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1、JALAFebruary2009 #JALAFebruary2009 KerstinThurow,Ph.D.Hilicombinationsoftheseelementstoarereported(Comb.Chem.High:2008,11,587601).SelectiveMonolithiationofDibroiobiarylsUsingMicroflowSysteisLiteratureHighlightsAutomationHighlightsfromtheLiteratureLABORATORYAUTOMATIONANDHIGH-THROUGHPUTCHEMISTRYRapidM
2、ultistepSynthesisof1,2,4-OxadiazolesinaSingleContinuousMicroreactorSequenceJALAFebruary2009 #JALAFebruary2009 #Ageneralmethodforthesynthesisofbissubstituted1,2,4-oxadiazolesfromreadilyavailablearylnitrilesandactivatedcarbonylsinasinglecontinuousmicroreactorsequenceisdescribedbyN.D.P.Cosfordetal.Thes
3、ynthesisincorporatesthreesequentialmicroreactorstoproduce1,2,4-oxa-diazolesinapproximately30mininquantities(4080mg)sufficientforfullcharacterizationandrapidlibrarysupply(J.Org.Chem.2009,73,721923).ExpandingtheCheiicalSpaceinPractice:Diversity-OrientedSynthesisDiversity-orientedsynthesis(DOS)aimstobr
4、oadenthefrontierofaccessiblecollectionsofcomplexanddiversesmallmolecules.M.Peuch-maurandY.-S.WongdissecttheDOSconceptthroughthreeelementsofdiversity:buildingblock,stereochemistry,andskeleton.RecentexamplesintheliteraturethatemphasizetheefficientCorrespondence:HilmarWeinmann,Ph.D.,BayerScheringPharma
5、AG,GlobalDrugDiscovery,MedicinalChemistryBerlin,D-13342Berlin,Germany;Phone:+49.30.468.17892;Fax:+49.30.468.18170;E-mail:Hilmar.Weinmann;orKerstinThurow,Ph.D.,UniversityofRostock,InstituteofAutomation,R.Wagner,Street31,18119Rostock,Germany;Phone:+49.381.498.7800;Fax:+49.381.498.7802;E-mail: HYPERLIN
6、K mailto:Kerstin.Thurowuni-rostock.deKerstin.Thurowuni-rostock.deJALA2009;14:15.1535-5535/$36.00Copyright2009byTheAssociationforLaboratoryAutomationdoi:10.1016/j.jala.2008.10.002Selectivemonolithiationofdibromobiarylswithoneequivalentofn-butyllithiumfollowedbythereactionwithelectrophilesisachievedby
7、J.-I.Yoshidaetal.usingamicroflowsystembyvirtueoffastmicromixingandprecisetemperaturecontrol.Sequentialintroductionoftwodifferentelectrophilesbasedonthismethodalsoisachievedusingamicroflowsystemcomposedoffourmicromixersandfourmicrotubereactors(Org.Lett.2008,10,39373940).CoibinatorialMaterialsResearch
8、AppliedtotheDevelopientofNewSurfaceCoatingsX:AHigh-ThroughputElectrocheiicalIipedanceSpectroscopyMethodforScreeningOrganicCoatingsforCorrosionInhibitionJ.Heetal.reportahigh-throughputelectrochemicalimpedancespectroscopy(HT-EIS)methodforrapidandquantitativeevaluationofcorrosionprotectivecoatings.A12-
9、element,spatiallyaddressableelectrochemicalplatformhasbeendesigned,fabricated,andvalidated.Thisplatformisinterfacedtoacommercialelectrochemicalimpedancespectroscopy(EIS)instrumentthroughanautomatedelectronicswitchingunit.TheHT-EISsystemenablesfourparallelEISmeasurementstoberunsimultaneously,whichsig
10、nificantlyreducescharacterizationtimecomparedtothatofserialEISmeasurementsusingamultiplexer.TheperformanceoftheHT-EISsystemisvalidatedusingaseriesofmodelsystems,includingaRandlesequivalentcircuit,anJALAFebruary2009 #JALAFebruary2009 #LiteratureHighlightsLiteratureHighlights JALAFebruary2009JALAFebru
