclear. Our study aimed to find out its effect on autophagy and possible molecular mechanisms. The results suggested that YSY-0 l A significantly （P〈0.001） inhibited proliferation of PC-3M cells （IC50 was 287 nM for 48 h） in a concentration-dependent and time-dependent manner. YSY-01A （100 nM, 3 h） also induced autophagy in PC-3M ceils through increasing the expression of P53 （P〈0.001）, Beclin-1 （P〈0.001） and LC3 （P〈0.001）, and decreasing the expression of p-roTOR （P〈0.001） as compared with the negative control group. Autophagy stayed at a final stage in PC-3M cells after treated with YSY-01A （400 nM） for 12 h. Meanwhile inhibition of autophagy with chloroquine increased the sensitivity to YSY-01A in PC-3M cells. In conclusion, YSY-01A showed high proliferation inhibitory activity of PC-3M cells and it could induce autophagy in PC-3M cells. Inhibiting autophagy increased the cytotoxic activity of YSY-01A in PC-3M cells.

关键词： Proteasome inhibitor YSY-01 A PC-3M Autophagy

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