IRAK_inhibitor_4_COA_12925_MedChemExpress
依达拉奉右莰醇通过抑制TLR4NF-κB信号通路减轻实验性自身免疫性脑脊髓炎小鼠炎症反应
实验研究依达拉奉右莰醇通过抑制TLR4/NF-κB信号通路减轻实验性自身免疫性脑脊髓炎小鼠炎症反应晚丽，李作孝△摘要：目的探讨依达拉奉右莰醇对实验性自身免疫性脑脊髓炎（EAE）小鼠炎症反应的影响及其机制。
方法30只雌性C57BL/6小鼠随机分为空白组、模型组、依达拉奉右莰醇干预组各10只。
除空白组外，其余2组小鼠均采用髓鞘少突胶质细胞糖蛋白35-55（MOG35-55）多肽诱导EAE模型。
从造模次日开始，依达拉奉右莰醇干预组腹腔注射依达拉奉右莰醇12.5mg/kg，空白组及模型组腹腔注射等量生理盐水，1次/d，连续14d。
观察小鼠发病情况，并行神经功能障碍评分；HE和LFB染色观察脊髓组织病理改变；实时荧光定量PCR检测脑组织匀浆中白细胞介素（IL）-1β、IL-6及肿瘤坏死因子（TNF）-αmRNA表达水平；蛋白免疫印迹法检测脊髓组织中Toll样受体4（TLR4）、核因子κB p65（NF-κB p65）蛋白表达水平。
结果空白组小鼠均未发病，其余2组小鼠不同程度发病。
与模型组相比，依达拉奉右莰醇干预组小鼠的发病潜伏期、高峰期延迟，高峰期神经功能障碍评分降低（P＜0.01）。
空白组小鼠脊髓组织未见异常；模型组脊髓组织大量炎性细胞浸润、髓鞘结构紊乱；依达拉奉右莰醇干预组较模型组的炎性细胞浸润减少、髓鞘结构紊乱情况改善。
与空白组相比，其余2组小鼠脑组织匀浆中IL-1β、IL-6、TNF-αmRNA表达水平以及脊髓组织中TLR4、NF-κB p65蛋白表达水平显著升高，以依达拉奉右莰醇干预可逆转建模引起的上述改变（P＜0.05）。
结论依达拉奉右莰醇可减轻EAE小鼠炎症反应，其机制可能与抑制TLR4/NF-κB信号通路活化有关。
关键词：脑脊髓炎，自身免疫性，实验性；Toll样受体4；NF-κB；炎症；白细胞介素类；肿瘤坏死因子α；依达拉奉右莰醇；TLR4/NF-κB信号通路中图分类号：R744.51文献标志码：A DOI：10.11958/20212362Edaravone dexborneol reduces inflammation in mice with experimental autoimmuneencephalomyelitis by inhibiting TLR4/NF-κB signaling pathwayWAN Li,LI Zuoxiao△Department of Neurology,the Affiliated Hospital of Southwest Medical University,Luzhou646000,China△Corresponding Author E-mail:****************Abstract:Objective To investigate the effect and mechanism of edaravone dexborneol on the inflammatory response in mice with experimental autoimmune encephalomyelitis(EAE).Methods Thirty female C57BL/6mice were randomly divided into the blank group,the model group and the edaravone dexborneol intervention group,with10mice in each group. Except for the blank group,EAE model was induced by myelin oligodendrocyte glycoprotein35-55(MOG35-55) polypeptide in the other two groups.From the day after modeling,mice in the edaravone dexborneol intervention group were intraperitoneally injected with edaravone dexborneol12.5mg/kg,while the mice in the blank group and the model group were intraperitoneally injected with the equal amount normal saline,once a day for consecutive14days.The behavioral changes of mice were observed,and neurological dysfunction scores were performed.HE and LFB staining were used to detect spinal cord pathological changes.The mRNA expression levels of interleukin(IL)-1β,IL-6and tumor necrosis factor-α(TNF-α)in brain homogenate were detected by real-time fluorescence quantitative PCR.The protein expression levels of Toll-like receptor4(TLR4)and nuclear factorκB p65(NF-κB p65)in spinal cord tissue were detected by Western blot assay.Results None of the mice in the blank group had the disease,and the other two groups of mice had different degrees of pared with the model group,the incubation period and peak period were delayed in the edaravone dexborneol intervention group,and neurological deficit scores in peak period decreased(P＜0.01).No abnormality was found in spinal cord tissue structure in mice of the blank group,and a large number of inflammatory cell infiltration,myelin structure 基金项目：泸州市人民政府-西南医科大学科技战略合作基金项目（2018LZXNYD-ZK17）作者单位：西南医科大学附属医院神经内科（邮编646000）作者简介：晚丽（1994），女，硕士在读，主要从事神经免疫方面研究。
利用网络药理学和分子对接技术分析“猫爪草-_冬凌草”对肝癌的治疗作用机制
[基金项目]贵州省科技计划项目（黔科合支撑[2020]4Y156号）。
△杨青斌，李进 贵州中医药大学2021级中西医结合临床专业在读硕士研究生△司维群，刘静 贵州中医药大学2022级中西医结合临床专业在读硕士研究生△吴佳龙 贵州中医药大学2023级中西医结合临床专业在读硕士研究生▲通讯作者利用网络药理学和分子对接技术分析“猫爪草-冬凌草”对肝癌的治疗作用机制杨青斌1△ 徐 静2▲ 李 进1△ 司维群1△ 刘 静1△ 吴佳龙1△1.贵州中医药大学，贵州贵阳 550000；2.贵州中医药大学第二附属医院肿瘤科，贵州贵阳 550000[摘要]目的 利用网络药理学和分子对接技术对猫爪草与冬凌草进行分析，探讨其治疗原发性肝癌的作用机制。
方法 基于对中药系统药理学数据库和分析平台（TCMSP）与传统中药百科全书（ETCM）数据库的检索，掌握有关药物的有效成分与其作用靶点，借助有机小分子生物活性数据库（PubChem）以及小分子药物预测作用靶点平台（Swiss Target Prediction）的支持下，收集一系列肝癌的靶点。
参照蛋白互作数据库（STRING）进行药物与肝癌的蛋白互作（PPI）网络的构建。
在将网络系统应用于探索药物的抗癌过程和作用机理的同时，结合Cytoscope3.9.1软件成功构建“成分-靶点-通路”体系，并借助Metascape 功能实现对共同靶点和京都基因与基因组百科全书（KEGG）通路的富集处理。
此外，利用分子模拟软件AutoDock 展开活性成分与关键靶点间分子对接情况的探究，获取所需的系列研究成果。
结果 筛选出冬凌草与猫爪草的有效活性成分分别有23、9个；两味药的药物靶点总共1020个，共同交集靶点299个；药物和肿瘤疾病共有26个常见靶点。
KEGG 通路的富集显示，药物靶点涉及的通路主要有癌症通路、脂质与动脉粥样硬化通路、PI3K-Akt 信号通路等。
结论 猫爪草与冬凌草相须配伍，具有多成分、多靶点、多通路的作用特点，能协同发挥抗肝癌作用，为后续机制研究提供了切实可行的参考依据。
semi-syntheticar...