11、ary2009 electrochemicalreaction(Ti/K4FeCN6,K3FeCN6),ahighlyuniformpolymerfilm,andseveralpolymercoatings.TheresultsofthevalidationstudiesshowthattheHT-EISsystemenablesamajorreductionincharacterizationtimeandprovideshighqualitydatacomparabletodataobtainedwithconventional,single-cellEISmeasurementsyste
12、ms(J.Comb.Chem.2008,10,704e713).ResinCapsules:PermeableContainersforParallel/CombinatorialSolid-PhaseOrganicSynthesisAresincapsuleisapermeablecontainerforresinbeadsdesignedforcombinatorialsolid-phaseorganicsynthesis.Resincapsulesconsistofahigh-densitypolyethyleneringsealedwithpeekmeshonbothsides.The
13、cylindricalshapeofresincapsulesenablesspace-savingpackingintoplasticcolumn-likereactionvesselscommonlyusedforsolid-phaseorganicsynthesis.ResincapsulesareevaluatedbyV.Krchnaketal.foruseincombinatorialsynthesis,andasetofmodelcompoundswithexcellentpurityisprepared(J.Comb.Chem.2008,10,714e720).HIGH-THRO
14、UGHPUTANALYTICSAmbientMolecularImagingandDepthProfilingofLiveTissuebyLaserAblationElectrosprayIonizationMassSpectrometryInconjunctionwithmassspectrometry,thedemandforatmosphericpressureionizationmethodsthatachieveefficientiongenerationundernative-likeexperimentalconditionsarises.A.Vertesandcoworkers
15、fromW.M.KeckInstituteforProteomicsTechnologyandApplications(GeorgeWashingtonUniversity,Washington,DC)presentthelateralmappingofmetabolitedistributionsandtheirvariationswithdepthonplantleaveswithlaserablationelectrosprayionizationmassspectrometry(LAESI-MS)(Anal.Chem.2008,80,4575e4582).Incontrasttoele
16、ctrospray-assistedlaserdesorption/ioni-zation,whichalsoreliesonthepostionizationofneutralsinalaserplumbyESI,thelaserenergyusedforLAESIcausesaresonantprocessinwater-richtargets.WiththeESIsourceinaxialsprayingmode,thelaserlight(2940nm)hitsthetarget18mmbelowand5e8mmdownstreamfromthetipoftheemitterandre
17、sultsinalaserablationareaof350lmindiameterandadepthof50lm.DetailsoftheproducedablationcratersareinvestigatedbyscanningelectronmicroscopyandcorrelatedwiththerecordedMSdata.Asanexample,thedistributionofmetabolitesinthegreenandyellowsectorsofaZebraplantleafisanalyzed.Atthis,over40metabolitesaredetected
18、and36couldbeassigned.Theresultsareingoodconformancewithothertechniques.Summarized,theirresultsdemonstratethatLAESI-MSopensanewwayforambientmolecularthreedimensionalimagingofmetabolitesinbiologicaltissuesandliveorganisms.OnlineCouplingofGasChromatographytoNuclearMagneticResonanceSpectroscopy:Methodfo
19、rtheAnalysisofVolatileStereoisomersAlthoughHPLC-NMRhasevolvedintoaversatiletoolintheanalysisofcomplexsamples,thecouplingofGCandNMRisstillinanearlystageofdevelopment,despitethefactthatfirstexperimentswereconductedinthe1970s.Intheirarticle,K.Albertandcolleagues(InstituteofOrganicChemistry,ChemischesZe
20、ntralinstitut,UniversityofTubingen)describeanewsystemofcoupledGCeNMRfortheanalysisofvolatilecis/transstereoisomersofalkenesforcontinuous-andstopped-flowgas-phaseexperiments(Anal.Chem.2007,80,5481e5486)InadditiontoashortreviewaboutearlierGCeNMRdevelopments,theauthorsdescribetheirnewtechnicalassemblyi
