【doc】四氢异喹啉化合物CPU23与硝苯啶的分子模拟及其构象分析

【doc】四氢异喹啉化合物CPU23与硝苯啶的分子模拟及其构象分析 四氢异喹啉化合物CPU23与硝苯啶的分子 模拟及其构象分析 中国药科大学 JournalofChinaPharmaceuticalUniversity1996,27(2):68,70 MolecularModelingandConformationalAnalysisof Tetrahydr0is0quin0lineGompoundCPU23andNifedipine XuGuoyou,HuangWenlong,WeiBaoyang,HuaWeiyi,PengSixun D/ms/onofMedicinalCindery,PharmaceutWdUmvevs/ty,?l翩细210009 AbstractTwomolecuhfstructLLre~ofCPU23.whichwasprovedtobeacalciumantagonistinteracting withDAPbindingsite.andnifedipineweremimicked0naSGI-4D25GoornputerwiththePOGENsoft- ware.Themolecularmodelingresuttsshowedthatthexew盯 esomesimi1ariti~taDonformatlonandrelevant properti~betweenCPU23andnifedipine.ItwasfurthersuggestedthatCPU23mighteKertitscardiovascu tareffectsbyinteractionwiththedihydropyridinereceptorontheB-typecalciumchanne1. KeywordsTetrahydroisoquinolinederivatives;Nifedipine;Calciumantagonists;Molecularmodeling; P0GEN?ftware AseriesofsubstitutedN—aminoacetylated tetrahydroisoquinolinesincludingCPU23(1一 {1一[(6一methoxy)一naphth一2一y1]卜ethyl-2一(1一 piperidiny1)一acetyl一6,7-dimethoxy一1.2,3,4一te trahydroisoquinoline)derivedfromthecleavage productSoftetrandrinewerefoundtoinhibit fHl—nitrendipinebindingtoratcerebralcortical membranesI'.Thebioohemiealandpharmaco- logicalre~ultasuggestedthatthesetetrahydrolso- quinolinederivativesmightexerttheircardiovas— culareffectsviainteractionwiththedihydropyri— dine(DHP)bindingsite(i.e.,DHPreceptor) ollthe,tvpecalciumehannelL.nIecadcium antagonisticactivityv#'roandthehypotensive effectvivoofCPU23,oneofthemostpotent compoundidentifiedinthisseries.wereleSspo— tentthanthoseofniledi【pine,butmorepatent tharlthoseoftetrandrinewhichinteractedwith thediltiazemreceptor.Therefore,itwasfound thatthesetetrahydroisoquinolinecompounds fsuchasCPU23)structurallydistinctfrom DHP—typecalciumantagonistsmhtalsointer actwiththeDHPreceptor. (a)(b】 Fig1.Ch~~nimls?uccuresofcompoundCPU23(a)and nifedipine[b) StructuresofCPU23andnifedipinewere mimickedbytheP0LYGEN—programmedcom— puter—aidedmolecularmodeling,Themethodof cliqHecoordinatetransformationwasinvolvedin theseprocesses.Sineeboththetetrahydroiso— quinolinederivative,CPU23,andtheDHP— typedrug.nifodipine.actedonthesamerecep tor,theDHPreceptoronthe上广pecalcium channel,moredetailedcomparativeanalysisbe tweenCPU23andnffedipineintermsofstruc— ruralfeature.conformarionanditspropertywas performedonthebasisoftheirdominantconfor— mations(seeFig2.)obtainedbytheabovemod elingonaSGI一4D25Gcomputer(seeTab1. fordetails).FtomtheresultsofTab1,there weresomesimilaritiesbetweenCPU23and nifedipine,furthersupportingthenotionthat CPU23mightexertitscardiovascuMreffectSby interactionwiththeDHPreceptorontheL-type calciumchannel,hutaIsosomedifferencesin— eludingtheMrgesttorsionanglewithintheirpar— entnucleus,thedihedralang3ebetweenthepar— entringandthesubstitutedaromaticring,and thedistancesbetweencertainfunctionatoms ere..thesedifferencesmightbeimportantfac- topswhichresultedintheactivityofCPU23to belesspotentthanthatofnifedipineboth础rD and/nt. 1-heTeweresimilarres~ltaobtainedbythe computer—aidedmolecularmodelingandthex— raydiffractionexperimentofnifedipine(seeh. Ra:euvdOcto/~l9.1995ThisworkwaspresentediapaxtattheThirdChinaJapanDrugI)龉jgnandDevelopmentSymposlum