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Synthesis and biological evaluation of novel derivatives of desloratadine

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Chinese Chemical Letters 2013年第6期24卷 531-534页

作者： Shuai Mu Xiao-Shuai Xie Duan Niu Da-Shuai Zhang Deng-Ke Liu Chang-Xiao Liu School of Chemical Engineering and Technology Tianjin University State Key laboratory of Drug Delivery Technology and Pharmacokinetics Tianjin Institute of Pharmaceutical Research Graduate School of Tianjin Medical University Tianjin Key laboratory of Molecular design and Drug Discovery Tianjin Institute of Pharmaceutical Research

Series of novel derivatives of desloratadine designed as arginine vasopressin receptor antagonists were synthesized and structurally characterized by melting points,^1H NMR and *** in vivo diuretic activities were evaluated on rats,and several target compounds showed promising diuretic results, especially compounds 8,18,27 and *** in vitro bonding assay and cAMP assay showed that these compounds had a higher affinity to vasopressin V2 receptor than VI a *** studies indicated that desloratadine may be an active substructure for novel arginine vasopressin receptor antagonist development.

关键词： Derivatives of desloratadine Arginine vasopressin receptor antagonists Diuretic activity

Development of a method to quantify total and free irinotecan and 7-ethyl-10-hydroxycamptothecin(SN-38) for pharmacokinetic and bio-distribution studies after administration of irinotecan liposomal formulation

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Asian Journal of pharmaceutical Sciences 2019年第6期14卷 687-697页

作者： Wenqian Yang Zimeng Yang Jieru Liu Dan Liu Yongjun Wang Wuya College of Innovation Shenyang Pharmaceutical UniversityShenyang 110016China Key laboratory of Structure-Based Drugs design&Discovery of Ministry of Education Shenyang Pharmaceutical UniversityShenyang 110016China

In 2015,liposomal formulation of irinotecan(ONIVYDE)has been approved by FDA and widely applied in the treatment of pancreatic *** is a novel liposome formulation,entrapping CPT-11 in the aqueous core of vesicles using a modified gradient loading *** to toxicity concerns,it is essential to explore a rapid and reliable method to effectively isolate and quantify the non-liposomal,namely,free CPT-11and total CPT-11 in *** study focuses on separation of non-liposomal CPT-11,evaluation of the pharmacokinetics of free CPT-11 and total CPT-11 and bio-distribution after intravenous administration of CPT-11 *** CPT-11 in plasma was separated by solid-phase extraction(SPE).The amount of total CPT-11 and main metabolite 7-ethyl-10-hydroxycamptothecin(SN-38)in plasma was quantified by ultra-performance liquid chromatography–MS/*** calibration curves fitted well and lower limit of quantitation for SN-38,free CPT-11,total CPT-11 and CPT-11 in tissue and were 5 ng/ml,10 ng/ml,4.44 ng/ml and 25 ng/ml *** recoveries,precision and accuracy of the method appear *** this method,the pharmacokinetics and bio-distribution of CPT-11 liposome formulation after an intravenous dose of 2.5 mg/kg were then investigated.

关键词： Irinotecan Liposome UPLC-MS-MS SPE Pharmacokinetics Bio-distribution

Two new C_(21) steroidal glycosides isolated from Cynanchum komarovii

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Chinese Journal of Natural Medicines 2018年第8期16卷 610-614页

作者： ZHAO Dan SU Shan-Shan CHEN Shao-Fei LU Xiao-Jie CHEN Gang WANG Yu-Bo SU Guang-Yue PEI Yue-Hu Key laboratory of Structure-Based Drug design & Discovery Ministry of EducationShenyang Pharmaceutical University School of Traditional Chinese Materia Medica Shenyang Pharmaceutical University Testing laboratory Qinghai Entry Exit Inspection and Quarantine Bureau School of Pharmacy Jinzhou Medical University

The present study was designed to further investigate the C_(21) steroidal glycosides in Cynanchum *** new steroidal glycosides based on a 13,14:14,15-disecopregnane-type aglycone,komaroside P(1) and komaroside Q(2),together with three known compounds(3-5) were isolated from the whole herbs of Cynanchum *** aglycones of compounds 1 and 2 were two new *** structures were elucidated on the basis of 1 D,2 D NMR spectroscopic data and acid *** the compounds(1-5) showed potent inhibitory activities against human leukemia cell lines(HL-60) with IC50 values ranging from 16.6 to 26.3 μmol·L^(-1),compared to the positive control 5-fluorouracil(6.4 μmol·L^(-1)).