Semi-synthetic aristolactams—inhibitors of CDK2enzymeVinod R.Hegde *,Scott Borges,Haiyan Pu,Mahesh Patel,Vincent P.Gullo,Bonnie Wu,Paul Kirschmeier,Michael J.Williams,Vincent Madison,Thierry Fischmann,Tze-Ming ChanSchering Plough Research Institute,2015Galloping Hill Road,Kenilworth,NJ 07033,USAa r t i c l e i n f o Article history:Received 7August 2009Revised 23December 2009Accepted 4January 2010Available online 7January 2010Keywords:Semi-synthetic analogs Aristolactams IC 50SARa b s t r a c tSeveral analogs of aristolochic acids were isolated and derivatized into their lactam derivatives to study their inhibition in CDK2assay.The study helped to derive some conclusions about the structure–activity relation around the phenanthrin moiety.Semi-synthetic aristolactam 21showed good activity with inhi-bition IC 50of 35nM in CDK2assay.The activity of this compound was comparable to some of the most potent synthetic compounds reported in the literature.Ó2010Elsevier Ltd.All rights reserved.In the preceding Letter we have reported on the isolation of a potent CDK2enzyme inhibitor SCH 546909,a natural product aris-tolactam analog with an inhibition IC 50of 140nM.This prompted us to undertake a semi-synthetic study of different analogs from this class.Many total syntheses of aristolactam analogs have been reported in the literature,1,2however sub-structure literature searches revealed that these compounds could be easily prepared from naturally occurring,aristolochic acids.HO H 3CONHOHOSCH 546909Several publications and reviews have been published on the occurrence,synthesis and biological activities of aristolochic acids.Aristolochic acids and aristolactams are classified as aporphinoids because of their basic skeleton which bears a distinct similarity to that of aporphins.Aristolochic acids exhibit tumor inhibitory activ-ity against the adenocarcinoma 755test system but in mice they induced papiloma.3They are also known to form covalent DNA adducts by enzymatic reductive activation of aristolochic acids in the presence of DNA.4They are also shown to induce mutagenicity in mice.5Aristolochic acid is commercially available from SigmaChemical Co.and ACROS.The commercially available aristolochic acid is a complex mixture of several analogs,with the major com-ponents being aristolochic acids II &I in 1:4ratio.We have sepa-rated commercial aristolochic acid mixtures on a preparative HPLC using YMC ODS-A C-18,10l m,5Â50cm HPLC column,eluting with 0.05%trifluoroacetic acid and acetonitrile (60:40)to obtain compounds 1–8.A typical 600mg of commercial aristolo-chic acid afforded 27.7,4.6,7.8,71.6,5.4,6.8,315.8,and 3.2mg of aristolochic acid C (5),6aristolochic D (7),77-hydroxy aristolo-chic A(6),8aristolochic acid II (1),aristolochic acid IV (4),97-meth-oxy aristolochic acid A (3),10aristolochic acid I (2),2and aristolochic acid III (8).11In our semi-synthetic modifications to prepare aristolactam analogs,the aristolochic acids were first converted to their lactams.The purified aristolochic acids were hydrogenated in ethanolic solution under 40psi hydrogen in presence of Pd/C catalyst,over-night at room temperature.The amino compound produced on reduction of nitro group,on further ring closure results in lactam.After separation and derivatization to the resulting lactam,the aromatic phenol ether derivatives were deprotected with BBr 3in methylene chloride solution.A typical demethylation 12involved stirring the aristolochic methyl ethers (15mg)in CH 2Cl 2(50ml)at 0°C with the dropwise addition of BBr 3(7.5ml,1M)in CH 2Cl 2at 0°C and then continue stirring overnight at room temperature.The reaction mixture was quenched in ice,extracted with ethyl acetate,and dried.The demethylated product was purified by HPLC.The Methylenedioxy group was removed by stirring aristolac-tams in CH 2Cl 2at 0°C and dropwise addition of a solution of PCl 5(1:1ratio).The reaction mixture was slowly allowed to attain room0960-894X/$-see front matter Ó2010Elsevier Ltd.All rights reserved.doi:10.1016/j.bmcl.2010.01.007*Corresponding author.Tel.:+19088203871;fax:+19088206166.E-mail address:**********************(V.R.Hegde).Bioorganic &Medicinal Chemistry Letters 20(2010)1384–1387Contents lists available at ScienceDirectBioorganic &Medicinal Chemistry Lettersj o ur na l h om e pa ge :w w w.e lse v ie r.c om /lo c at e/bm c ltemperature during2h and then quenched with ice,extracted with CH2Cl2and dried.The O-dihydroxy compound formed was purified by HPLC.3,4-Dihydroxy-12-chloro aristolactams were prepared from methylenedioxy containing derivatives via treatment with the dropwise addition of PCl5(1:2.5ratio)in CH2Cl2at0°C and slowly allowing the reaction mixture to attain room temperature during 3h.The reaction mixture was quenched in ice,extracted with CH2Cl2and dried.The halogenated product was further purified by HPLC.O OCOOHNO2OONR1R2R31. R1 = R2 = R3 = -H2. R1 = -OCH3, R2 = R3 = -H3. R1 = R2 = -OCH3, R3 = -H4. R1 = R3 = -OCH3, R2 = -H5.R1 = R2 = -H, R3 = -OH6. R1 = -OCH3, R2 = -OH, R3 = -H7. R1 = -OCH3, R2 = -H, R3 = -OH8. R1 = -OH,R2 = R3 = -H9. R1 = R2 = -OCH3, R3 = -HOR1R2R3R4R515. R1 = R2 = R3 = R4 = R5 =-H16. R1 = -OCH3, R2 = R3 = R4 =R5 = -H17. R1 = R2 =-OCH3 ,R3 =R4 = R5 = -H18. R1 = R3 = -OCH3, R2 = R4 = R5 = -H19. R1 = -OCH3, R2 = -OH, R3 = R4 =R5 = -H20. R1 = -OCH3, R3 = -OH, R2 = R4 = R5 = -H21. R1 = -OH, R2 = R3 = R4 = R5 = -H22. R1 = R2 = -OH, R3 = R4 = R5 = -H23. R1 = R3 = -OH, R2 = R4 = R5 = -H24. R1 = R2 = R4 = R5 = -H, R3 = -OH,25. R1 = -OCH3, R2 = R3 = R4 = -H, R5 = -CH326. R1 = -OH, R2 = R3 = R4 = -H, R5 = -CH3ARISTOLOCHIC ACID ANALOGSHO HOCOOHNO2R4R1R2R310. R1 = R2 = R3 = R4 = -H11. R1 = R2 = R3 = -H, R4 = -Cl12. R1 = -OCH3, R2 = R3 = R4 = -H13. R1 = -OH, R2 = R3 = R4 = -H14. R1 = -OCH3, R2 = R3 = -H, R4 = -Cl 27. R1 = R2 = R3 = R4 = -H28. R1 = R2 = R3 = -H, R4 = -Cl29. R1 = -OCH3, R2 = R3 = R4 = -H30. R1 = -OH, R2 = R3 = R4 = -H31. R1 = -OCH3,R2 =R3 = -H, R4 = -ClHOHONHOR4R1R2R3The aristolochic acid analogs prepared were tested in CDK2as-say13with the resulting inhibition IC50s are tabulated in Table1. Many analogs showed CDK2activity>10l M,however compounds 13,16,19,21,and24exhibited CDK2inhibition under10l M. Compound21showed a CDK2inhibition IC50of35nM,potency similar to the most potent CDK2inhibitor reported in the litera-ture14Compound13,having a hydroxyl group at C-9also showed activity in the l M range.Several natural products,like aporphinoids,morphine,and fused berberine classes of compounds,were also tested to evaluate importance of the lactam ring in the CDK2activity.All these com-pounds excepting sinomenine,sinoacutine,and tetrahydroberber-ine,have tetrahydro pyridine ring attached to phenanthrine moiety.Sinomenine and sinoacutine have morphine like ring sys-tem but tetrahydroberberine has two tetrahydro-isoquinoline ring system.All these compounds failed to show inhibition in CDK2as-say at50l M.Only compound21,displayed strong CDK2inhibition,about threefold better than the natural product SCH546909.Based on the activity profile of the different aristolochic acid and aristolactam analogs,it appears the lactam ring is essential for potent CDK2inhibition.This has been shown to be true for sev-eral potent inhibitors reported in literature.31,32Hydroxyl groups at C-7or C-9positions also appear to enhance CDK2inhibition. Additionally,theprotection of the dihydroxy groups atthe C-4 and C-5positions contributes toward the potency.However,pro-tection of amide–NH by a methyl group or substitution by a halo-gen at C-10results in reduced activity.The observations are only empirical and a detailed study would be necessary to evaluate a complete structure–activity relationship.Protection increasesthe potency in CDK2assay-CH3 in this positiondecreases activityhalogen in this positiondecrease in potencyincreases the potencyAristolochic acids and aristolactams have phenanthrin aromatic moiety similar to another class of natural product that includes staurosporine,isolated from fungus.Staurosporins are also potent kinase inhibitors and have been extensively studied as antitumor compounds.Like staurosporine,these compounds are also planar molecules and are sparingly soluble in various solvents including water.Increasing the solubility properties by salt formation or by Table1CDK2inhibition IC50s of aristolochic acids and aristolactam analogs Compound CDK2IC50(l M)1>202>203>204>205306257258159>201013.4111812>3013 5.71416.51516151616 1.217>151815>1519 2.92018>3521180.03522>302318>502420,21 2.152519,21>352617>35274>3528>2529>353016>353110Dicentrine22>50Crebanine23>50Roemerine-HBr24>50Isocorydine25>50Corydine26>50Corytuberine27>50Sinoacutine28>50Sinomenine29>50Stephanine,25>50Tetrahydro-berberine30>50V.R.Hegde et al./Bioorg.Med.Chem.Lett.20(2010)1384–13871385forming inclusion compounds with b -cyclodextrin appear to improve cellular activity.Aristolactam 21was further tested in a kinase counter screen assays,along with the natural product SCH 546909and 3233,as shown in Table 2.The results indicate that the inhibitors share a similar activity in the CDC2(cyclin-A dependent kinase,$90%homology)assay,and a lesser selectivity in other kinases assays like CDK4,AUR2(Aurora kinase),MAPK (mitogen-activated protein kinase),and AKT (ATP kinase).Cellular activities:Compound 21,the most potent and selective CDK2inhibitor from this series,was evaluated in two cellular pro-liferation assays:a colony forming assay and a soft agar growth as-say.In the soft agar growth assay compound 21showed comparable activity to 32,although compound 32appeared to lose some potency in this assay format compared to the clonogenicity assay (Table 2).In the clonogenicity assay using MCF-7cells,all three compounds inhibited growth at similar micromolar pound 21inhibited proliferation of tumor cells,with IC 50values consistent with CDK2inhibitors that are competitive with respect to ATP.The anti-proliferative activity of the com-pounds was up to eightfold selective for the tumor cells relative to the HFF normal cell line.The anti-proliferative activity of 21ar-rests the tumor cells and protects the normal cells from chemo-therapy-induced toxicity.32These data are consistent with an anti-proliferative mechanism expected for inhibition of CDK2and revealed that the aristolactam class of compounds have potential for treating proliferative disorders,including chemotherapy-in-duced alopecia.NN HNORPyrazoloquinolines32. R = -OCH 3 (SCH47089)Computer based interaction design of 21with CDK2enzyme:Thedocking experiments on CDK2enzyme with 21(SCH535270)and staurosporine were performed and are shown in Figure 1A and B.The computer docking model suggests the lactam of 21(SCH 535270)interacts with CDK2enzyme active sites in a manner anal-ogous to that observed for compounds of staurosporine class of inhibitors bound to fibroblast growth factor receptor kinase.34Two hydrogen bonds were formed between the c -lactam moi-ety of 21and CDK2.Specifically,the amide nitrogen was hydrogen bonded to the backbone carbonyl of glu-81of the CDK2enzyme and the lactam carbonyl oxygen was hydrogen bonded with the backbone NH of leu-83amide.Staurosporin also binds to the CDK2enzyme in a similar fashion.The C-9hydroxy group also ap-pears to stabilize the binding at some other sight of enzyme core.35SCH 535270,like staurosporin,is a planar molecule and exhibits similar biological properties.X-ray crystallography:Our attempts to determine the X-ray structure of inhibitor SCH 535270bound to CDK2have failed.The crystals