21、ndetail.Incontrasttoformerexperiments,thelargerinnerdiameterofthetransfercapillariesaswellasoftheinletofthedetectioncelldramaticallyreducesthenecessaryinjectionamount,hithertoamajordrawback.Furthermore,therecentNMRspectrometerwithhigherfieldstrengthfacilitatesveryshortdwelltimesandcruciallyenhancest
22、hesignal-to-noiseratio.Withthechosenassembly,itispossibletoseparatethecisandtransisomersof2-penteneand2-hexeneinthegasphaseandperformcontinuous-flowNMRdetectiontoobtainadefinite2Dcontourplot.Itisalsoshownthatwhenstopped-flowexperimentsusereferencespectrafromanavailablespectradatabase,distinctionbetw
23、eentwocis/transstereoisomerscanbeachieved.ThepresentedresultsdemonstratethehighpotentialofthecouplingofcapillaryGCandmicroprobe1H-NMRdetection,butsometechnicalchallengesstillmustbeovercome.BIOAUTOMATIONANDSCREENINGNewConnectionsacrossPathwaysandCellularProcesses:IndustrializedMutantScreeningRevealsN
24、ovelAssociationsbetweenDiversePhenotypesinArabidopsisItiswidelyknownthathigh-throughputapproachesarenotlimitedtothefieldsofdrugdiscoveryandwhitebiotechnology.Thesetechniquesenterintomanyotherareas,amongthem,differentpartsofplantbiology.High-throughputanalysesledtothesequencingofthefirstgenomeofahigh
25、ereukaryoticorganism,themouse-earcressArabidopsisthaliana,andwerealsoessentialforsettinguplargerepositoriesofclones,microarraydataandmutantsfromdifferentmodelandcropplants.Today,thesepartiallypubliclyavailableresourcesareindispensableforprogressinanyfieldofplantresearch,butthefutureofhigh-throughput
26、approachesisnotlimitedtoparticularfields.Theseplantbiologytechniquescanbehelpfulinanyareaofresearch.Luetal.presentaninterestingexampleforthisdevelopment.Theauthorsanalyze13differentArabidopsismutantsbiochemicallyandphenotypically.ThebiochemicalanalysesareperformedwithdifferentLC,GC,andMSmethodstodet
27、erminethecontentsoffreeaminoacids,fattyacids,starch,andchlorophyllindifferentorgans.Oneresultofthedataisthatseveralnewphenotypesarediscoveredinparticularmutants.Inafurtherapproach,statisticalandbioinfor-maticcalculationsareperformedwiththedatasets,whichrevealnovelconnectionsandassociationsbetweendif
28、ferentmetabolicandcatabolicpathways.InoneconclusionbyLuetal.,parallelanalysesofplantgermplasm,likemutantsorecotypes,harborsanenormouspotentialforplantbiology,especiallyforplantbreeding.Theexploitationofthispotentialdependsontheapplicationofhigh-throughputmethods,especiallyofautomatedones.Currently,s
29、uchmethodsneedtobeimprovedorinventedinthefieldofplantresearchtoaddressfutureneedsforcropplants(PlantPhysiol.2008,146,1482e1500).Live-CellHigh-ContentScreeninginDrugDevelopmentCell-basedassaysarestateoftheartindrugdiscoveryanddevelopment.Theyprovidetoxicologicaldataduringanearlyphaseofdrugdiscoveryan
30、dcanthushelptoreducecosts.Thepowerofhigh-contentscreeningtechnologyusinglivingcellsissummarizedbyM.Bickle(Eur.Pharm.Rev.2008,4,54e60).Live-cellimagingmeansafurtherlevelofcomplexitytohigh-contentscreening(HCS),andrelatestonewtechnologicalchallenges.Examplesoflive-cellHCSapplications,suchastoxicityass