关键词： Cynanchum komarovii C21 steroidal glycosides Cytotoxic activity

A novel mitochondria-targeting tetrapeptide for subcellular delivery of nanoparticles

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Chinese Chemical Letters 2019年第7期30卷 1435-1439页

作者： Yanhui Sun Aiyan Zhan Shuang Zhou Xiao Kuang Hongyan Shen Hongzhuo Liu Youjun Xu School of Pharmaceutial Engineering Key Laboratory of Structure-Based Drug Design & Discovery(Ministry of Education) Shenyang Pharmaceutical University Shenyang 110016 China Wuya College of Innovation Shenyang Pharmaceutical University Shenyang 110016 China

Mitochondrial dysfunction is associated with the emergence of several neurological and cardiovascular diseases. Hence, mitochondria-targeting delivery strategies are highly significant and critically needed. In this study, we developed a small library of peptides simulating the mitochondria-targeting peptide SS-31, a promising tetra-peptide with antioxidant character, and subsequently evaluated the toxicity, antioxidant ability and mitochondrial delivery of nanoparticles. Among the designed peptides, RF-2 (DArg-Dmt-Arg-Phe-NH2) showed controlled toxicity and excellent protection against gentamicin-induced hair cell damage, as compared with SS-31. More importantly, RF-2-modified PLGA nanoparticles demonstrated high colocalization with mitochondria and comparable specific subcellular accumulation, when compared with SS-31. Taken together, the obtained results supported RF-2 as a mitochondriatargeting peptide with high potential as a targeted carrier.

关键词： Mitochondrial targeting Peptide SS-31 Toxicity Nanoparticles Zebrafish

Distinctive Cassane Diterpenoids Corroborated Biogenetic Evolutionary Process from Caesalpinia mimosoides with Anti-renal Fibrosis Activity

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Chinese Journal of Chemistry 2022年第5期40卷 617-627页

作者： Xinxin Zhang Yan Yin Yu Zhou Tianliang Zhu Miao Wang Huiyuan Gao School of Traditional Chinese Materia Medica Shenyang Pharmaceutical UniversityShenyangLiaoning110016 China Key laboratory of Structure-Based Drug design&Discovery of Ministry of Education Shenyang Pharmaceutical UniversityShenyangLiaoning110016 China

Eighteen diterpenoids were isolated from the seeds of Caesalpinia mimosoides,including four extremely infrequent cassane diterpenes,together with nine new and five known *** 7 and 8 represent the first examples of cassane diterpenoids fused with a ketone carbonyl and a ternary oxygen ring at C-4,*** 9 and 10 possess a rare five-member ring in cassane ***,these isolated components are a clue to the fact that there are lower and higher levels in the plant secondary metabolites,demonstrating the evolution of secondary metabolism of *** the isolated compounds were tested for their anti-renal fibrosis activity against TGF-β1 induced NRK-52E cell *** mRNA levels of fibrosis markerα-SMA,E-cadherin,Collagen I were tested by *** data showed compounds 6 and 9 exhibited the best anti-renal fibrosis activity and provided preliminary structure−activity relationships.

关键词： Cassane diterpene Caesalpinia mimosoides Natural products Molecular evolution Biological activity

Directly targeting BAX for drug discovery:Therapeutic opportunities and challenges

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Acta Pharmaceutica Sinica B 2024年第6期14卷 2378-2401页

作者： Zhenwei Zhang Linghui Hou Dan Liu Shenglin Luan Min Huang Linxiang Zhao Key laboratory of Structure-Based Drugs design&Discovery of Ministry of Education Shenyang Pharmaceutical UniversityShenyang 110016China China Resources Sanjiu Medical&pharmaceutical Co. Ltd.Shenzhen 518000China

For over two decades,the development of B-cell lymphoma-2(Bcl-2)family therapeutics has primarily focused on anti-apoptotic proteins,resulting in the first-in-class drugs called BH3 mimetics,especially for Bcl-2 inhibitor *** pro-apoptotic protein Bcl-2-associated X protein(BAX)plays a crucial role as the executioner protein of the mitochondrial regulated cell death,contributing to organismal development,tissue homeostasis,and *** dysregulation of BAX is closely associated with the onset and progression of diseases characterized by pathologic cell survival or death,such as cancer,neurodegeneration,and heart *** addition to conducting thorough investigations into the physiological modulation of BAX,research on the regulatory mechanisms of small molecules identified through biochemical screening approaches has prompted the identification of functional and potentially druggable binding sites on BAX,as well as diverse all-molecule BAX *** review presents recent advancements in elucidating the physiological and pharmacological modulation of BAX and in identifying potentially druggable binding sites on ***,it highlights the structural and mechanistic insights into small-molecule modulators targeting diverse binding surfaces or conformations of BAX,offering a promising avenue for developing next-generation apoptosis modulators to treat a wide range of diseases associated with dysregulated cell death by directly targeting BAX.

