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Pyrene Excimer-based Bis-triazolyl Pyranoglycoligands as Specific Mercury Sensors

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Chinese Journal of Chemistry 2012年第12期30卷 2874-2878页

作者： He Xiaopeng Xie Juan chen Guorong chen kaixian Key Laboratory for Advanced Materials & Institute of Fine Chemicals East China University of Science and Technology Shanghai 200237 China PPSM Institut d'Alembert ENS de Cachan CNRS UMR 8531 61 Avenue du pt Wilson F-94235 Cachan France State Key Laboratory of Drug Research Shanghai Institute ofMateria Medica Chinese Academy of Sciences Shanghai 201203 China

New C3,4-disubstituted bis-triazolyl glycoligands that feature a glucosyl or galactosyl scaffold incorporating two pyrenyl groups were synthesized via the Cu^1-catalyzed azide-alkyne 1,3-dipolar cycloaddition reaction （Cue-AAC）. These compounds exert a major emission band corresponding to that of pyrene excimer and respond specifically to mercury with a markedly quenched fluorescence. The epimeric nature of the pyranoglycosyl scaffold is determined influential toward the selectivity of the sensors.

关键词： glycoligand click chemistry sugar mercury chemosensor

Determining PPARg-ligand binding affinity using fluorescent assay with cis-parinaric acid as a probe

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Science China Chemistry 2005年第2期48卷 122-131页

作者： GAO Zhenting LUO Haibin chen Lili SHEN Jianhua chen kaixian JIANG Hualiang SHEN Xu Drug Discovery and Design Center Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China

Upon the study of small-molecules binding to proteins, the traditional methods for calculating dissociation constants (Kd and Ki) have shortcomings in dealing with the single bind- ing site models. In this paper, two equations have been derived to solve this problem. These two equations are independent of the total concentration or initial degree of saturation of receptor and the activity of the competitive molecule. Through nonlinear fitting against these two equations, Kd value of a probe can be obtained by binding assay, and Ki value of a ligand can be obtained by competitive assay. Moreover, only the total concentrations of receptor([R]t), ligand([L]t) and probe([P]t) are required for the data fitting. In this work, Ki values of some typical ligands of PPARγ were successfully determined by use of our equations, among which the Ki value of PPARγ-LY171883 was reported for the first time.

关键词： displacement assay IC_(50) equilibrium dissociation constant PPAR cis-parinaric acid fluorescent probe

Steered molecular dynamics simulations of protein-ligand interactions

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Science China Chemistry 2004年第5期47卷 355-366页

作者： XU Yechun SHEN Jianhua LUO Xiaomin SHEN Xu chen kaixian JIANG Hualiang Center for Drug Discovery and Design State Key Laboratory of New Drug Research Shanghai Institute of Materia Medica Shanghai Institutes for Biological Sciences Chinese Academy of Sciences Shanghai 201203 China Center for Drug Discovery and Design State Key Laboratory of New Drug Research Shanghai Institute of Materia Medica Shanghai Institutes for Biological Sciences Chinese Academy of Sciences Shanghai 201203 China

Studies of protein-ligand interactions are helpful to elucidating the mechanisms of ligands, providing clues for rational drug design. The currently developed steered molecular dy- namics (SMD) is a complementary approach to experimental techniques in investigating the biochemical processes occurring at microsecond or second time scale, thus SMD may provide dynamical and kinetic processes of ligand-receptor binding and unbinding, which cannot be ac- cessed by the experimental methods. In this article, the methodology of SMD is described, and the applications of SMD simulations for obtaining dynamic insights into protein-ligand interactions are illustrated through two of our own examples. One is associated with the simulations of bind- ing and unbinding processes between huperzine A and acetylcholinesterase, and the other is concerned with the unbinding process of α-APAfrom HIV-1 reverse transcriptase.

关键词： molecular dynamics simulation, steered molecular dynamics simulation, atomic force microscope, avidin, biotin,huperzine A, acetylcholinesterase, HIV-1 reverse transcriptas, non-nucleoside RT inhibitor.

Epimedin B exhibits pigmentation by increasing tyrosinase family proteins expression,activity,and stability

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Journal of Pharmaceutical Analysis 2024年第1期14卷 69-85页

作者： chen Hong Yifan Zhang Lili Yang Haoyang Xu Kang cheng Zhi Lv kaixian chen Yiming Li Huali Wu Department of TCM Chemistry School of PharmacyShanghai University of Traditional Chinese MedicineShanghai200000China Department of Dermatology Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese MedicineShanghai200000China International Education College Shanghai University of Traditional Chinese MedicineShanghai200000China Shanghai Inoherb Cosmetics Co. Ltd.Shanghai200000China