31、aysinHepG2cells,themonitoringofsubcellularlocalizationchanges,orthedeterminationofpharmacokineticdataarepresented.Theyshow,thatlive-cellHCSwillbecomemoreandmorepopularindrugdevelopmentinfuture.Oneaspectofthearticleaddressesthechallengesandrequirementsforsoftwaresolutions,forexample,kineticHCSoffertr
32、ackingofobjectscapabilities.Thereareveryfewcommerciallyavailablesoftwareproducts,andoneisdescribedbriefly(Eur.Pharm.Rev.2008,4,54e60).Chemogenomics:ADisciplineattheCrossroadofHigh-ThroughputTechnologies,BiomarkerResearch,CombinatorialChemistry,Genomics,Cheminformatics,Bioinformatics,andArtificialInt
33、elligenceE.Marechalgivesanoverviewonchemogenomicsandrelatedtechnologies.Chemogenomicsisthestudyoftheinteractionoffunctionalbiologicalsystemswithexogenoussmallmolecules,orinabroadersense,thestudyoftheintersectionofbiologicalandchemicalspaces.Chemogenomicsrequiresexpertisesinbiology,chemistry,andcompu
34、tationalsciences.Chemogenomicsisadescendentofconventionalpharmaceuticalapproaches,becauseitinvolvesthescreeningofchemicallibrariesfortheireffectsonbiologicaltargets,andbenefitsfromtheadvancesinthecorrespondingenablingtechnologiesandtheintroductionofnewbiologicalmarkers(Comb.Chem.HighThroughputScreen
35、.2008,11,583e586).Cell-BasedAssaysinPractice:CellMarkersfromAutofluorescentProteinsoftheGFPFamilyTherecentlydiscoveredanthozoanfluorescentproteins(FPs)andtheclassicAequoreavictoriaGreenFluorescentProtein(avGFP)aswellastheirderivativeshavebecomeversatiletoolsaslive-cellmarkersinfluorescencemicroscopy
36、.R.Heilkeretal.reviewtheuseoftheseFPsindrugdiscoveryassays.AssayexamplesaregivenfortheapplicationofFPsinmultiplexedimaging,asphotosensitizers,asfluorescenttimers,aspulse-chaselabels,andforroboticallyintegratedcompoundtesting.Thedevelopmentoffastmicroscopicimagingdevicesenablestheapplicationofautomat
37、edfluorescencemicroscopycombinedwithimageanalysistopharmaceuticalhigh-throughputdrugdiscoveryassays,generallyreferredtoashigh-contentscreening(Comb.Chem.HighThroughputScreen.2008,11,602e609).DesignofPhenotypicScreensforBioactiveChemicalsandIdentificationoftheirTargetsbyGeneticandProteomicApproachesC
38、ell-basedscreeningusingphenotypicassaysisausefulmeansofidentifyingbioactivechemicalsforuseastoolstoelucidatecomplexcellularprocesses.M.Robergeetal.describehowcell-basedscreeningassayscanbedesignedtomaximizethelikelihoodofdiscoveringselectivecompoundsthroughthechoiceofpositivereadouts,lowchemicalconc
39、entrations,andlongincubationperiods.Identifyingthecellulartargetsofactivechemicalscanbeespeciallydemanding.Strategiesforunbiasedtargetidentificationbysamplingpotentialtargetsatthegenome-wideandproteome-widelevelsalsoarediscussed(Comb.Chem.HighThroughputScreen.2008,11,610e616).ChemogenomicsandCancerC
40、hemotherapy:CellBasedAssaystoScreenforSmallMoleculesthatImpairMicrotubuleDynamicsMicrotubulesarestillapromisingtargetfornewtherapeuticagents.Thus,thereisongoinginterestincompoundsthatareabletomodifymicrotubuleassembly.Becauseofitsdynamiccharacteristics,themicrotubulecytoskeletonisasuitabletargetfors
