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Chemical Research in Chinese Universities 2011年第6期27卷 955-957页

作者： YUAN Jing SU Xin ZHANG Xin CONG Lin GUO Chun Key Laboratory of Structure-based Drug Design ＆ discovery Ministry of Education Shenyang Pharmaceutical University Shenyang 110016 P. R. China

A series of 6-fluoro-3,3a,4,5-tetrahydro-2H-pyrazolo[4,3-c]quinoline-2-carboxamide derivatives was designed based on the bioisosterism and combination principle in drug design. The target compounds were synthesized from substituted aniline through Michael addition, cyclization, Mannich reaction and condensation with 4-substituted semicarbazides, and the structures were confirmed by mass spectrometry（MS） and 1H NMR. The antifungal assay was carried out in vitro by two-fold dilution. The result shows that all the compounds are of antifungal activities against the tested fungi at different levels.

关键词： 6-Fluoro-3 3a 4 5-tetrahydro-2H-pyrazolo[4 3-c]quinoline-2-carboxamide derivative Cysteine protease in-hibitor Antifungal activity

Synthesis and Biological Evaluation of Novel 5,7-Diphenylimidazo[1,2-a]pyridine Derivatives

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Chemical Research in Chinese Universities 2014年第5期30卷 759-763页

作者： LIAO Huimin CHONG Lian'e TAN Li CHEN Xiaodan YOU Rui GONG Ping Key Laboratory of Structure-Based Drug Design and discovery Ministry of Education Shenyang Pharmaceutical University Shenyang 110016 P. R. China

A series of novel 5,7-diphenylimidazo[1,2-a]pyridine derivatives was designed and synthesized. The in vitro cytotoxic activities of all the target compounds against human colorectal cancer（HT-29）, human lung can- cer（H460）, human gastric cancer（MKN45） and human breast cancer（MDA-MB-231） cell lines were evaluated. The pharmacological results indicated that most of the target compounds showed moderate to excellent activities against the tested cell lines. The most promising compound 4h（0.20, 0.006, 0.08, 0.021 μmol/L） was 2.6, 5.1, 3.6 and 21.9 times more active than EPC2407（0.52, 0.031, 0.29, 0.46 μmol/L） against HT-29, H460, MKN45 and MDA-MB-231 cell lines, respectively.

关键词： Imidazo[1,2-a]pyridine Biological evaluation Antitumor activity

TRIB3-GSK-3β interaction promotes lung fibrosis and serves as a potential therapeutic target

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Acta Pharmaceutica Sinica B 2021年第10期11卷 3105-3119页

作者： Shanshan Liu Xiaoxi Lv Xupeng Wei Chang Liu Qiao Li Jiali Min Fang Hua Xiaowei Zhang Ke Li Pingping Li Yang Xiao Zhuowei Hu Bing Cui State Key Laboratory of Bioactive Substance and Function of Natural Medicines Institute of Materia MedicaCAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and TumorigenesisChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100050China Department of Pharmacy Pharmacy CollegeHebei UniversityBaoding 071000China National Clinical Research Center for Metabolic Diseases Department of Metabolism and Endocrinologythe Second Xiangya HospitalCentral South UniversityChangsha 410011China Institute of Medicinal Biotechnology Chinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100050China

Pulmonary fibrosis(PF)is a chronic,progressive,fatal interstitial lung disease with limited available therapeutic *** recently reported that the protein kinase glycogen synthase kinase-3β(GSK-3β)interacts with and inactivates the ubiquitin-editing enzyme A20 to suppress the degradation of the transcription factor CCAAT/enhancer-binding protein beta(C/EBPβ)in alveolar macrophages(AMs),resulting in a profibrotic phenotype of AMs and promoting the development of ***,we showed that chronic lung injury upregulated the stress response protein tribbles homolog 3(TRIB3),which interacted with GSK-3βand stabilized GSK-3βfrom ubiquitination and *** GSK-3βexpression phosphorylated A20 to inhibit its ubiquitin-editing activity,causing the accumulation of C/EBPβand the production of several profibrotic factors in AMs and promoting PF *** C/EBPβ,in turn,increased the transcription of TRIB3 and GSK-3β,thereby establishing a positive feedback loop in *** knockdown of TRIB3 expression or the pharmacologic disruption of the TRIB3-GSK-3βinteraction was an effective PF *** study reveals an intact profibrotic axis of TRIB3-GSK-3β-A20-C/EBPβin AMs,which represents a target that may provide a promising treatment strategy for PF.