were prepared by soaking the compound in presence of CDK2enzyme and cyclin A.The parameters like compound concentration and duration of soak were screened.Examination of the electronic density maps did not reveal the binding mode of the compound.In some cases,X-ray crystallogra-phy has failed to determine the co-structures of a compound bound to the CDK2protein even in the case of potent inhibitors.A possible explanation is that inhibitor binding requires the com-plete CDK2-cyclin-A complex,which is protocol in our screening assay.CDK2is activated by complexing with cyclin-A that induces conformational changes in the protein that affect the ATP binding site to some degree.The most significant effect involves a rotation of the C-helix,which alters the active-site geometry in the region of the triad of catalytic active-site residues Lys-33,Glu-51,and Asp-145.The amino group of Lys-33can be potential interaction site for inhibitors.The amino nitrogen appears to hydrogen bond with the oxygen of methylenedioxy group.Efforts to grow crystalsTable 2Inhibition (IC 50)of SCH 546909,21and 32in different kinases CompoundActivity IC 50(nM)Selectivity (nM)Cellular activity (l M)CDC2CDK4AUR2MAPK AKT SAG MCF7Clonogenicity SCH5469091402141420214035,335———32(SCH47089)2020020005000>50,000—>10 3.021(SCH535270)352009000350012,00011,4002–2.53.5Figure puter modeling of binding of 21(SCH 535270)and staurosporin with CDK2enzyme.1386V.R.Hegde et al./Bioorg.Med.Chem.Lett.20(2010)1384–1387of the activated CDK2-cyclin-A protein complex are in progress and will be reported in future publications.The aristolactam class of compounds represents a novel class of CDK2inhibitors.Exploration into semi-synthetic analogs provided a potent CDK2inhibitor from this class.Binding interactions by docking experiments suggested carbonyl of glu-81and NH of leu-83amide of the CDK2enzyme are involved in hydrogen bond-ing with the lactam functionality of aristolactams.CDK2inhibition causes an arrest of the cell cycle and exhibits a selective killing effect on several tumor cell lines.36AcknowledgmentsAuthors gracefully acknowledge Dr.E.Lees and Dr.R.Doll for their helpful discussion on CDK2inhibitors.References and notes1.Mix,D.B.;Guinaudeau,H.;Shamma,M.J.Nat.Prod.1982,45,657.2.Shamma,M.;Monit,J.C.Isoquinoline Alkaloids Research1972–1977;PlenumPress:New York,1978.3.(a)Kupchan,S.M.;Wormser,.Chem.1965,30,3792;(b)Kupchan,S.M.;Merianos,.Chem.1968,33,3735.4.(a)Stiborova,M.;Frei,E.;Breuer,C.A.;Schmeiser,H.H.Cancer Res.1990,50,5464;(b)Cinca,S.;Voiculetz,N.;Schmeiser,H.;Wiessler,M.J.Med.Biochem.1997,1,3.5.Pistelli,L.;Nieri,E.;Bilia,A.R.;Marsili,A.;Scarpato,R.J.Nat.Prod.1993,56,1605.6.Hong,L.;Sakagami,Y.;Marumo,S.;Xinmin,C.Phytochemistry1994,37,237.7.Nakanishi,T.;Iwasaki,K.;Nasu,M.;Miura,I.;Yoneda,K.Phytochemistry1982,21,1759.8.Wu,T.-S.;Leu,Y.-L.;Chan,Y.-Y.Chem.Pham.Bull.1999,47,571.9.De 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11,405.15.Priestap,H.Phytochemistry1985,24,849.16.Coutts,R.T.;Stenlake,J.B.;Williams,W.D.J.Chem.Soc.1957,4120.17.Chakraborty,S.;Nandi,R.;Maiti,M.;Achari,B.;Bandyopadhyay,S.Photochem.Photobiol.1989,50,685.18.Eckhardt,G.;Urzua,A.;Cassels,B.K.J.Nat.Prod.1983,46,92–97.19.Achari,B.;Bandyopadhyay,S.;Chakravarty,A.K.;Pakrashi,.Magn.Reson.1984,22,741.20.Mizuno,M.;Oka,M.;Tanaka,T.;Yamamoto,H.;Iinuma,M.;Murata,H.Chem.Pharm.Bull.1991,39,1310.21.(a)Chakraborty,S.;Nandi,R.;Maiti,M.;Sur,P.Indian J.Phys.B.1991,65B,587;(b)Priestap,H.A.Magn.Reson.Chem.1989,27,460.22.Chen,C.C.;Huang,Y.L.;Ou,J.C.;Su,M.J.;Yu,S.M.;Teng,C.M.Planta Med.1991,57,406.23.Shamma,M.;Slusarchyk,W.A.Chem.Rev.1964,64,59.24.You,M.;Wickramaratne, D. 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E.;Farnsworth,N.R.;Cordell,G.A.;Kinghorn,A.D.;Pezzuto,J.M.J.Nat.Prod.1995,58,598.25.Roblot,F.;Hocquemiller,R.;Cave,A.;Moretti,C.J.Nat.Prod.1983,46,862.26.Manske,R.H.F.Can.J.Res.1932,7,258.27.Wang,C.-C.;Kuoh,C.-S.;Wu,T.-S.J.Nat.Prod.1996,59,409.28.Kunitomo,J.;Ju-Ichi,M.;Yoshikawa,Y.;Chikamatsu,H.J.Pharm.Soc.Jpn.1974,94,97.29.Terui,Y.;Tori,K.;Maeda,S.;Sawa,Y.K.Tetrahedron Lett.1975,33,2853.30.Chen,C.Y.;MacLean,D.B.Can.J.Chem.1968,46,2501.31.Dumas,J.Exp.Opin.Ther.Patents2000,11,405.32.Davis,S.T.;Benson,B.G.;Bramson,H.N.;Chapman,D.E.;Dickerson,S.H.Science2001,291,134.33.Afonso,A.;Kelly,J.M.;Chackalamannil,S.U.S.Patent5459146,1995,pp13.34.Mohammadi,M.;McMahon,G.;Sun,L.;Tang,C.;Hirth,P.Science1997,276,955.35.Bramson,H.N.;Corona,J.;Davis,S.T.;Dickerson,S.H.;Edelstein,M.;Frye,S.V.,;Gampe,R.T.,Jr.;Harris,P.A.;Hassell,A.;Holmes,W.D.;Hunter,R.N.;Lackey,K.E.;Lovejoy,B.;Luzzio,M.J.;Montana,V.;Rocque,W.J.;Rusnak,R.D.;Shewchuk,L.;Veal,J.M.;Walker,D.H.;Kuyper,L.F.J.Med.Chem.2001,44, 4339.36.Walker,D.H.;Luzzio,M.;Veal,J.;Dold,K.;Edelstein,M.Proc.Am.Assoc.CancerRes.1999,40,A4783Physico-chemical properties:Aristolochic acid C(5):UV k max:225,256,308,410nm;FABMS328(M+H)+,350 (M+Na)+,366(M+K)+,1H NMR(DMSO-d6)d:10.63(COO H),8.48(9-H),8.46(d, J=4Hz,5-H),8.10(d,J=17Hz,8-H),7.75(s,2H),7.29(dd,J=17,4Hz,7-H),6.48(s,12-H2).13C NMR(DMSO-d6)ppm:168.0(11-C),159.8(6-C),145.8(3-C),145.5(4-C),143.1(10-C),132.5(8-C),131.0(4b-C),126.4(9-C),123.7(1-C),121.5(8a-C),118.8(7-C),117.2(10a-C),116.2(4a-C),111.9(2-C),111.1(5-C), 102.8(12-C).7-Hydroxy aristolochic acid A(6):UV k max:224,271,318,384nm;ESMSÀve mode,m/z356(MÀH)À.Aristolochic acid D(7):UV k max:224,243,333,408nm;ESMS m/z358(M+H)+.Compound(21)18:UV k max:214,242,258,294,328,398nm;ESMS:m/z280 (M+H)+;1H NMR(DMSO-d6)d:10.72(s,NH),10.2(s,–OH),8.03(d,J=15Hz,5-H),7.63(s,2-H),7.37(t,J=15Hz,6-H),7.36(s,9-H),7.06(d,J=15Hz,7-H),6.46(s,12-H2).13C NMR(DMSO-d6)ppm:168.1(11-C),153.8(8-C),148.8(3-C),147.1(4-C),134.0(10-C),125.8(6-C),125.3(4b-C),125.3(10a-C),123.2(8a-C),119.3(1-C),117.5(5-C),112.3(7-C),111.3(4a-C),105.4(2-C),103.2 (12-C),98.7(9-C).Compound(16)16:UV k max:225,239,258,295,329,394nm;ESMS:m/z294 (M+H)+;1H NMR(DMSO-d6)d:10.67(s,NH),8.22(d,J=16Hz,5-H),7.70(s,2-H),7.50(t,J=16Hz,6-H),7.35(s,9-H),7.20(d,J=16Hz,7-H),6.48(s,12-H2),4.0(s,13-H3).13C NMR(DMSO-d6)ppm:168.1(11-C),155.3(8-C),148.8(3-C),147.1(4-C),134.7(10-C),125.7(6-C),125.0(11a-C),124.8(4b-C),124.0(10a-C),119.3(1-C),118.7(5-C),111.0(4a-C),108.3(7-C),105.7(2-H),103.3(12-C),97.9(9-C)add–OCH3value.Compound(29):ESMS:m/z316(M+H)+;1H NMR(DMSO-d6)d:9.12(d, J=16Hz,5-H),7.52(t,J=16Hz,6-H),7.50(s,2-H),7.22(d,J=16Hz,7-H),3.92 (s,–OCH3),13C NMR(DMSO-d6)ppm:NOE from–OCH3to proton doublet at d7.22due to7-H and no NOE from–OCH3.All the new compounds were purified by HPLC and identified by MS.V.R.Hegde et al./Bioorg.Med.Chem.Lett.20(2010)1384–13871387。