41、mallmoleculesthatrapidlydiffuseinthecellcytoplasm.Moreover,compoundstargetingthemicrotubulecytoskeletonprovetobevaluabletoolsforbasicresearchincellbiology.L.Lafanecherereviewsthepotentialandimpactofchemogenomicsandcell-basedassaysinthediscoveryofnewtherapeuticcompoundsandofnewregulatorsofthemicrotub
42、ulecytoskeleton(Comb.Chem.HighThroughputScreen.2008,11,617e623).ChemogenomicsandParasitology:SmallMoleculesandCell-BasedAssaystoStudyInfectiousProcessesInfectiousdiseasescausedbyprotozoanparasitesremainchronicproblemsforhumanity.Currentadvancesinhigh-throughputscreening(HTS)technologiesandavailabili
43、tyofdiversesmallmoleculelibrariesofferthepromiseofaccelerateddiscoveryofnewdrugtargetsandnewdrugsthatwillreducediseaseburdensimposedonhumanitybyparasiticprotozoa.M.-J.GvideastatusreportonHTStechnologiesinhandandcell-basedassaysunderdevelopmentforbiologicalinvestigationsanddrugdiscoverydirectedtoward
44、thethreebestcharacterizedparasiticprotozoa:Trypanosomabrucei,Plasmodiumfalciparum,andToxoplasmagondii.Smallmoleculesthatinterferewithspecificaspectsofprotozoanbiology,identifiedinsuchscreens,willbevaluabletoolsfordissectingparasitecellbiologyanddevelopingantiprotozoandrugs(Comb.Chem.HighThroughputSc
45、reen.2008,11,624e646).PlantPathogenRecognitionasaNatural,Original,andSimpleModelforChemogenomics:ABriefOverviewofCell-BasedAssaystoScreenforPeptidesActingasPlantDefenseActivatorsAsplantslackacirculatorysystemandadaptiveimmunesystem,theyhaveevolvedtheirowndefensesystemsdistinctfromanimalsinwhicheachp
46、lantcelliscapableofdefendingitselffrompathogens.Plantsinduceanumberofdefenseresponses,whicharetriggeredbyavarietyofmoleculesderivedfrompathogenicmicroorganisms,referredtoasmicrobe-associatedmolecularpatterns(MAMPs).MAMPsincludepeptides,proteins,lipopolysaccharide,b-glucan,chitin,andergosterol.Theint
47、eractionbetweenplantsandchemicalsinthecontextofplantdefenserepresentsanaturalandsimplemodelforchemogenomicsattheintersectionofchemicalandbiologicaldiversities.Toprotectcropplantsfromdiseases,ithasbeenshowntoeffectivelystimulateplantimmunitybychemicalcompounds,theso-calledplantdefenseactivators.Combi
48、natorialchemistrytechniquescanbeappliedtothesearchfornovelplantdefenseactivators,butitisessentialtoestablishanefficientandreliablescreeningsystemforlibraryscreening.M.Miyashitaetal.describethecell-basedlawnformatassayforidentificationofpeptidesactingasplantdefenseactivatorsfromcombinatorialpeptideli
49、braries.Therequirementsandlimitationsinconstructingthescreeningsystemusingcombinatoriallibrariesinthestudiesofplantsciencesarealsodiscussed(Comb.Chem.HighThroughputScreen.2008,11,647e652).BuildingaBiologicalSpaceBasedonProteinSequenceSimilaritiesandBiologicalOntologiesAssignmentoffunctiontoproteinse
50、quenceisataskofgrowingimportanceinthelifesciencesasnewhigh-throughputsequencingDNAtechnologiesgenerateever-increasingquantitiesofgenomicdata.Clusteringsimilarsequencesisausefultechniqueforfindingconservedsequences.TheCluSTrdatabaseisapubliclyavailabledatabasethatarrangesproteinsinahierarchystructure
