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Design,synthesis,antitumor evaluations and molecular modeling studies of novel 3.5-substituted indolin-2-one derivatives

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Acta Pharmacologica Sinica 2007年第1期28卷 140-152页

作者： Hai-hong LI~2 Xiu-hua ZHANG~3.Jin-zhi TAN~2 Li-li CHEN~2 Hong LIU~(2,5) Xiao-min LUO~(2,5) Xu SHEN~(2,4) Li-ping LIN~(3.5) Kai-xian CHEN~2 Jian DING~3.Hua-liang JIANG~(2,4)2 Center for drug Discovery and Design,state key laboratory of drug research,shanghai Institute of Materia Medica,shanghai Institutes for biological sciences,and Graduate School,chinese academy of sciences,shanghai 201203.china 3.division of anti-tumor pharmacology,shanghai Institute of Materia Medica,shanghai Institutes for biological sciences,chinese academy of sciences,shanghai 201203.china 4 School of Pharmacy,East china University of Science and Technology,shanghai 20023.,china Center for drug Discovery and Design State Key Laboratory of Drug Research Shanghai Institute of Materia Medica Shanghai Institutes for Biological Sciences and Graduate School Chinese Academy of Sciences Shanghai China division of anti-tumor {3. Shanghai Institute of Materia Medica Shanghai Institutes for Biological Sciences Chinese Academy of Sciences Shanghai China School of Pharmacy East China University of Science and Technology Shanghai China

Aim:To design and synthesize a novel class of antitumor agents,featuring the 3.5-substituted indolin-2-one ***:based on enzyme binding fea-tures of（Z）-SU5402,introducing a β-pyrrole group at the 3.position of the indolin-2-one core,a series of novel 3.5-substituted indolin-2-ones were designed *** human carcinoma cell lines of A-43.,A-549,MDA-Mb-468,and Autosomal Dominant Polycystic Kidney disease were chosen for the cellproliferation ***:Twenty new compounds（1a-t）with E configurationhave been designed,synthesized and *** structural features weredetermined by nuclear magnetic resonance（NMR）spectra,low-and high-resolu-tion mass spectra,and confirmed by X-ray *** the enzymeassay showed a weak inhibition effect against the epidermal growth factor receptor,vascular endothelial growth factor receptor,fibroblast growth factor receptor andplatelet-derived growth factor receptor tyrosine kinases,the cell-based antitumoractivity was *** 1 g and lh showed higher inhibitory activitytoward the A-549 and MDA-Mb-468 cell lines with IC50of 0.065-9.4 μmol/***:This study provides a new template for further development ofpotent antitumor drugs.

关键词： protein-tyrosine kinase indolin-2-one antitumor drug screening assays drug design molecular models

Design,synthesis and antitumor evaluation of a new series of N-substi-tuted-thiourea derivatives

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Acta Pharmacologica Sinica 2006年第9期27卷 1259-1271页

作者： Jian LI~2 Jin-zhi TAN~2 Li-li CHEN~2 Jian ZHANG~2 Xu SHEN~(2,3.Chang-lin MEI~(4,6)Li-li FU~4 Li-ping LIN~5 Jian DING~5 bing XIONG~2 Xi-shan XIONG~4 Hong LIU~(2,6)Xiao-min LUO~(2,6)Hua-liang JIANG~(2,3.2 drug Discovery and Design Centre,state key laboratory of drug research,shanghai Institute of Materia Medica,shanghai Institutes for biological sciences,chinese academy of sciences,shanghai 201203.china 3.School of Pharmacy.East china University of Science and Technology,shanghai 20023.,china 4 division of Nephrology,Department of Internal Medicine,Changzheng Hospital,Second Military Medical University,shanghai 200003.china 5 division of antitumor pharmacology,shanghai Institute of Materia Medica,shanghai 201203.china drug Discovery and Design Centre State Key Laboratory of Drug Research Shanghai Institute of Materia Medica Shanghai Institutes for Biological Sciences Chinese Academy of Sciences Shanghai China School of Pharmacy East China University of Science and Technology Shanghai China division of Nephrology Department of Internal Medicine Changzheng Hospital Second Military Medical University Shanghai China division of antitumor {3. Shanghai Institute of Materia Medica Shanghai China

