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Protecting-Group-Free One-Step Palladium-Catalyzed Coupling on C25 of Cucurbitacin B Expands Chemical Diversity with Improved Cytotoxicity against A549 Cells

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Chinese Journal of Chemistry 2022年第14期40卷 1662-1666,I0002页

作者： Ning Zhuo Jie Ma Lei Cao Linhai Chen fajun nan University of Chinese Academy of Sciences No.19A Yuquan RoadBejing 100049China State Key Laboratory of Drug Research Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China School of Chinese Materia Medica Nanjing University of Chinese MedicineNanjingJiangsu 210046China Drug Discovery Shandong Laboratory Bohai Rim Advanced Research Institute for Drug DiscoveryYantaiShandong 264117China

The natural product cucurbitacin B has been widely studied because of its multiple biological activities,especially its potent antitumor effects.However,modifications of cucurbitacin B are mainly focused on the C2 and C16 site,studies on the C25 acetoxy group are still limited.We successfully developed a palladium-catalyzed allylic coupling of cucurbitacin B with boronic acids,providing a one-step approach to expand the chemical diversity of the C25 position.Our method was protecting-group-free,showing a good functional group tolerance and a wide substrate scope under mild reaction conditions.A library of 29 derivatives was prepared,compounds 2q and 2u showed higher cytotoxicity against A549 cells than cucurbitacin B,compounds 2n and 2o maintained potency,and the introduced hydroxyl and amino groups could be further derived.

关键词： Natural products Cucurbitacin B Palladium-catalyzed coupling Divergent synthesis Structure-activity relationships

The HDAC inhibitor GCJ-490A suppresses c-Met expression through IKKα and overcomes gefitinib resistance in non-small cell lung cancer

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Cancer Biology & Medicine 2022年第8期19卷 1172-1192页

作者： Ting He Yinglei Gao Yanfen Fang Yangming Zhang Shuwei Zhang fajun nan Jian Ding Yi Chen Division of Anti-Tumor Pharmacology Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China University of Chinese Academy of Sciences Beijing 100049China State Key Laboratory of Drug Research the National Center for Drug ScreeningShanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China

Objective:The novel compound GCJ-490A has been discovered as a pan-histone deacetylase(HDAC)inhibitor that exerts potent inhibitory activity against HDAC1,HDAC3,and HDAC6.Because of the important roles of HDACs in lung cancer development and the high distribution of GCJ-490A in lung tissue,we explored the anti-tumor potency of GCJ-490A against non-small cell lung cancer(NSCLC)in vitro and in vivo in this study.Methods:The in vitro effects of GCJ-490A alone or combined with the EGFR inhibitor gefitinib against NSCLC were measured with proliferation,apoptosis,and colony formation assays.NSCLC xenograft models were used to investigate the efficacy of GCJ-490A combined with gefitinib for the treatment of NSCLC in vivo.Western blot assays,luciferase reporter assays,chromatin immunoprecipitation assays,quantitative real time-PCR,immunohistochemistry,and transcription factor activity assays were used to elucidate possible mechanisms.Results:GCJ-490A effectively inhibited NSCLC cell proliferation and induced apoptosis in vitro and in vivo.Interestingly,inhibition of HDAC1 and HDAC6 by GCJ-490A increased histone acetylation at the IKKαpromoter and enhanced IKKαtranscription,thus decreasing c-Met.Moreover,this c-Met downregulation was found to be essential for the synergistic anti-tumor activity of GCJ-490A and gefitinib.Conclusions:These findings highlight the promising potential of HDAC inhibitors in NSCLC treatment and provide a rational basis for the application of HDAC inhibitors in combination with EGFR inhibitors in clinical trials.

关键词： HDAC inhibitor c-Met IKKα NSCLC gefitinib

Development of the novel ACLY inhibitor 326E as a promising treatment for hypercholesterolemia

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Acta Pharmaceutica Sinica B 2023年第2期13卷 739-753页

作者： Zhifu Xie Mei Zhang Qian Song Long Cheng Xinwen Zhang Gaolei Song Xinyu Sun Min Gu Chendong Zhou Yangming Zhang Kexin Zhu Jianpeng Yin Xiaoyan Chen Jingya Li fajun nan State Key Laboratory of Drug Research Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China University of Chinese Academy of Sciences Beijing 100049China Burgeon Therapeutics Co. Ltd.Shanghai 201203China Drug Discovery Shandong Laboratory Bohai Rim Advanced Research Institute for Drug DiscoveryYantai 264117China

Hepatic cholesterol accumulation is an important contributor to hypercholesterolemia,which results in atherosclerosis and cardiovascular disease(CVD).ATP-citrate lyase(ACLY)is a key lipogenic enzyme that converts cytosolic citrate derived from tricarboxylic acid cycle(TCA cycle)to acetyl-CoA in the cytoplasm.Therefore,ACLY represents a link between mitochondria oxidative phosphorylation and cytosolic de novo lipogenesis.In this study,we developed the small molecule 326E with an enedioic acid structural moiety as a novel ACLY inhibitor,and its CoA-conjugated form 326E-CoA inhibited ACLY activity with an IC_(50)=5.31±1.2μmol/L in vitro.326E treatment reduced de novo lipogenesis,and increased cholesterol efflux in vitro and in vivo.326E was rapidly absorbed after oral administration,exhibited a higher blood exposure than that of the approved ACLY inhibitor bempedoic acid(BA)used for hypercholesterolemia.Chronic 326E treatment in hamsters and rhesus monkeys resulted in remarkable improvement of hyperlipidemia.Once daily oral administration of 326E for 24 weeks prevented the occurrence of atherosclerosis in ApoE^(-/-)mice to a greater extent than that of BA treatment.Taken together,our data suggest that inhibition of ACLY by 326E represents a promising strategy for the treatment of hypercholesterolemia.