关键词： E3 ligase Lung injury Protein phosphorylation Protein-protein interaction Ubiquitination TRIB3 GSK-3β

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动态预涂层在CE联用技术中的应用

生命科学仪器 2007年第2期5卷 24-27页

作者： William W.P. Chang Christine Hobson David C. Bomberger Luke V. Schneider Dr. Chang is Scientist Ms. Hobson is Associate Scientist Target Discovery Inc. Palo Alto CA 94303 U.S.A Dr. Bomberger is Director of Manufacturing Target Discovery Inc. Palo Alto CA 94303 U.S.A Dr. Schneider is Chief Scientific Officer Target Discovery Inc. Palo Alto CA 94303 U.S.A

毛细管电泳与传统分离方法相比,具有分析时间短、分辨率高、样品/缓冲液用量少、易于自动化、功能多样性等优点。尽管如此,毛细管电泳在分析领域仍未能展现出全部的潜力。这是由于在大多数要求比较苛刻的实际应用中,毛细管电泳难以获得... 详细信息

毛细管电泳与传统分离方法相比,具有分析时间短、分辨率高、样品/缓冲液用量少、易于自动化、功能多样性等优点。尽管如此,毛细管电泳在分析领域仍未能展现出全部的潜力。这是由于在大多数要求比较苛刻的实际应用中,毛细管电泳难以获得较高的重现性。本文对该问题进行了阐述,并提出了一个很有前途的解决方法。

关键词：联用技术应用预涂层毛细管电泳 CE 功能多样性分离方法分辨率

Recent advances in developing active targeting and multi-functional drug delivery systems via bioorthogonal chemistry

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Signal Transduction and targeted Therapy 2023年第1期8卷 13-37页

作者： Wenzhe Yi Ping Xiao Xiaochen Liu Zitong Zhao Xiangshi Sun Jue Wang Lei Zhou Guanru Wang Haiqiang Cao Dangge Wang Yaping Li State Key Laboratory of Drug Research&Center of Pharmaceutics Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China Yantai Key Laboratory of Nanomedicine&Advanced Preparations Yantai Institute of Materia MedicaYantai 264000China Shandong Laboratory of Yantai Drug discovery Bohai Rim Advanced Research Institute for Drug DiscoveryYantai 264000China

Bioorthogonal chemistry reactions occur in physiological conditions without interfering with normal physiological *** metabolic engineering,bioorthogonal groups can be tagged onto cell membranes,which selectively attach to cargos with paired groups via bioorthogonal *** to its simplicity,high efficiency,and specificity,bioorthogonal chemistry has demonstrated great application potential in drug *** the one hand,bioorthogonal reactions improve therapeutic agent delivery to target sites,overcoming off-target *** the other hand,nanoparticles and biomolecules can be linked to cell membranes by bioorthogonal reactions,providing approaches to developing multi-functional drug delivery systems(DDSs).In this review,we first describe the principle of labeling cells or pathogenic microorganisms with bioorthogonal *** then highlight recent breakthroughs in developing active targeting DDSs to tumors,immune systems,or bacteria by bioorthogonal chemistry,as well as applications of bioorthogonal chemistry in developing functional bio-inspired DDSs(biomimetic DDSs,cell-based DDSs,bacteria-based and phage-based DDSs)and ***,we discuss the difficulties and prospective direction of bioorthogonal chemistry in drug *** expect this review will help us understand the latest advances in the development of active targeting and multi-functional DDSs using bioorthogonal chemistry and inspire innovative applications of bioorthogonal chemistry in developing smart DDSs for disease treatment.

关键词： functional orthogonal breakthrough

Design,Synthesis and Biological Evaluation of Pyrrolo[2,1-c][1,4]benzodiazepine-3,11-dione Derivatives as Novel Neuroprotective Agents

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Chemical Research in Chinese Universities 2021年第3期37卷 647-654页

作者： QUAN Jishun ZHANG Dongping ZHANG Zhuo WANG Jian MA Chao CHENG Maosheng Key Laboratory of Structure-based Drug Design&discovery of Ministry of Education School of Pharmaceutical EngineeringShenyang Pharmaceutical UniversityShenyang110016P.R.China