theh~sIituteofMateriaMedica.ChineseAcademyofMedicalSciene~,August23-25,l993B eijlng;China 袋 一豫 Nm2XuGu.y0u":Molecularmodelingandcc:nformationalanalysisofCPU23andnlfedipin e69 i.JinTab】.) Fig2Dominant?nf0rm肚【imsofCPU23&nffedlpin~obtainedbythePoLYG日— progzammedcomputeraidedmolevuin) moaedng TabI.Comparisonsofstr~tumlf~mr~corffozmaUonandhydrophobieliybetwe~compound CPU23蚰dnlfedipine bag鲥0nthePOLYGEN—programmedcomputer—aidedmotecularmodeling Note:()一 (e)showedsimilarlti=~instructuraLfeature}fd)(g)showedsimiLaxitie*jn~onformatinna ndhydrophcblcJty; (h)一(k)showedd【ffertn0嚣inconformationandmolocularvolume.(的 rept~entedthedistae~fromthen】【r0g如atoIll 'nparentringtothehydrophobiccenter(agomaticring)}(g)wasdefinedastheratiovalIleofhy ckophobi~surfa~~are且 ofmoleculetothehydr0曲ilk{【h)wasthelarg~ttov~onangleamongthepantring}【】)w 鹧thetotalsumofabsoJute vat.sofsixtorsionangl~withinthesn0msintheI~entringi(】),雌 thedihedralangtehetwe~theparentrjn8and thearomaticring'Obtainedbythex-raydlffraetionexperimentIntheLitcratureE?】.(unit:length一曲斟rom.angi~? 'de~'ee). AcknowledgementsWethanktheNationalNaturalSci enO幅FoundationofChinaforfinancialsupportofpart ofwork. R~[erenccs 1HuangwL.SongX0,Pengsx,.Synthesisaad biologicalactivityofsul:cXitutedteti'ahydroJso0,oln01com poundsActaP韧?妊脑阱.1990.25:8l5 2XuGY.PengSX,HuawY.S.tedie.gonsynthesis,ol雌i— calactivityands【ruc【ureac"vity~ladonshipofN aminoaeety[benzyltet)ahydrinso0, uin01irt~andrelatedCom poundsJ凸n?,1993.24l93 3DongH.LeeCM.Huan$wL.Cardlov~eulareffecb of?bsttutedte~ahydvc)isoqalnobrt~lnrabBeJ,%mTrI co/,1992107262 4FosshelmR-Svart~gK-M~tadA."Crysm[sttuc一 【uresandpharmaeotogiealactivityofcaIdum~hamtelantag 0n-2.6=dJmethy[-3,5-dicaTbomethoxy-4-funsub~titute— d.3methy1dme~yl一3一niUo4nitro,aad2.4一 dinitropheny1)tj,4一dihydmpy~idineJMed0m.j982. 25:126 5Tri~leAM.Shef~rE.T~iggieDJ.Crystalg?uc【…ofcal ciumcha:mctantagonists:2,6-dlmeth. v3,5一diear bomethoxy4L2niU-o—t3cyano,4(dimethylamlno). and2.3,d,5.6一pentafinoropheny[]一I,4dihydropyr~lne JMedCAeot.1980.231442 ?/70JournalofChinaPharmaceuticalUniversityVo1.27 四氢异喹啉化合物CPU23与硝苯啶的分子模拟及其构象分析 许国友黄文堑韦苞洋华维一彭司勋 卜77z7f吐,'中国药科大学药物化学研究室,南京2100o9) A摘要借助于POLYGEN软件包在SGI一4D25G超级工作站上对四氢异喹啉化台物CPU23和硝苯啶的 化学结掏进行丁分子模拟.从分子模拟所得掏象的分析比较发现:两者在空间构象及其有关性质方面存在一 定相似性,从而进一步从理论上证实了药理试验结果 关键词四氢异喹啉祈生物;硝苯啶;钙拮抗荆;分子模拟;POLYGEN软件包 【文摘0l3】国产海龙科药用鱼类研究进展张 朝晖,棘国钧.待珞珊等.中国海洋药物,1995.14 ():95 对国产海龙科药用鱼类从分类学研究,药材资 蔼研究,组织学研究,化学成分研究药理作用研究 等7十方面的进展进行综述,全文综述文献3l篇 '文摘014】:抄散生物碱粪成分的定量分析 球婷,棘强,严永请.中国实验方l学杂惠, l995,l(2):20 在前报对二妙散水提物中的免疫抑毒9活性成分 进行定性分析的基础上,应用TL及HPLC法对其 中的生物碱进行了定量测定.并与黄柏水提物中的 各生物碱含量进行了比较,结果 表 关于同志近三年现实表现材料材料类招标技术评分表图表与交易pdf视力表打印pdf用图表说话 pdf 明t二妙散中各生 物碱的古量低于黄柏,其中小檗碱和巴弓汀的含量 减少幅度最大. 【文摘0l5】大肠杆菌天门毒酰胺酶?的基因克 隆与表达孛晶,刘景晶,吴梧桐等.药特生轴技 采,1995,2(4):8 用一对与大肠杆菌编码天门冬酰胺酶I(L ASPsI)的基因ansB两侧序刊互补的寡棱苷酸L-, L.作引物,以L~ASPsI的野生型生产菌CPU210009 染色体为模板,经PCR扩增得到长约1.6Kb的DNA 片段该片段通过以LP-,LP:为内引物的PCR反应, 证明包含了ansB基因的编码序列.将此片段经xba l,HindI消化,插入质粒PUCl9,PUCI9上构建重 组质粒PUAI8,PUAI9,分别转化As1.1J87,As 1.儿93,HB1Oi.9637,JM107,71,i8.CPU2l0099 等宿主菌.筛选得到L-ASPs口酶活力明显提高的8 株阳性转化子.在lL生物反应器中,LB培养基37C 下培养2h,其酶活在6.2,31.9IU/ml之间其中 CTAa表达L~ASPsI水平最高,达到31.8lO/ml各 基固工程菌株较之野生型生产菌体CPU210099.其 生产L~ASPs口水平提高了5,26倍.而且IPTG诱导 对工程菌表达ASPsi的水平几无影响SDS PAGE{剜得工程菌表进的L-ASPs1分子量约为140 Kd.薄层扫描结果显示:CTA,CTBhCTA所产生的 L—ASPsI占宿主菌可溶性蛋白总量的28.3, 35.7,33.6