FUNDC1调控肺癌A549细胞及其干细胞的生长、自噬、凋亡和细胞干性的研究
Ｗｅｓｔｅｒｎｂｌｏｔｔｉｎｇ实验被用来检测目标蛋白的表达水平。 首先，将收集到的细胞在低温条件下使用含 １％蛋白酶抑制
剂的预冷细胞裂解缓冲液进行裂解，４℃ １１４５１×ｇ离心 ３０ ｍｉｎ，使用 ＢＣＡ试剂盒（翊圣生物，上海）测定上清液中的蛋 白含量。ＳＤＳ－ＰＡＧＥ（１０％）被用来分离等量的蛋白样本，随 后进行转膜，并使用 ５％的脱脂牛奶于室温下封闭两小时。 经过三次的 ＴＢＳ缓冲液清洗后，一抗 （均为 兔 抗 多 克 隆 抗 体）过夜孵育蛋 白 膜 （ａｎｔｉ－ＦＵＮＤＣ１、ａｎｔｉ－Ｂａｘ、ａｎｔｉ－Ｂｃｌ－ ２、ａｎｔｉ－ｃａｓｐａｓｅ３、ａｎｔｉ－ｐ６２、ａｎｔｉ－Ｂｅｃｌｉｎ－１、ａｎｔｉ－ＬＣ３－Ⅱ、 ａｎｔｉ－ＣＤ１３３、ａｎｔｉ－Ｓｏｘ２、ａｎｔｉ－Ｏｃｔ４、ａｎｔｉ－β－ａｃｔｉｎ，稀 释度 １∶１０００，４℃），ＨＲＰ标记的山羊抗兔 ＩｇＧ二抗孵育一小时 （稀释度 １∶２０００，３７℃）。所有抗体均购自 Ａｂｃａｍ（上海）公 司。添加 ＥＣＬ试剂曝光显影蛋白条带 １ｍｉｎ。β－ａｃｔｉｎ为本 实验的内参蛋白。 １．６ ＣＣＫ－８细胞增殖实验
【收稿日期】 ２０２０－０９－２９ 【修回日期】 ２０２０－１１－２２ 【基金项目】 陕西省西安市科技攻关项目［编号：２０１７１１３ＳＦ／ＹＸ００７（１）］ 【作者单位】 西安市中心医院呼吸与危重症医学科，陕西 西安
７１０００３ 【作者简介】 董玉（１９７３－），女，贵州贵阳人，主任医师，研究方向：
海洋生物碱Pityriacitrin及其衍生物的合成与生物活性研究
海洋生物碱Pityriacitrin及其衍生物的合成与生物活性研究张朴永，孙小飞，万升标，任素梅，江涛*中国海洋大学医药学院，教育部海洋药物重点实验室，青岛，中国摘要：目的本文对源自海洋细菌的β－咔啉生物碱Pityriacitrin的全合成与体外细胞毒性进行了描述，其衍生物的合成也是首次报道。
方法使用色氨酸或五位被取代的色氨酸与5-取代吲哚作为起始原料，通过改进的Pictet–Spengler反应合成了Pityriacitrin及其衍生物。
结果所有化合物均通过红外、核磁共振氢谱、核磁共振碳谱和质谱进行了结构表征。
对肿瘤细胞MDA-231进行了体外的细胞毒性测试，其中化合物5显示对MDA-231具有高活性(IC50 = 0.08 uM)。
结论β－咔啉生物碱Pityriacitrin是一个结构新颖的具有抗肿瘤活性的先导化合物，所使用的全合成的反应路线为以后类似物的合成提供了良好的借鉴。
关键词：Pityriacitrin；β－咔啉；抗肿瘤；全合成；海洋生物碱；Pictet–Spengler反应Synthesis and Bioactivity of the Marine Alkaloid Pityriacitrin and ItsDerivativesPuyong Zhang, Xiaofei Sun, Sumei Ren, Shengbiao Wan, Tao Jiang*, College of Medicine and Pharmacy, Key Laboratory of Marine Drugs,Ministry of Education, OceanUniversity of China, Qingdao, ChinaABSTRACT：OBJECTIVE Total chemical synthesis and in vitr o cytotoxic evaluation of β-carboline alkaloid pityriacitrin, originally isolated from a marine bacterium, and its derivatives is reported for the first time. METHODS Using tryptophan or 5-hydroxyl tryptophan and 5-substituted indole as starting materials, via the modified Pictet–Spengler reaction, pityriacitrin and its derivatives were synthesized. RESULTS All compounds have been characterized by IR, NMR and mass spectrometry. All the compounds were tested for in vitro cytotoxicity against MDA-231. Compound 5 exhibited high cytotoxicity (IC50 = 0.08 uM) against MDA-231 cell line. CONCLUSION β-carboline alkaloid pityriacitrin was a lead compound of antitumor, the route of synthesis may be as the reference for the synthesis of anologues.KEY WORDS:Pityriacitrin; β-carboline; antitumor; totalsynthesis; marine alkaloid; Pictet–Spengler reactionβ－咔啉类化合物是自然界存在的一大类吲哚生物碱，由于其生物活性广泛而引起越来越多的关注。
新型AChE抑制剂胡椒碱衍生物对阿尔茨海默病小鼠的治疗作用评价
网络出版时间：２０２３－１０－３０１９：３３：３１ 网络出版地址：ｈｔｔｐｓ：／／ｌｉｎｋ．ｃｎｋｉ．ｎｅｔ／ｕｒｌｉｄ／３４．１０８６．Ｒ．２０２３１０２７．１５３１．０２２◇神经精神药理◇新型ＡＣｈＥ抑制剂胡椒碱衍生物对阿尔茨海默病小鼠的治疗作用评价孙佳磊，朱仁德，吴 静，曹国敏，刘新华，李 荣，石静波（安徽医科大学药学院，安徽合肥 ２３００３２）收稿日期：２０２３－０６－０９，修回日期：２０２３－０９－２３基金项目：国家自然科学基金资助项目（Ｎｏ２１９７７００１）；药学创新基金科研项目（ＮｏＹＸＣＸ２０２１０２）作者简介：孙佳磊（１９９８－），男，硕士生，研究方向：小分子药物的设计、合成及抗炎活性评价，Ｅ ｍａｉｌ：２９７１７９９９８０＠ｑｑ．ｃｏｍ；石静波（１９７５－），男，博士，副教授，硕士生导师，研究方向：药物设计与合成／药物化学生物学，通信作者，Ｅ ｍａｉｌ：ｓｊｂｏ６１６＠１２６．ｃｏｍ；李 荣（１９７９－），男，博士，教授，博士生导师，研究方向：类风湿关节炎发病机制及药物药理学，通信作者，Ｅ ｍａｉｌ：ｌｉｒｏｎｇ＠ａｈｍｕ．ｅｄｕ．ｃｎｄｏｉ：１０．１２３６０／ＣＰＢ２０２３０６０２６文献标志码：Ａ文章编号：１００１－１９７８（２０２３）１１－２０６４－０６中国图书分类号：Ｒ ３３２；Ｒ２８２ ７１；Ｒ３３８ ６４；Ｒ３４５ ６１；Ｒ７４５ ７摘要：目的 研究胡椒碱衍生物４ａ对乙酰胆碱酯酶的抑制活性及对阿尔茨海默病（Ａｌｚｈｅｉｍｅｒ′ｓｄｉｓｅａｓｅ，ＡＤ）小鼠的神经保护的作用。
方法 雄性Ｃ５７ＢＬ／６Ｊ小鼠３０只，随机分：（ｉ）空白对照组，（ｉｉ）模型组，（ｉｉｉ）多奈哌齐（１０ｍｇ·ｋｇ－１，阳性对照）组，（ｉｖ）４ａ低浓度（２０ｍｇ·ｋｇ－１）组，（ｖ）４ａ高浓度（４０ｍｇ·ｋｇ－１）组。
ｉｉｉ至ｖ组，小鼠给药东莨菪碱（３ｍｇ·ｋｇ－１）３０ｍｉｎ后，口服多奈哌齐和４ａ，连续１０ｄ，Ｍｏｒｒｉｓ水迷宫实验观察由东莨菪碱诱导的认知功能障碍小鼠的记忆功能。
益生菌对阿尔茨海默病作用的研究进展
益生菌对阿尔茨海默病作用的研究进展发布时间：2021-12-14T06:08:15.523Z 来源：《中国结合医学杂志》2021年12期作者：宋鑫萍1,2，李盛钰2，金清1[导读] 阿尔茨海默病已成为威胁全球老年人生命健康的主要疾病之一，患者数量逐年攀升，其护理的经济成本高，给全球经济造成重大挑战。
近年来研究显示，益生菌在适量使用时作为有益于宿主健康的微生物，在防治阿尔茨海默病方面具有积极影响，其作用机制可能通过调节肠道菌群，影响神经免疫系统，调控神经活性物质以及代谢产物，通过肠-脑轴影响该病发生和发展。
宋鑫萍1,2，李盛钰2，金清11.延边大学农学院，吉林延吉 1330022.吉林省农业科学院农产品加工研究所，吉林长春 130033摘要：阿尔茨海默病已成为威胁全球老年人生命健康的主要疾病之一，患者数量逐年攀升，其护理的经济成本高，给全球经济造成重大挑战。
近年来研究显示，益生菌在适量使用时作为有益于宿主健康的微生物，在防治阿尔茨海默病方面具有积极影响，其作用机制可能通过调节肠道菌群，影响神经免疫系统，调控神经活性物质以及代谢产物，通过肠-脑轴影响该病发生和发展。
本文综述了近几年来国内外益生菌对阿尔茨海默病的作用进展，以及其预防和治疗阿尔茨海默病的潜在作用机制。
关键词：益生菌；阿尔茨海默病；肠道菌群；机制Recent Progress in Research on Probiotics Effect on Alzheimer’s DiseaseSONG Xinping1,2，LI Shengyu2，JI Qing1*(1.College of Agricultural, Yanbian University, Yanji 133002，China)(2.Institute of Agro-food Technology, Jilin Academy of Agricultural Sciences, Chanchun 130033, China)Abstract：Alzheimer’s disease has become one of the major diseases threatening the life and health of the global elderly. The number of patients is increasing year by year, and the economic cost of nursing is high, which poses a major challenge to the global economy. In recent years, studies have shown that probiotics, as microorganisms beneficial to the health of the host, have a positive impact on the prevention and treatment of Alzheimer’s disease. Its mechanism may be through regulating intestinal flora, affecting the nervous immune system, regulating the neuroactive substances and metabolites, and affecting the occurrence and development of the disease through thegut- brain axis. This paper reviews the progress of probiotics on Alzheimer’s disease at home and abroad in recent years, as well as its potential mechanism of prevention and treatment.Key words：probiotics; Alzheimer’s disease; gut microbiota; mechanism阿尔茨海默病（Alzheimer’s disease, AD），系中枢神经系统退行性疾病，属于老年期痴呆常见类型，临床特征主要包括：记忆力减退、认知功能障碍、行为改变、焦虑和抑郁等。