关键词： Hypercholesterolemia Atherosclerosis Liver ATP-Citrate lyase(ACLY) Lipogenesis Cholesterol efflux ACLY inhibitor

Dynamic Perception of Jasmonates by the F-Box Protein C0l1

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Molecular Plant 2018年第10期11卷 1237-1247页

作者： Jianbin Yan Ruifeng Yao Li Chen Suhua Lit Min Gut fajun nan Daoxin Xie MOE Key Laboratory of Bioinformatics Tsinghua-Peking Joint Center for Life Sciences School of Life Sciences Tsinghua University Beijing 100084 China State Key Laboratory of Drug Research the National Center for Drug Screening Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai201203 China These authors contributed equally to this article.

Jasmonates （JAs） are cyclic fatty acid-derived phytohormones that regulate diverse aspects of plant defense and development. The endogenous active JA molecule （＋）-7-iso-JA-L-Ile （JA-Ile） and its analog coronatine trigger formation of a complex with the F-box protein C011 and JAZ repressors to induce degra- dation of the JAZs through the 26S proteasome pathway in a COil-dependent manner. To reveal the forma-tion process of COI1-JA-JAZ ternary complex, we employed several biochemical approaches to examine how JA is dynamically perceived. These analyses showed that the COI1 proteins of Arabidopsis and rice bind JA with appreciable binding affinity and revealed the kinetics and thermodynamics of the COI1-JA-JAZ ternary complex. Our results suggest that COI1 is the primary receptor perceiving the active JA molecule to initially form a COI1-JA complex that subsequently recruits JAZs for further signal transduction.

关键词： phytohormone receptor jasmonate C011

新型选择性半胱氨酰白三烯受体1(CysLT1R)拮抗剂的设计合成及构效关系研究

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有机化学 2024年第1期44卷 259-276页

作者：王婧怡刘金羽陈东升陈华燕谢欣南发俊中国科学院大学北京100049 中国科学院上海药物研究所上海201203 南京中医药大学南京210023

半胱氨酰白三烯(CysLTs)是炎症脂介质,其受体(CysLTsR)在哮喘、过敏性鼻炎和癌症等疾病的发生发展中发挥重要作用.已发现3-取代1H-吲哚-2-羧酸衍生物具有半胱氨酰白三烯受体1(CysLT1R)拮抗活性,但较差的溶解度限制了其进一步研究.基于... 详细信息

半胱氨酰白三烯(CysLTs)是炎症脂介质,其受体(CysLTsR)在哮喘、过敏性鼻炎和癌症等疾病的发生发展中发挥重要作用.已发现3-取代1H-吲哚-2-羧酸衍生物具有半胱氨酰白三烯受体1(CysLT1R)拮抗活性,但较差的溶解度限制了其进一步研究.基于已有研究基础继续进行结构优化,设计合成了多个系列化合物,其中3-{2-[(1E)-3-({3-[(1E)-2-(7-氯喹啉-2-基)乙烯基]苯基}氨基)-3-氧亚基丙-1-烯基]苯基}丙酸(T9)展现出良好的选择性CysLT1受体拮抗活性和改善的溶解度,其IC50值为(0.0066±0.0023)μmol/L,在水中溶解度为4.16×10^(-5) g/mL.

关键词：半胱氨酰白三烯半胱氨酰白三烯受体1(CysLT1R) 选择性拮抗剂

Small molecule compound induces chromatin de-condensation and facilitates induced pluripotent stern cell generation

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Journal of Molecular Cell Biology 2014年第5期8卷 409-420页

作者： Xiaoyuan Wei Yueting Chen Yongyu Xu YangZhan Ru Zhang Min Wang Qiuhong Hua Haifeng Gu fajun nan Xin Xie Shanghai Key Laboratory of Signaling and Disease Research Laboratory of Receptor-based Bio-medicine School of Life Sciences and Technology Tongji University Shanghai 200092 China CAS Key Laboratory of Receptor Research the National Center for Drug Screening Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai 201203 China State Key Laboratory of Drug Research the National Center for Drug Screening Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai 201203 China