Epimedin B(EB)is one of the main flavonoid ingredients present in Epimedium brevicornum Maxim.,a traditional herb widely used in *** previous study showed that EB was a stronger inducer of melanogenesis and an activator of tyrosinase(TYR).However,the role of EB in melanogenesis and the mechanism underlying the regulation remain ***,as an extension to our previous investigation,we provide comprehensive evidence of EB-induced pigmentation in vivo and in vitro and elucidate the melanogenesis mechanism by assessing its effects on the TYR family of proteins(TYRs)in terms of expression,activity,and *** results showed that EB increased TYRs expression through microphthalmia-associated transcription factor-mediated p-Akt(referred to as protein kinase B(PKB))/glycogen synthase kinase 3β(GSK3β)/β-catenin,p-p70 S6 kinase cascades,and protein 38(p38)/mitogen-activated protein(MAP)kinase(MAPK)and extracellular regulated protein kinases(ERK)/MAPK pathways,after which EB increased the number of melanosomes and promoted their maturation for melanogenesis in melanoma cells and human primary melanocytes/skin ***,EB exerted repigmentation by stimulating TYR activity in hydroquinone-and N-phenylthiourea-induced TYR inhibitive models,including melanoma cells,zebrafish,and ***,EB ameliorated monobenzone-induced depigmentation in vitro and in vivo through the enhancement of TYRs stability by inhibiting TYR misfolding,TYR-related protein 1 formation,and retention in the endoplasmic reticulum and then by downregulating the ubiquitination and proteolysis *** data conclude that EB can target TYRs and alter their expression,activity,and stability,thus stimulating their pigmentation function,which might provide a novel rational strategy for hypopigmentation treatment in the pharmaceutical and cosmetic industries.

关键词： Epimedin B Melanosome Tyrosinase Melanogenesis

Improved synthesis of rupintrivir

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Science China Chemistry 2012年第6期55卷 1101-1107页

作者： LIN DaiZong QIAN WangKe HILGENFELD Rolf JIANG HuaLiang chen kaixian LIU Hong State Key Laboratory of Drug Research Shanghai Institute of Materia Medica Shanghai Institutes for Biological Sciences Chinese Academy of Sciences Shanghai 201203 China School of Pharmaceutical Engineering Shenyang Pharmaceutical University Shenyang 110016 China Institute of Biochemistry Center for Structural and Cell Biology in Medicine University of Luebeck 23538 Luebeck Germany

An improved synthesis of rupintrivir (AG7088) was accomplished using three amino acids (L-glutamic acid, D-4-fluorophenylalanine, and L-valine) as the building blocks. The key fragment ketomethylene dipeptide isostere was constructed with the valine derivative and phenylpropionic acid derivative, followed by coupling with a lactam derivative and an isoxazole acid chloride to provide AG7088 totally in eight steps.

关键词： rupintrivir AG7088 synthesis

Advances in studying of the pharmacological activities and structure–activity relationships of natural C-glycosylflavonoids

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Acta Pharmaceutica Sinica B 2013年第3期3卷 154-162页

作者： Peng Zeng Yong Zhang chen Pan Qi Jia Fujiang Guo Yiming Li Weiliang Zhu kaixian chen School of Pharmacy Shanghai University of Traditional Chinese MedicineShanghai 201203China Drug Discovery and Design Centre Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China

C-glycosylflavonoids are characterized by a bond between the anomeric carbon of a sugar moiety and the C-6 or C-8 position of a flavonoid A *** compounds are widespread in nature and have become the subject of increasing research interest due to their high biological *** review focuses on the biological effects of various C-glycosylflavonoids and their structure–activity relationships(SAR)as elucidated over the last 5 years.

关键词： C-glycosylflavonoids Pharmacological activities Structure–activity relationship Antioxidant activity

Astragaloside Ⅳ suppresses post-ischemic natural killer cell infiltration and activation in the brain:involvement of histone deacetylase inhibition

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Frontiers of Medicine 2021年第1期15卷 79-90页

作者： Baokai Dou Shichun Li Luyao Wei Lixin Wang Shiguo Zhu Zhengtao Wang Zunji Ke kaixian chen Zhifei Wang School of Basic Medical Sciences Shanghai University of Traditional Chinese MedicineShanghai 201203China Institute of Chinese Materia Medica Shanghai University of Traditional Chinese MedicineShanghai 201203China Academy of Integrative Medicine Shanghai University of Traditional Chinese MedicineShanghai 201203China