IRAK-1-4_Inhibitor_I_SDS_MedChemExpress
Inhibitors, Agonists, Screening LibrariesSafety Data Sheet Revision Date:Sep.-12-2017Print Date:Sep.-12-20171. PRODUCT AND COMPANY IDENTIFICATION1.1 Product identifierProduct name :IRAK-1-4 Inhibitor ICatalog No. :HY-13329CAS No. :509093-47-41.2 Relevant identified uses of the substance or mixture and uses advised againstIdentified uses :Laboratory chemicals, manufacture of substances.1.3 Details of the supplier of the safety data sheetCompany:MedChemExpress USATel:609-228-6898Fax:609-228-5909E-mail:sales@1.4 Emergency telephone numberEmergency Phone #:609-228-68982. HAZARDS IDENTIFICATION2.1 Classification of the substance or mixtureNot a hazardous substance or mixture.2.2 GHS Label elements, including precautionary statementsNot a hazardous substance or mixture.2.3 Other hazardsNone.3. COMPOSITION/INFORMATION ON INGREDIENTS3.1 SubstancesSynonyms:IRAK–1/4 Inhibitor I; Benzamide, N–[1–[2–(4–morpholinyl)ethyl]–1H–benzimidazol–2–yl]–3–nitro–Formula:C20H21N5O4Molecular Weight:395.41CAS No. :509093-47-44. FIRST AID MEASURES4.1 Description of first aid measuresEye contactRemove any contact lenses, locate eye-wash station, and flush eyes immediately with large amounts of water. Separate eyelids with fingers to ensure adequate flushing. Promptly call a physician.Skin contactRinse skin thoroughly with large amounts of water. Remove contaminated clothing and shoes and call a physician.InhalationImmediately relocate self or casualty to fresh air. If breathing is difficult, give cardiopulmonary resuscitation (CPR). Avoid mouth-to-mouth resuscitation.IngestionWash out mouth with water; Do NOT induce vomiting; call a physician.4.2 Most important symptoms and effects, both acute and delayedThe most important known symptoms and effects are described in the labelling (see section 2.2).4.3 Indication of any immediate medical attention and special treatment neededTreat symptomatically.5. FIRE FIGHTING MEASURES5.1 Extinguishing mediaSuitable extinguishing mediaUse water spray, dry chemical, foam, and carbon dioxide fire extinguisher.5.2 Special hazards arising from the substance or mixtureDuring combustion, may emit irritant fumes.5.3 Advice for firefightersWear self-contained breathing apparatus and protective clothing.6. ACCIDENTAL RELEASE MEASURES6.1 Personal precautions, protective equipment and emergency proceduresUse full personal protective equipment. Avoid breathing vapors, mist, dust or gas. Ensure adequate ventilation. Evacuate personnel to safe areas.Refer to protective measures listed in sections 8.6.2 Environmental precautionsTry to prevent further leakage or spillage. Keep the product away from drains or water courses.6.3 Methods and materials for containment and cleaning upAbsorb solutions with finely-powdered liquid-binding material (diatomite, universal binders); Decontaminate surfaces and equipment by scrubbing with alcohol; Dispose of contaminated material according to Section 13.7. HANDLING AND STORAGE7.1 Precautions for safe handlingAvoid inhalation, contact with eyes and skin. Avoid dust and aerosol formation. Use only in areas with appropriate exhaust ventilation.7.2 Conditions for safe storage, including any incompatibilitiesKeep container tightly sealed in cool, well-ventilated area. Keep away from direct sunlight and sources of ignition.Recommended storage temperature:Powder-20°C 3 years4°C 2 yearsIn solvent-80°C 6 months-20°C 1 monthShipping at room temperature if less than 2 weeks.7.3 Specific end use(s)No data available.8. EXPOSURE CONTROLS/PERSONAL PROTECTION8.1 Control parametersComponents with workplace control parametersThis product contains no substances with occupational exposure limit values.8.2 Exposure controlsEngineering controlsEnsure adequate ventilation. Provide accessible safety shower and eye wash station.Personal protective equipmentEye protection Safety goggles with side-shields.Hand protection Protective gloves.Skin and body protection Impervious clothing.Respiratory protection Suitable respirator.Environmental exposure controls Keep the product away from drains, water courses or the soil. Cleanspillages in a safe way as soon as possible.9. PHYSICAL AND CHEMICAL PROPERTIES9.1 Information on basic physical and chemical propertiesAppearance Light yellow to yellow (Solid)Odor No data availableOdor threshold No data availablepH No data availableMelting/freezing point No data availableBoiling point/range No data availableFlash point No data availableEvaporation rate No data availableFlammability (solid, gas)No data availableUpper/lower flammability or explosive limits No data availableVapor pressure No data availableVapor density No data availableRelative density No data availableWater Solubility No data availablePartition coefficient No data availableAuto-ignition temperature No data availableDecomposition temperature No data availableViscosity No data availableExplosive properties No data availableOxidizing properties No data available9.2 Other safety informationNo data available.10. STABILITY AND REACTIVITY10.1 ReactivityNo data available.10.2 Chemical stabilityStable under recommended storage conditions.10.3 Possibility of hazardous reactionsNo data available.10.4 Conditions to avoidNo data available.10.5 Incompatible materialsStrong acids/alkalis, strong oxidising/reducing agents.10.6 Hazardous decomposition productsUnder fire conditions, may decompose and emit toxic fumes.Other decomposition products - no data available.11.TOXICOLOGICAL INFORMATION11.1 Information on toxicological effectsAcute toxicityClassified