Aim:To design and synthesize a novel class of protein tyrosine kinase inhibitors,featuring the N-(2-oxo-1,2-dihydroquinolin-3.yl-methyl)-thiourea ***:First,compounds 1 and 2 were identified using the virtual screeningapproach in conjunction with binding assay based on surface plasmon ***,3.regions of compounds 1 and 2 were selected for chemical *** compounds were characterized potent inhibitory activities toward thehuman lung adenocarcinoma cell line SPAC ***:Forty new compounds(1-2,3.-g,4a-w,and 5a-l)were designed,synthesized and *** com-pounds(1,3.,41,4w,5a,and 5b)were found to show promising inhibitory activityagainst the SPAC1 tumor cell *** inhibitory activity of compound 5aincreases approximately 10 times more than that of the original compound ***:This study provides a promising new template with potential antitu-mot activity.

关键词： N-substituted-thiourea derivatives antitumor SPAC1 tyrosine kinase inhibitor virtual screening

Effects of (-)-stepholidine on NMDA receptors:comparison with haloperidol and clozapine

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Acta Pharmacologica Sinica 2007年第7期28卷 953-958页

作者： Wei-hua GU~2,Shen YANG~2,Wei-xing SHI~3.Xue-chu ZHEN~2,Guo-zhang JIN~(2,4)~2 Department of pharmacology,state key laboratory of drug research,shanghai Institute of Materia Medica,shanghai Institutes ofbiological sciences,Graduate School of the chinese academy of sciences,chinese academy of sciences,shanghai 201203.china ~3.Neuropsychopharmacological research Unit,Department of Psychiatry,Yale University School of Medicine,New Haven,Connecticut06511,USA Department of pharmacology State Key Laboratory of Drug Research Shanghai Institute of Materia Medica Shanghai Institutes of Biological Sciences Graduate School of the Chinese Academy of Sciences Chinese Academy of Sciences Shanghai China Department of Psychiatry Neuropsychopharmacological Research Unit Yale University School of Medicine New Haven USA

Aim:To examine whether （-）-stepholidine （SPD） has a direct effect on the N-methyl-D-aspartic acid receptors （NMDAR） containing the NMDA receptor sub-units NR2A or NR2b and to compare its effect with those of haloperidol （Hal） andclozapine （Cloz）.Methods:NMDAR was transiently expressed in human embry-onic kidney 293.（HEK293. *** in intracellular calcium concentration([Ca2+]i) induced by NMDAR activation were monitored with Fura-2 ratio ***:SPD had no significant effects on either subunit of NMDARat a concentration of less than 100 μmol/*** selectively inhibited NMDARcontaining the NR2b subunit,whereas Cloz inhibited both subunits of *** both Hal and Cloz inhibited NR1a/NR2b receptor-mediated Ca2+influx,their effects were *** was more potent and had a faster peak effect ***:both Hal and Cloz inhibit NMDAR-mediated function,whereasSPD produced only a little inhibition at a high *** on our otherstudies,the modulation of SPD on NMDAR function may be via D1receptoraction underlying an indirect mechanism.

关键词： (-)-stepholidine haloperidol clozapine NMDA receptor calcium imaging neuroleptics

Requirement of PSD-95 for dopamine D1 receptor modulating glutamate NR1a/NR2b receptor function

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Acta Pharmacologica Sinica 2007年第6期28卷 756-762页

作者： Wei-hua GU~2,Shen YANG~2,Wei-xing SHI~(2,3.4),Guo-zhang JIN~2,Xue-chu ZHEN~(2,4)~2 Department of pharmacology,state key laboratory of drug research,shanghai Institute of Materia Medica,shanghai Institutes ofbiological sciences,chinese academy of sciences,shanghai 201203.china ~3.Neuropsychopharmacological research Unit,Department ofPsychiatry,Yale University School of Medicine,New Haven CT 06511,USA Department of pharmacology State Key Laboratory of Drug Research Shanghai Institute of Materia Medica Shanghai Institutes of Biological Sciences Chinese Academy of Sciences Shanghai China Department of Psychiatry Neuropsychopharmacological Research Unit Yale University School of Medicine New Haven USA