关键词： Apoptosis Pro-apoptotic protein BAX Dynamic conformational activation Small-molecule apoptosis modulators

design,synthesis,and screen of cathepsin K inhibitors

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Chinese Chemical Letters 2013年第8期24卷 715-718页

作者： Ying-Ying Yu Wei Sun Lei Dong Hai-Dong Liu Dan Jiang Jun-Hai Xiao Xiao-Hong Yang Song Li School of pharmaceutical Sciences Jilin University laboratory of Computer-Aided Drug design and Discovery Beijing Institute of Pharmacology and Toxicology First Affiliated Hospital of Jilin University

We synthesized a series of epoxysuccinic acid derivatives and evaluated their in vitro cathepsin K inhibitory activity The screening results show that the potency of compounds 9e,9d,9p,9j and 9k （IC_（50）≤0.005μmol/L） were equal to or greater than that of the lead compound *** hydrophobic compounds showed weaker potency,which can be explained by the hydrophobic nature of the cathepsin K binding pockets.

关键词： Epoxysuccinic acid derivatives Synthesis Inhibitors Cathepsin K

Synthesis,Crystal Structure and Biological Activity of 2-[(Pyridin-2-yl)methylthio]-1H-benzimidazole Derivatives

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Chinese Journal of Structural Chemistry 2017年第12期36卷 2020-2026页

作者：高迪陈固洲曹胜杜月金辄刘晓平欧阳贵平胡春 Key laboratory of Green Pesticide and Agricultural Bioengineering Ministry of EducationResearch and Development Center of Fine Chemicals Guizhou University Key laboratory of Structure-based Drug design & Discovery Ministry of EducationShenyang Pharmaceutical University

In order to discover the novel anti-tumor agents, a series of 2-[（pyridin-2-yl）methylthio]-1 H-benzimidazole derivatives were designed and synthesized, and the structures were characterized by IR, MS, and proton NMR. 2-[（3,4-Dimethoxypyridin-2-yl）methylthio]-1 Hbenzimidazole was investigated with X-ray crystallography, and the molecule is in orthorhombic system, space group P212121, with a = 9.1828（16）, b = 11.625（2）, c = 13.463（2）？, Z = 4, R = 0.0231 and wR = 0.0596. The antitumor activities of target compounds were evaluated against human liver cancer cell line HepG2, and human liver normal cell line HL7702 using MTT assay. The target compounds have demonstrated weak or moderate anti-tumor activity against HepG2, while all the target compounds exhibit no cytotoxic effects on HL7702.

关键词： 2-[(pyridin-2-yl)methylthio]-lH-benzimidazole derivatives synthesis crystal structure antitumor activity

Ratiometric delivery of doxorubicin and berberine by liposome enables superior therapeutic index than Doxil?

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Asian Journal of pharmaceutical Sciences 2020年第3期15卷 385-396页

作者： Ruoshi Zhang Yingxi Zhang Yue Zhang Xin Wang Xuanming Gao Yuyan Liu Xuanbo Zhang Zhonggui He Dun Wang Yongjun Wang Wuya College of Innovation Shenyang Pharmaceutical UniversityShenyang 110016China Department of Pharmaceutics Shenyang Pharmaceutical UniversityShenyang 110016China Key laboratory of Structure-Based Drug design and Discovery of Ministry of Education Shenyang Pharmaceutical UniversityShenyang 110016China

Although the appearance of Doxil alleviated the cardiotoxicity of DOX, the progression-free survival of patients was not prolonged compared with traditional medication regimens, and side effects such as hand-foot syndrome has occurred. In order to solve this dilemma, we have designed a novel co-delivery strategy to construct a co-loaded liposome of berberine(BER) and doxorubicin(DOX), which was called Lipo Be Do. The optimal synergistic ratio of the two drugs was screened by cell cytotoxicity experiments in vitro, and the optimal attenuation ratio was further determined by in vivo cardiac H&E staining pathological sections. The optimal combination treatment caused a robust increase in apoptotic cells of 4T1, as compared to drug alone treatment. The prepared co-loaded liposome, Lipo Be Do, had high encapsulation efficiency and good stability. The nanoliposome carrier controlled the biological fate of the drugs and maintained a pre-defined optimal ratio in vivo. The Lipo Be Do significantly inhibited tumor growth in 4T1 murine mammary carcinoma model compared with Doxil(P < 0.05), and completely overcame the myocardial rupture toxicity caused by Doxil in mice. Our co-loaded liposome delivery platform technology provided a new direction for the clinical treatment of triple-negative breast cancer and the safe application of DOX.

关键词： Berberine Doxorubicin Nanoliposomes Remote loading Combination therapy Cardiotoxity