based on available data. For more details, see section 2Skin corrosion/irritationClassified based on available data. For more details, see section 2Serious eye damage/irritationClassified based on available data. For more details, see section 2Respiratory or skin sensitizationClassified based on available data. For more details, see section 2Germ cell mutagenicityClassified based on available data. For more details, see section 2CarcinogenicityIARC: No component of this product present at a level equal to or greater than 0.1% is identified as probable, possible or confirmed human carcinogen by IARC.ACGIH: No component of this product present at a level equal to or greater than 0.1% is identified as a potential or confirmed carcinogen by ACGIH.NTP: No component of this product present at a level equal to or greater than 0.1% is identified as a anticipated or confirmed carcinogen by NTP.OSHA: No component of this product present at a level equal to or greater than 0.1% is identified as a potential or confirmed carcinogen by OSHA.Reproductive toxicityClassified based on available data. For more details, see section 2Specific target organ toxicity - single exposureClassified based on available data. For more details, see section 2Specific target organ toxicity - repeated exposureClassified based on available data. For more details, see section 2Aspiration hazardClassified based on available data. For more details, see section 212. ECOLOGICAL INFORMATION12.1 ToxicityNo data available.12.2 Persistence and degradabilityNo data available.12.3 Bioaccumlative potentialNo data available.12.4 Mobility in soilNo data available.12.5 Results of PBT and vPvB assessmentPBT/vPvB assessment unavailable as chemical safety assessment not required or not conducted.12.6 Other adverse effectsNo data available.13. DISPOSAL CONSIDERATIONS13.1 Waste treatment methodsProductDispose substance in accordance with prevailing country, federal, state and local regulations.Contaminated packagingConduct recycling or disposal in accordance with prevailing country, federal, state and local regulations.14. TRANSPORT INFORMATIONDOT (US)This substance is considered to be non-hazardous for transport.IMDGThis substance is considered to be non-hazardous for transport.IATAThis substance is considered to be non-hazardous for transport.15. REGULATORY INFORMATIONSARA 302 Components:No chemicals in this material are subject to the reporting requirements of SARA Title III, Section 302.SARA 313 Components:This material does not contain any chemical components with known CAS numbers that exceed the threshold (De Minimis) reporting levels established by SARA Title III, Section 313.SARA 311/312 Hazards:No SARA Hazards.Massachusetts Right To Know Components:No components are subject to the Massachusetts Right to Know Act.Pennsylvania Right To Know Components:No components are subject to the Pennsylvania Right to Know Act.New Jersey Right To Know Components:No components are subject to the New Jersey Right to Know Act.California Prop. 65 Components:This product does not contain any chemicals known to State of California to cause cancer, birth defects, or anyother reproductive harm.16. OTHER INFORMATIONCopyright 2017 MedChemExpress. The above information is correct to the best of our present knowledge but does not purport to be all inclusive and should be used only as a guide. The product is for research use only and for experienced personnel. It must only be handled by suitably qualified experienced scientists in appropriately equipped and authorized facilities. The burden of safe use of this material rests entirely with the user. MedChemExpress disclaims all liability for any damage resulting from handling or from contact with this product.Caution: Product has not been fully validated for medical applications. For research use only.Tel: 609-228-6898 Fax: 609-228-5909 E-mail: tech@Address: 1 Deer Park Dr, Suite Q, Monmouth Junction, NJ 08852, USA。
《国际药学研究杂志》稿约
《国际药学研究杂志》原名《国外医学药学分册》，是军事医学科学院主管、军事医学科学院毒物药物研究所和中国药学会主办的大型综合性药学刊物，为月刊，国内外公开发行。
设置有专家论坛、专题报道、综述、论著、医药信息等栏目。
本刊以从事药学研究的科技人员、临床医师和药师、制药工程技术人员、医药院校师生为读者对象，根据国内药学科研、教学、临床和生产的需要，追踪报道国际药学领域的新进展、新动向、新技术和新成果，包括药物化学、药剂学、药物代谢、药物分析、药理和毒理学、生化药学和临床药学等基础研究和应用研究方面的内容。
是中国科技论文统计源期刊（中国科技核心期刊）、北大图书馆中文核心期刊，中国生物医学核心期刊，被美国《化学文摘》、美国《剑桥科学文摘》、荷兰《医学文摘》、世界卫生组织西太平洋地区医学索引、英国《农业与生物科学研究中心数据库》、中国核心期刊（遴选）数据库、中文科技期刊数据库、中国学术期刊综合评价数据库、中国生物医学期刊引文数据库、中文生物医学期刊文献数据库、中国药学文献数据库和中国生物学文献数据库等多个国内外权威检索系统收录。
2011、2014年连续两届被评为“中国精品科技期刊”。
多篇论文入选“F5000中国精品科技期刊顶尖学术论文”及中国药学会优秀论文。
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抗肿瘤药阿法替尼的合成
武汉轻工大学学报Journal of Wuhan Polytechnic University Vcl.39Nc.1Feb.2020第39卷第1期2020年2月文章编号：2095-386(2020)01-0037-03DOI：10.3969/L.issn.2095-386.2020.01.007抗肿瘤药阿法替尼的合成吴淑慧1，杨博2，赵玲1（1.武汉轻工大学生物与制药工程学院，湖北武汉430023；2,武汉英普瑞医药科技有限公司，湖北武汉430000）摘要：以7-氟-6酶肖基-4-酶基喳哇咻为原料经氯化取代反应制得关键中间体N-(3-氯-4-氟苯基)--氟酶酶肖基--酶哇咻胺3!最后经取代，还原，酰化反应制得抗肿瘤药Afatinib。
结果显示目标化合物的结构经1H-NMR谱和质谱确证，总收率为66%。
所作合成工艺与文献报道的工艺比较，新工艺步骤短，成本低廉，操作简单，所研制的合成工艺路线各步收率均较高，无需特殊试剂和条件，预期适合工业化生产的要求。