Aim:To elucidate the role of scaffold protein postsynaptic density （PSD）-95 inthe dopamine D1receptor （D1R）-modulated NR1a/NR2b receptor ***:The human embryonic kidney 293.cells expressing D1R （tagged with theenhanced yellow fluorescent protein） and NR1a/NR2b with or without co-expres-sion of PSD-95 were used in the *** Ca2+influx measured by imagingtechnique was employed to monitor N-methyl-D-aspartic acid receptors （NMDAR）***:The application of dopamine （DA,100 μmol/L） did not alterglutamate/glycine （Glu/Gly）-induced NMDAR-mediated Ca2+influx in cells onlyexpressing the D1R/NR1a/NR2b ***,DA increased Glu/Gly-induced Ca2+influx in a concentration-dependent manner while the cells wereco-expressed with PSD-95.D1R-stimulated Ca2+influx was inhibited by a selectiveD1R antagonist ***,pre-incubation with either the proteinkinase A （PKA） inhibitor H89,or the protein kinase C （PKC） inhibitor chelerythrineattenuated D1R-enhanced Ca2+influx induced by the N-methyl-D-aspartic acid（NMDA） *** results clearly indicate that D1R-modulated NR1a/NR2breceptor function depends on PSD-95 and is subjected to the regulation of PKAand ***:The present study provides the first evidence that PSD-95is essential in D1R-regulated NR1a/NR2b receptor function.

关键词： D1 dopamine receptor NMDA PSD-95 signal transduction calcium

Synthesis and SAR Studies of Phenanthroindolizidine and Phenanthroquinolizidine Alkaloids as Potent antitumor Agents

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Synthesis and SAR Studies of Phenanthroindolizidine and Phen...

2011年全国药物化学学术会议——药物的源头创新

作者： Ziwen Wang~a,Meng Wu~a,Zheng Li~a,Lei Wang~a,Gui fang Han~a,Fazhong Chen~a,Yu xiu Liu~a, Kai liang Wang~b,Ao Zhang ~(*,b),Linghua Meng~c,Qing min Wang~(*,a) a:state key laboratory of Elemento-Organic Chemistry,{3. Institute of Elemento-Organic Chemistry,Nankai University,Tianjin 3.0071,People’s Republic of {3. b:division of anti-tumor pharmacology,state key laboratory of drug research,shanghai Institute of Materia Medica(SIMM), chinese academy of sciences,shanghai 201203.china c:Synthetic Organic & Medicinal Chemistry laboratory(SOMCL),shanghai Institute of Materia Medica(SIMM),chinese {13. of sciences, shanghai 201203.china.

A series of phenanthroindolizidine and phenanthroquinolizidine alkaloids and their (13.S,14S)-14-amino-derivatives(1-44) were prepared and first systematically evaluated for their anti-tumor activities against A549 an... 详细信息

关键词： phenanthroindolizidine phenanthroquinolizidine anti-tumor activity blood-brain barrier

Curcumin induces DNA damage and ATM/ATR-independent cell cycle arrest in colorectal carcinoma HCT 116 cells

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Curcumin induces DNA damage and ATM/ATR-independent cell cyc...

2011医学科学前沿论坛第十二届全国肿瘤药理与化疗学术...

作者： Jin-Jian Lu~(a,b),Yu-Jun Cai~(a,*),Jian Ding~(a,*) a division of anti-tumor {3.,state key laboratory of drug research,shanghai Institute of Materia Mcdica,chinese academy of Science,shanghai 201203,P R.china b ''College of Life sciences,Zhejiang chinese Medical University,Hangzhou,Zhejiang Province,3.0053.E R.china