A series of pyrrolo[2,1-c][1,4]benzodiazepine-3,11-dione derivatives was designed and synthesized,and their neuroprotective activity against SH-SY5Y cell injury induced by N-methyl-D-aspartic acid(NMDA)was *** the compounds showed significant neuroprotective effects,especially B16,which showed excellent performance and better activity than the positive control ifenprodil(B16:56.2%±0.6%;ifenprodil:41.0%±2.7%).Further investigation indicated that B16 could attenuate the Ca^(2+)influx induced by NMDA in SH-SY5Y cells and Western blotting also showed that B16 could attenuate the NR2B upregulation in SH-SY5Y cells induced by *** molecular docking results showed that compound B16 fitted in the binding pocket of NR2B-NMDAR well and could interact with binding sites of compounds 1 and 2 *** ADME/Tox prediction results suggested that compound B16 had good blood-brain barrier(BBB)permeability and the zero alert of Pan Assay Interference Structures(PAINS)indicated that B16 could not elicit false-positive *** results strongly suggest that B16 is a promising and effective candidate neuroprotective compound,and that NR2B-NMDAR is a potential target of B16.

关键词： Neuroprotective activity Ca^(2+)influx Western blotting NR2B-NMDA receptor Molecular docking

discovery of first-in-class DOT1L inhibitors against the R231Q gain-of-function mutation in the catalytic domain with therapeutic potential of lung cancer

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Acta Pharmaceutica Sinica B 2024年第8期14卷 3605-3623页

作者： Zehui Tan Ning Guo Zhi Cao Shuyu Liu Jiayu Zhang Deyi Ma Jiahao Zhang Wencai Lv Nan Jiang Linghe Zang Lihui Wang Xin Zhai Key Laboratory of Structure-Based Drug Design and discovery Ministry of EducationShenyang Pharmaceutical UniversityShenyang 110016China Department of Pharmacology Shenyang Pharmaceutical UniversityShenyang 110016China

Recent research certified that DOT1L and its mutations represented by R231Q were potential targets for the treatment of lung ***,a series of adenosine-containing derivatives were identified with DOT1LR231Q inhibition through antiproliferation assay and Western blot analysis in the H460R231Q *** most promising compound 37 significantly reduced DOT1LR231Q mediated H3K79 methylation and effectively inhibited the proliferation,self-renewal,migration,and invasion of lung cancer cell lines at low micromolar *** cell permeability and cellular target engagement of 37 were verified by both CETSA and DARTS *** the H460R231Q OE cell-derived xenograft(CDX)model,37 displayed pronounced tumor growth inhibition after intraperitoneal administration at 20 mg/kg dose for 3 weeks(TGI=54.38%),without obvious toxicities.A pharmacokinetic study revealed that 37 possessed tolerable properties(t_(1/2)=1.93±0.91 h,F=97.2%)after intraperitoneal administration in *** study confirmed that 37 suppressed malignant phenotypes of lung cancer carrying R231Q gain-of-function mutation via the MAPK/ERK signaling ***,analysis of the binding modes between molecules and DOT1LWT/R231Q proteins put forward the“Induced-fit”allosteric model in favor to the discovery of potent DOT1L candidates.

关键词： DOT1L R231Q mutation Lung cancer Adenosine-containing inhibitors Epigenetics

Moutan Cortex and Paeoniae Radix Rubra reverse high-fat-diet-induced metabolic disorder and restore gut microbiota homeostasis

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Chinese Journal of Natural Medicines 2017年第3期15卷 210-219页

作者： ZHONG Ling-Jun XIE Zhi-Sheng YANG Hua LI Ping XU Xiao-Jun State Key Laboratory of Natural Medicines China Pharmaceutical UniversityNanjing 210009China Jiangsu Key Laboratory of Drug discovery for Metabolic Diseases China Pharmaceutical UniversityNanjing 210009China