The revolutionary induced pluripotent stem cell (iPSC) technology provides a new means for cell replacement therapies and drug screening. Small molecule compounds have been found extremely useful to improve the generation of iPSCs and understand the reprogramming mechanism. Here we report the identification of a novel chemical, CYT296, which improves OSKM-mediated induction of iPSCs for >10 folds and enables efficient reprogramming with only Oct4 in combination with other small molecules. The derived iPSCs are genuinely pluripotent and support the development of two ‘All-iPSC’ mice by tetraploid complementation. CYT296 profoundly impacts heterochromatin formation without affecting cell viability. MEFs treated with CYT296 exhibit de-condensed chromatin structure with markedly reduced loci containing heterochromatin protein 1α (HP1α) and H3K9me3, which is very similar to the chromatin configuration in embryonic stem cells (ESCs). Given that an open chromatin structure serves as a hallmark of pluripotency and has to be acquired to fulfill reprogramming, we propose that CYT296 might facilitate this process by disrupting condensed chromatin, thereby creating a more favorable environment for reprogramming. In agreement of this idea, shRNA targeting HP1α also promotes the generation of iPSCs. Thus current findings not only provide a novel chemical for efficient iPSC induction, but also suggest a new approach to regulate somatic cell reprogramming by targeting chromatin de-condensation with small molecules.

关键词：小分子化合物多能干细胞异染色质诱导凝聚染色质结构船尾凯尔特人

Effect of GR24 Stereoisomers on Plant Development in Arabidopsis

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Molecular Plant 2016年第10期9卷 1432-1435页

作者： Suhua Li Linhai Chen Yuwen Li Ruifeng Yao Fei Wang Mai Yang Min Gu fajun nan Daoxin Xie Jianbin Yan School of Life Sciences Tsinghua University Beijing 100084 China Shanghai Institute of Materia Medica Chinese Academy of Science Shanghai 201203 China The Tsinghua University-Peking University Center for Life Sciences MOE Key Laboratory of Bioinformatics Center for Plant Biology Tsinghua University Beijing 100084 China Center for Synthetic and Systems Biology Tsinghua University Beijing 100084 China

Dear Editor,Strigolactones （SLs） are a group of carotenoid-derived terpenoid lactones with similar structures. They can promote symbiotic interactions of plants with soil microbes （Akiyama et al., 2010）, stimulate the germination of parasitic weeds Striga and Orobanche （Cook et al., 1966; Johnson et al., 1976）, and regulate plant growth and development, including inhibition of shoot （tiller） outgrowth （Gomez-Roldan et al., 2008; Umehara et al., 2008）, suppression of hypocotyl elongation in Arabidopsis （Scaffidi et al., 2014）, and regulation of root architecture （Koltai, 2011）.

关键词： STRUCTURAL REQUIREMENTS STRIGOLACTONES INHIBITION GERMINATION HORMONES STRIGA RICE

Synthetic Analogues of Betulinic Acid as Potent Inhibitors of PS1/BACE1 Interaction to Reduce Aβ Generation

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Chinese Journal of Chemistry 2017年第1期35卷 103-112页

作者： Chenlu Zhang Xiaoyin Wang Jin Cui Xiaohang Li Yangming Zhang Xin Wang Haifeng Gu Wei Li Xin Xie Jian Zhao Gang Pei fajun nan National Center for Drug Screening State Key Laboratory of Drug Research Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai 201203 China State Key Laboratory of Cell Biology Institute of Biochemistry and Cell Biology Shanghai Institutes for Biological Sciences Chinese Academy of Sciences Shanghai 200031 China Translational Medical Center for Stem Cell Therapy Shanghai East Hospital School of Medicine Tongii University Shanghai 200092 China

The lupane-type triterpenoids are endowed with a wide range of biological activities such as antiviral, anti-inflammatory and anticancer activity. We describe here its potential application in Alzheimer＇s disease （AD） treatment as an inhibitor of PS1/BACE1 interaction. 3-a-Akebonoic acid, which emanated from a high throughput screening （HTS）, was discovered to interfere with P S 1/BACE 1 interaction and reduce amyloid β-protein （Aβ） production. In view of the limited source, we instead used naturally rich betulinic acid （compound 2） as starting material for lead optimization and a focused library of its derivatives was constructed to gain a better understanding of the structure activity relationship （SAR） of triterpenoid-type inhibitor of PS1/BACE1 interaction. Compound 22 was finally chosen as the most potent PS 1/BACE 1 interaction inhibitor, which reduced Aβgeneration effectively.

关键词： Alzheimer＇s disease PS 1/BACE 1 interaction Aβ betulinic acid SAR

Synthesis toward the Lindenane-type Sesquiterpenoid Monomer of Chlorahololide A

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Chinese Journal of Chemistry 2013年第1期31卷 84-92页

作者： Haizhen Zhang fajun nan Chinese National Center for Drug Screening State Key Laboratory of Drug Research Shanghai Institute of Mate- ria Medica Shanghai Institutes for Biological Sciences Chinese Academy of Sciences Shanghai 201203 China

向用一个 Yamamoto 重新整理， intramolecular cyclopropanation 反应， 1,3-dipolar 环合，和 intramolecular 的 Chlorahololide A 的 lindenane 类型 sesquiterpenoid 单体的合成的调查哎呀反应给了枢轴的中介 20。这给能产生 Chlor... 详细信息

关键词：单体合成 ne型倍半萜环丙烷化反应 Heck反应金粟兰科合成路线天然产品