＜正＞Curcumin（CUR） is a polyphenol derived from the plant Curcuma longa and displays potential anti-cancer *** of the mechanisms stems from its ability to induce cancer cell cycle arrest followed by suppression of cell proliferation. Herein,we reported that CUR significantly mediated DNA damage and S and G2/M phase arrest in colorectal carcinoma HCT116 *** etoposide（VP16）,a topoisomeraseⅡinhibitor,mediated cell cycle arrest,CUR-mediated G2/M phase arrest was hardly reversed by caffeine（CAFF）,an inhibitor of activated ataxia-telangiectasia-mutated （ATM）/ATM-and Rad3.related（ATR）,indicating that ATM and ATR signaling pathways are not involved in CUR-mediated cell cycle arrest in HCT116 ***,we demonstrated that CUR mediated mitosis arrest in HCT116 cells by using mitotic protein monoclonal antibody-2（MPM-2） as a mitosis marker and binds to tubulin using the surface plasmon resonance（SPR） *** findings provide new mechanisms of cell proliferation inhibition mediated by CUR in HCT116 cells.

关键词： curcumin DNA damage caffeine S phase arrest mitosis arrest tubulin

Discovery of potent and selective c-Met inhibitor

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Discovery of potent and selective c-Met inhibitor

2011年全国药物化学学术会议——药物的源头创新

作者： Fang Chen,~aJing Ai,~b Ying Wang,~b Zhengsheng Zhan,~a Yongcong Lu,~a Yi Chen,~b Jian ding,Meiyu Geng~b and Wenhu Duan~(*,a) a Department of Medicinal Chemistry,shanghai Institute of Materia Medica,chinese academy of {3.,shanghai 201203,PR china bdivision of anti-tumor pharmacology,state key laboratory of drug research,shanghai Institute of Materia Medica,chinese academy of {3.,shanghai 201203,PR china

＜正＞HGF/c-Met signaling pathway mediates a variety of important biological activities but deregulation of the pathway is closely associated with poor prognosis in a number of major human ***,c-Met has been considered as a good target for anti-cancer drug ***,we report the discovery of a series of triazolotriazine derivatives as selective

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Thiosemicarbazones derivatives design,synthesis and their anti-cancer activity study

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Thiosemicarbazones derivatives design,synthesis and their an...

第六届全国化学生物学学术会议

作者： Hong Liu,He Huang,Qin Chen,Linghua Meng,Jian Ding,Hualiang Jiang division of drug Discovery and Design Center and anti-{3. pharmacology,state key laboratory of drug research,shanghai Institute of Materia Medica,chinese academy of sciences,555 Zu Chong Zhi Road,Zhangjiang Hi-Tech Park,shanghai 201203,P.R.china

＜正＞Thiosemicarbazones are a class of iron chelators that have shown potent anti-cancer activities,some of which are under preclinical or clinical *** synthesized a class of novel thiosemicarbazone derivatives which...

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天然产物来源的抗肿瘤药物的发现和研究(英文)

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天然产物来源的抗肿瘤药物的发现和研究(英文)

第四届中国肿瘤学术大会暨第五届海峡两岸肿瘤学术会议

作者： Ding Jian division of anti-tumor {3., state key laboratory of drug research, shanghai Institute of Materia Medica, chinese academy of sciences, shanghai, china.

＜正＞Natural Product is a very important resource for anticancer lead *** of the most promising research areas of shanghai Institute of Materia Medica （SIMM） is novel anticancer agent discovery from Traditional chinese *** is a natural alkaloid isolated from Camptotheca *** developed its derivative 10-hydroxycamptothecin in 1970s and it is still widely used in ***, we synthesized a novel amphoteric 9-substituted camptothecin, Chimmitecan, which confers unproved anti-cancer pharmacological profiles both in vitro and in ***, a natural product derivative from Salvia prionitis, is a new topoisomerase II *** also showed prominent anti-multidrug resistance effects and transcription factor c-Jun played a principal role in exerting this *** acid b got from chinese plant Pseudolarix *** caused depolymerization of tubulin by binding to a novel site, and abrogated secretion of VEGF due to reducing hypoxia-inducible factor la protein by promoting proteasome pathway, which may responsible for its powerful anti-angiogenic effect

关键词： natural product Camptothecin Salvicine Chimmitecan Pseudolarix acid b