The present study was designed to investigate the therapeutic effcts of Moutan Cortex(CM,root bark of Paeonia suffruticosa Andr) and Paeoniae Radix Rubra(PR,root of Paeonia veitchii Lynch) on metabolic disorders,focusing on the infuence of CM and PR on the obesity-related gut microbiota *** diet-induced obese(DIO) mouse model was used to test the therapeutic effects of CM and *** mice were orally administered with CM and PR for 6 weeks,and oral glucose tolerance test(OGTT) and insulin tolerance test(ITT) were performed to evaluate the insulin sensitivity of the ***-regulatory element binding proteins(SREBPs) and their target genes were measured by quantitative ***-throughput 16 S ribosomal RNA(16S rR NA) gene sequencing technology was used to determine the composition of gut microbiota,and the metabolites in serum were analyzed by *** results indicated that CM and PR combination alleviated obese and insulin resistance in the DIO mice,leading to increased glucose uptake and gene expression in muscle and liver,and down-regulated SREBPs and their target genes in ***,neither the CM-PR extracts,nor the major components of CM and PR did not affect SREBPs activity in cultured ***,CM and PR significantly modulated the gut microbiota of the high-fat diet(HFD) treated mice,similar to metformin,and CM-PR reversed the overall microbiota composition similar to the normal chow diet(NCD) treated *** conclusion,our results provide novel mechanisms of action for the effects of CM and PR in treating DIO-induced dysregulation of sugar and lipid metabolism.

关键词： Moutan Cortex Paeoniae Radix Rubra Insulin resistance Gut microbiota

Synthesis, Crystal, Calculated Structure and Biological Activity of N-((6-bromo-2-methoxyquinolin-3-yl)(phenyl) methyl)-N-(1-adamantyl)-3-(dimethylamino) Propanamide

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Chinese Journal of Structural Chemistry 2012年第2期31卷 205-210页

作者：白跃飞袁雷王丽娟高健王志强王晓菲孙铁民 Key Laboratory of Original New Drug Design&discovery Ministry of Education School of Pharmaceutical EngineeringShenyang Pharmaceutical University State Key Laboratory of Supramolecular Structure and Materials Jilin University

The halogenated hydrocarbon amination reaction between the original raw material N-（（6-bromo-2-methoxyquinolin-3-yl）（phenyl）methyl）-3-chloro-N-（1-adamantyl） propanamide and dimethylamine hydrochloride produces the target molecule N-（（6-bromo-2-methoxyquinolin-3- yl）（phenyl）methyl）-N-（1-adamantyl）-3-（dimethylamino） propanamide （C32H38BrN3O2, Mr = 576.56）, and its structure was confirmed by elemental analysis, IR, 1H NMR, MS, and X-ray diffraction. This crystal is of monoclinic system, space group P21/c with a = 10.760（5）, b = 14.768（5）, c = 19.635（5）, β = 113.969（16）°, V = 2851.0（18）3, Z = 4, Dc = 1.343 g/cm3, F（000） = 1208, μ（MoKα） = 1.475 mm-1, the final R = 0.0645 and wR = 0.2039. In total, 4681 independent reflections including 3164 observed ones with I 〉 2σ（I） were collected. The dihedral angle between substituted quinolyl and phenyl is 64.0°. Through C-H···O, C-H···N and C-H···Br weak hydrogen bonds among molecules, the whole molecule is stacked into a three-dimensional structure. The optimized geometric bond lengths and bond angles obtained by using density functional theory （DFT） have been compared with X-ray diffraction values. In addition, the preliminary biological test showed that the title compound has anti-Mycobacterium phlei 1180 activity.

关键词： synthesis X-ray diffraction DFT biological activity

Design,synthesis and primary activity of thiomorpholine derivatives as DPP-Ⅳinhibitors

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Chinese Chemical Letters 2012年第3期23卷 297-300页

作者： Bei Han Jing Long Liu Yi Huan Peng Li Qi Wu Zi Yun Lin Zhu Fang Shen Da Li Yin Hai Hong Huang Beijing Key Laboratory of Active Substances discovery and Druggability Evaluation Institute of Materia MedicaPeking Union Medical College&Chinese Academy of Medical SciencesBeijing 100050China

Thirteen thiomorpholine-bearing compounds were designed and synthesized as dipeptidyl peptidase IV（DPP-IV） inhibitors, with natural and non-natural L-amino acids as the starting *** structures were characterized by ~1H NMR,^（13）C NMR and *** target compounds were screened for the DPP-IV inhibition,and the preliminary SAR result was ***, compounds 4c,4d and 4f with good DPP-IV inhibition in vitro were further evaluated through a mouse oral glucose tolerance test （OGTT）.The preliminary result showed the potential value for further studies on those thiomorpholine-bearing compounds as DPP-IV inhibitors.

关键词： Thiomorpholine Dipeptidyl peptidaseⅣinhibitor Synthesis Structure-activity relationship Oral glucose tolerance test