关键词：抗肿瘤药物;阿法替尼;合成;工艺优化中图分类号：R914.5文献标识码:ASyn t hesis of an t itumor age n t afatinibWU Shu-hui,YANG Bo2,ZHA0Ling1(1.School of BWI oxc and Pharmaceutical Engineering,Wuhan Polytechnic University, Wuhan430023,China；2.Wuhan Ying Purui Pharmaceutic/Tehnomgy Co.,Ltd.,Wuhan430000,China)Abstract：AO/nib(BIIW2992)，/novel potent and selective inhibitor of the VEGF and HER2,was designed te inhibit tumor growta.In order te improve ye synthesis of Afa/nif and te optimize its procedure,a stream lined syn-yyic route was designed.The key intemiediate4-(3-chmro-4-fiuoro-phenylamino)-V-Cuoro-6-nitroq-unin-v-voline was synaiesized from2,7-Fluoro-6-Pitro-4(H)-Quinazoline via,chlorination,substitution reaction On/ty,yia substitution,reduction acylation reaction te afford ymf compound Afatinib.The overall yield of the ymf compound was 66%,and fs stmcturo was confimied by1H-NMR and MS.Conclusion:In comparison with the reported procedure, during our optimized process, thW stream lined synthetic process of afatinb highlights excellent yielg in aloost evero procedure,ease of operation,robustne s,as wel l as green chemistro,and thus should be amenable io larae-scale production.Key words：antitumor ayent；Afatinif；syntUesis;procedure improvement1基］-4-(二甲基氨基)--丁烯酰胺，是德国勃引口林格殷格翰制药公司开发多靶点受体酪氨酸激酶抑阿法替尼(Afatinif),化学名为N-4-((3-氯-4-制剂，用于治疗性非小细胞肺癌的口服生物可利用氟苯基)氨基］--［［(3S)-四氢-3-咲喃基］氧基］--制剂，为不可逆双重受体酪氨酸激酶(RTK)抑制收稿日期：2019-12-10.作者简介：吴淑慧（1994-），女，硕士研究生，E-mail：wushuhuW212@.通信作者：赵玲（1982-），女，副教授，E-mail：.38武汉轻工大学学报2020年。
藏药骨关节止痛凝胶贴膏剂制备工艺研究
焦作市中医院药剂科…河南……焦作……454002；2.江西中方法：以初黏力、持黏性、剥离强度、感官评价为指标，通过流变仪测定不同载药量凝胶贴膏剂的复数模量与复数扩散池对贴膏剂经皮渗透性研究进行质量评价。
结果：筛选所得凝、甘羟铝0.7…g 、柠檬酸1.5…g 、羧甲基纤维素钠0.9…g 、NP700…4…g 。
结论：优选的凝胶贴膏剂处方及制备工艺可行，膏均匀性、渗透性良好，可为临床制剂开发奠定基础。
基金项目：江西省自然科学基金项目（20202BAB206081）。
通信作者：管咏梅，博士，教授，硕士生导师。
E-mail ：******************。
的研究[J].新中医, 2018, 50(1):151-154.［7］张春玲, 范顺明, 王佳琪, 等.中药防治慢性前列腺炎的实验研究进展[J/OL].中国实验方剂学杂志:1-12[2020-03-24].https:///10.13422/ki.syfj-x.20201061.［8］Xu HY, Zhang YQ, Liu ZM, et al. ETCM: an encyclopaedia of traditionalChinese medicine[J]. Nucleic acids research, 2018, 47(D1):976-982.［9］宋子健, 吴涵潇, 陈锐.前列腺炎与前列腺癌关系的研究进展[J/OL].现代泌尿外科杂志:1-5[2020-03-24]./kcms/detail/61.1374.R.20191008.1553.002.html.［10］齐旻芳, 黄高翔, 周雪娟.慢性非细菌性前列腺炎发病机制的研究进展[J].广西医科大学学报, 2017, 34(8):1 247-1 249.［11］刘祎, 陈先国, 梁朝朝.慢性前列腺炎相关免疫机制研究进展[J].中华男科学杂志, 2017, 23(7):652-655.［12］刘祎. 自噬调控Treg 细胞分化和功能在慢性前列腺炎中的作用[D].合肥:安徽医科大学, 2019.［13］杜宏, 赵维明.慢性前列腺炎的疼痛发病机制[J].现代泌尿外科杂志, 2017, 22(1):76-78.［14］崔仙红, 张鹏, 朱笛.茯苓三萜类化合物药理活性研究进展[J].中国药物经济学, 2019, 14(12):123-125.［15］汪电雷, 陈卫东, 徐先祥.茯苓总三萜的抗炎作用研究[J].安徽医药, 2009, 13(9):1 021-1 023.［16］Seulah Lee, Dahae Lee, Sung Ok Lee, et al. Anti-inflammatory activity ofthe sclerotia of edible fungus, Poria cocos Wolf and their active lanostane triterpenoids[J]. Journal of Functional Foods, 2017(32):27-36.［17］周宏超, 高立云, 范光丽, 等.茯苓酸对SLT-Ⅱ导大鼠肠黏膜微血管内皮细胞分泌细胞因子的影响[J].中国兽医科学, 2008(10):884-888.［18］Mizushina Y, Akihisa T, Ukiya M, et al.A novel DNA topoisomeraseinhibitor:dehydroebriconic acid, one of the lanostane-type triterpene acids from Poria cocos[J].Cancer Science, 2004, 95(4):354-360.［19］刘珊珊, 郭杰, 李宗艾, 等.泽泻化学成分及药理作用研究进展[J].中国中药杂志, 2020, 45(7):1 578-1 595.［20］Wang BinYan, Chen Liang, Dai LingHao, et al. Alisol B 23-AcetateAmeliorates Lipopolysaccharide-Induced Cardiac Dysfunction by Suppressing Toll-Like Receptor 4 (TLR4)/NADPH Oxidase 2 (NOX2) Signaling Pathway.[J]. Medical science monitor : international medical journal of experimental and clinical research, 2019(25):8 472-8 481.［21］Chang Woo Han, Min Jung Kwun, Kyun Ha Kim, et al. Ethanol extract ofAlismatis Rhizoma reduces acute lung inflammation by suppressing NF-κB and activating Nrf2[J]. Journal of Ethnopharmacology, 2013, 146(1):402-410.［22］林娜, 黄锦芳, 张雪, 等.泽泻总三萜的抗炎活性研究[J].福建中医药, 2018, 49(4):68-71.［23］Roh Y S, Park S, Kim J W, et al. Toll-like receptor 7-mediated typeI interferon signaling prevents cholestasis- and hepatotoxin-induced liver fibrosis[J]. Hepatology, 2014, 60(1):237-249.（收稿日期：2020-04-23）编辑：翟兴英骨关节疼痛是由局部关节软骨劳损和周围关节滑膜持续性炎症引起的，与饮食、生活环境等密切相关。
骨化三醇治疗糖尿病肾病对患者血糖水平和肾功能的影响
·内科研究·系统医学SYSTEMS MEDICINE 系统医学2021年3月第6卷第6期糖尿病是一类常见的慢性代谢性疾病,糖尿病肾病是其严重的并发症之一,也是导致终末期肾病的重要原因。
有报道显示[1]:临床有近1/2的2型糖尿病患者并发糖尿病肾病,近年来呈高涨态势,严重影响患者的身体健康,加大治疗难度。
目前,临床对该病的治疗主要是控制血糖,积极对患者的血糖与血压加以控制,阻断患者的血管紧张素系统,保护患者的肾脏与肾功能,延缓患者的病情发展,但其疗效仍需进一步提高。
骨化三醇的应用,可显著提高血钙的浓度,增加钙质的摄入量,提高钙质的沉积和骨质的钙化[2]。
该研究对2019年1月—2020年3月纳入的60例糖尿病肾病患者分组采取不同方式治疗,观察治疗效果,现报道如下。
DOI:10.19368/ki.2096-1782.2021.06.052骨化三醇治疗糖尿病肾病对患者血糖水平和肾功能的影响李守杰,杨洪洪沂水县人民医院内分泌科,山东沂水276400[摘要]目的研究骨化三醇治疗糖尿病肾病对患者血糖水平和肾功能的影响。
方法选取2019年1月—2020年3月收治的60例糖尿病肾病患者作为研究对象,随机分成对照组(n=30,贝那普利治疗)、观察组(n=30,骨化三醇治疗),比较治疗效果。
结果治疗后,观察组的空腹血糖(FPG)(6.46±0.77)mmol/L、餐后2h血糖(2hPG)(9.77±1.14)mmol/L水平均比对照组(7.63±1.07)mmol/L、(11.24±1.34)mmol/L低,差异有统计学意义(t=4.861、4.577,P< 0.05)。
治疗后,观察组患者的血肌酐(116.59±11.04)μmol/L、血尿素氮(4.32±0.21)mmol/L、24h尿蛋白(1.13±0.31)g/L、24h尿微量蛋白排泄(404.34±28.81)mg明显比对照组(160.39±17.49)μmol/L、(8.11±0.71)mmol/L、(1.91±0.22) g/L、(602.21±39.50)mg低,差异有统计学意义(t=11.599、28.037、11.239、22.168,P<0.05)。
化学发光酶免疫分析法检测水产品中残留的麻醉剂丁香酚
化学发光酶免疫分析法检测水产品中残留的麻醉剂丁香酚王强;王旭峰;赵东豪;张英霞;黄珂【期刊名称】《分析测试学报》【年(卷),期】2022(41)3【摘要】将丁香酚(Eul)与4-溴丁酸叔丁酯进行衍生化反应,合成了半抗原4-(4-烯丙基-2-甲氧基-苯氧基)-丁酸(Eul-4-Tbl)。
通过偶联载体蛋白并免疫动物后获取丁香酚多克隆抗体,建立了丁香酚的间接竞争化学发光酶免疫分析方法(ic-CLEIA)。
水产样品经乙腈提取,Oasis PRiME HLB固相萃取小柱净化后用于测定。
结果表明,ic-CLEIA的最佳反应条件为:包被原质量浓度为0.125μg/mL,抗体稀释40000倍,抗体反应时间为30 min,药物稀释液为PBS。
该方法的半抑制浓度(IC_(50))为1.28μg/L,检测线性范围为0.25~6.43μg/L,检出限(LOD,IC_(10))为0.11μg/L。
样品中丁香酚的加标回收率为76.6%~108%,相对标准偏差(RSD)为5.9%~12%,测定结果与液相色谱-串联质谱法具有良好的相关性(r=0.9904),可用于水产品中麻醉剂丁香酚残留的快速测定。
【总页数】7页(P354-360)【作者】王强;王旭峰;赵东豪;张英霞;黄珂【作者单位】中国水产科学研究院南海水产研究所【正文语种】中文【中图分类】O657.3;F762.6【相关文献】1.MISPE-HPLC检测水产品5种丁香酚麻醉剂的残留量2.化学发光免疫分析与酶联免疫分析法检测水产品药物残留的比较研究3.化学发光免疫分析与酶联免疫分析法检测水产品药物残留的比较研究4.UPLC-MS/MS同时测定水产品中4种丁香酚类麻醉剂残留量5.水产品中丁香酚类麻醉剂残留检测技术研究进展因版权原因，仅展示原文概要，查看原文内容请购买。
颗粒蛋白前体在博来霉素致肺纤维化小鼠中的表达
颗粒蛋白前体在博来霉素致肺纤维化小鼠中的表达刘洁婷;张蕾;赵洁;谢甜【期刊名称】《海南医学院学报》【年(卷),期】2024(30)5【摘要】目的:探讨颗粒蛋白前体(PGRN)在博来霉素致肺纤维化小鼠肺组织中的表达。
方法:选取C57BL/6小鼠36只,随机分为3组,博来霉素模型组向气管内灌注博来霉素(5 mg/kg)后第14、28天分批处死小鼠,生理盐水对照组注入等量的生理盐水。
肺组织采用HE染色和Masson染色观察小鼠肺组织炎症和纤维化情况,以免疫组化法检测PGRN在肺组织中的分布和表达,蛋白印迹法检测PGRN在小鼠肺组织中的蛋白表达水平。
结果:光镜下观察发现,生理盐水对照组小鼠肺组织结构完整,少量炎症细胞浸润;博来霉素组小鼠肺组织结构破坏,炎症细胞浸润,呈弥漫性肺纤维化改变。
免疫组化检测可见博来霉素组小鼠PGRN在肺泡巨噬细胞和肺泡上皮细胞中的阳性率明显高于生理盐水对照组,肺组织中PGRN蛋白表达水平明显升高(P<0.05)。
结论:PGRN可能参与了博来霉素致小鼠肺纤维化的过程。
【总页数】5页(P337-341)【作者】刘洁婷;张蕾;赵洁;谢甜【作者单位】海南医学院附属海南医院【正文语种】中文【中图分类】R563【相关文献】1.百合多糖抑制博来霉素致肺纤维化小鼠肺组织MMP-9及TIMP-2的表达2.颗粒蛋白前体缺陷型小鼠的鉴定及Ⅱ型胶原诱导颗粒蛋白前体缺陷型小鼠关节炎模型的建立3.博来霉素致大鼠肺纤维化模型中赖氨酰氧化酶蛋白表达与活性的动态变化4.IL-17A在博来霉素致小鼠肺纤维化形成中的表达5.参龙煎剂对博来霉素致肺纤维化大鼠肺组织基质金属蛋白酶2与金属蛋白酶组织抑制剂1表达的影响(英文)因版权原因，仅展示原文概要，查看原文内容请购买。