Natural killer(NK)cells,a type of cytotoxic lymphocytes,can infiltrate into ischemic brain and exacerbate neuronal cell *** Ⅳ(ASIV)is the major bioactive ingredient of Astragalus membranaceus,a Chinese herbal medicine,and possesses potent immunomodulatory and neuroprotective *** study investigated the effects of ASIV on post-ischemic brain infiltration and activation of NK *** reduced brain infarction and alleviated functional deficits in MCAO rats,and these beneficial effects persisted for at least 7 *** NK cells infiltrated into the ischemic hemisphere on day 1 after brain ischemia,and this infiltration was suppressed by ***,ASIV reversed NK cell deficiency in the spleen and blood after brain *** inhibited astrocyte-derived CCL2 upregulation and reduced CCR2+NK cell levels in the ischemic ***,ASIV attenuated NK cell activating receptor NKG2D levels and reduced interferon-γ*** restored acetylation of histone H3 and the p65 subunit of nuclear factor-κB in the ischemic brain,suggesting inhibition of histone deacetylase(HDAC).Simultaneously,ASIV prevented p65 nuclear *** effects of ASIV on reducing CCL2 production,restoring acetylated p65 levels and preventing p65 nuclear translocation were mimicked by valproate,an HDAC inhibitor,in astrocytes subjected to oxygen-glucose *** findings suggest that ASIV inhibits post-ischemic NK cell brain infiltration and activation and reverses NK cell deficiency in the periphery,which together contribute to the beneficial effects of ASIV against brain ***,ASIV’s effects on suppressing NK cell brain infiltration and activation may involve HDAC inhibition.

关键词： astragalosideⅣ brain ischemia natural killer cells histone deacetylase nuclear factor-κB

Remarkable research achievements in traditional Chinese medicine during 2012–2022

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Science of Traditional Chinese Medicine 2024年第1期2卷 5-13页

作者： Xiaoxiao Zhang Xianghong He Liangzhen You Junfeng chen Jun Ma Guochen Wang kaixian chen China Association of Chinese Medicine BeijingChina School of Pharmacy Chengdu University of Traditional Chinese MedicineChengduChina Dongzhimen Hospital Beijing University of Chinese MedicineBeijingChina School of Pharmacy Shanghai University of Traditional Chinese MedicineShanghaiChina

The period since the 18th National Congress of the Communist Party of China(CPC)has witnessed the emerging of innovative achievements in traditional Chinese medicine(TCM).To fulfill the requirements proposed at the 20th National Congress of the CPC and in the Opinions of the CPC Central Committee and the State Council on Promoting the Preservation,Innovation,and Development of Traditional ChineseMedicine and give play to the demonstrative role ofmajor research achievements,the China Association of ChineseMedicine has organized TCM researchers and practitioners to comprehensively review the major research achievements in TCM since the 18th National Congress of the *** collection and organization of achievements,report writing,expert evaluation,and public opinion soliciting,we have compiled the Remarkable Research Achievements of Traditional Chinese Medicine during 2012–2022.

关键词： New era Remarkable research achievements Clinical advantages of traditional Chinese medicine Modern technology of Chinese medicine

Transfer learning enhanced graph neural network for aldehyde oxidase metabolism prediction and its experimental application

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Acta Pharmaceutica Sinica B 2024年第2期14卷 623-634页

作者： Jiacheng Xiong Rongrong Cui Zhaojun Li Wei Zhang Runze Zhang Zunyun Fu Xiaohong Liu Zhenghao Li kaixian chen Mingyue Zheng Drug Discovery and Design Center State Key Laboratory of Drug ResearchShanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China University of Chinese Academy of Sciences Beijing 100049China College of Computer and Information Engineering Dezhou UniversityDezhou 253023China AI Department Suzhou Alphama Biotechnology Co.Ltd.Suzhou 215000China Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and TechnologyShanghaiTech UniversityShanghai 200031China State Key Laboratory of Pharmaceutical Biotechnology Nanjing UniversityNanjing 210023China

Aldehyde oxidase(AOX)is a molybdoenzyme that is primarily expressed in the liver and is involved in the metabolism of drugs and other ***-mediated metabolism can result in unexpected outcomes,such as the production of toxic metabolites and high metabolic clearance,which can lead to the clinical failure of novel therapeutic *** models can assist medicinal chemists in rapidly evaluating the AOX metabolic risk of compounds during the early phases of drug discovery and provide valuable clues for manipulating AOX-mediated metabolism *** this study,we developed a novel graph neural network called AOMP for predicting AOX-mediated *** integrated the tasks of metabolic substrate/non-substrate classification and metabolic site prediction,while utilizing transfer learning from 13C nuclear magnetic resonance data to enhance its performance on both *** significantly outperformed the benchmark methods in both cross-validation and external *** AOMP,we systematically assessed the AOX-mediated metabolism of common fragments in kinase inhibitors and successfully identified four new scaffolds with AOX metabolism liability,which were validated through in vitro ***,for the convenience of the community,we established the first online service for AOX metabolism prediction based on AOMP,which is freely available at https://***.

关键词： Drugmetabolism Aldehyde oxidase Transferlearning Graph neural network Kinase inhibitor