51、dbysimilarity.TheproteinclassificationtoolInterProScanbuildsonthisapproachbyapplyingarangeofmethodstodetectproteinsthatcontainsignaturesindicativeofthepresenceofparticularconserveddomains.P.Kerseyetal.reviewtheuseofontologiestodescribeaproteinfunctionthatprovidesaflexibleandabstractlanguagetoclassif
52、yproteins(Comb.Chem.HighThroughputScreen.2008,11,653e660).BuildingaChemicalSpaceBasedonFragmentDescriptorsI.BaskinandA.Varnekreviewtheapplicationoffragmentdescriptorsatdifferentstagesofvirtualscreeningdfil-tering,similaritysearch,anddirectactivityassessmentdusingQSAR/QSPRmodels.Theydemonstratethatth
53、epoweroffragmentdescriptorsstemsfromtheiruniversality,veryhighcomputationalefficiency,simplicityofinterpretation,andversatility(Comb.Chem.HighThroughputScreen.2008,11,661e668).ALigand-BasedApproachtoMiningtheChemogenomicSpaceofDrugsThepracticalimplementationandvalidationofaligandbasedapproachtominin
54、gthechemogenomicspaceofdrugsispresentedbyJ.Mestresetal.andappliedtotheinsilicotargetprofilingof767drugsagainst684targetsoftherapeuticrelevance.Theresultsrevealthatdrugstargetingaminer-gicGprotein-coupledreceptors(GPCRs)showthemostpromiscuouspharmacologicalprofiles.Thedetectionofcross-pharmacologiesb
55、etweenaminergicGPCRsandtheopioid,sigma,NMDA,and5-HT3receptorsaggravatethepotentialpromiscuityofthosedrugs,whichpredominantlyincludeanalgesics,antidepressants,andantipsychotics(Comb.Chem.HighThroughputScreen.2008,11,669e676).MachineLearningforInSilicoVirtualScreeningandChemicalGenomics:NewStrategiesS
56、upportvectormachinesandkernelmethodsbelongtothesameclassofmachinelearningalgorithmsthathasrecentlybecomeprominentinbothcomputationalbiologyandchemistry,althoughbothfieldshavelargelyignoredeachother.Thesemethodsarebasedonasoundmathematicalandcomputationallyefficientframeworkthatimplicitlyembedsthedat
57、aofinterest,respectively,proteinsandsmallmolecules,inhigh-dimensionalfeaturespaceswherevariousclassificationorregressiontaskscanbeperformedwithlinearalgorithms.J.-P.VertandL.Jacobpresentthemainideasunderlyingtheseapproaches,surveyhowboththebiologicalandthechemicalspaceshavebeenseparatelyconstructedu
58、singthesamemathematicalframeworkandtricks,andsuggestdifferentavenuestounifybothspacesforthepurposeofinsilicochemogenomics(Comb.Chem.HighThroughputScreen.2008,11,677e685).LIMSANDPROCESSCONTROLSYSTEMSInformationAutomationinR&DLaboratories:PastandFutureCh.Sodano,authorandfounderofeOrganizedWorld,consid
59、ersITtrendsofe-recordsinanarticlethattracesthehistoryofLaboratoryInformationManagementSystems(LIMS)andElectronicLaboratoryJournals(ELNs).ThewaythefirstcommercialLIMSappearedinthe1980stothefuturearediscussedintermsofgeneralrequirements,interfacing,theneedofstandardization,andITinfrastructureforcollab
60、orationnetworks.Theoverviewshelptointerpretnewdevelopments.Theretentiontimeforexperimentscapturedinpaper-basedlaboratorynotebookorbymicrofilmiscomparedwithelectronicrecords(lifetimeofstoragemedia,etc).Oneoftheproblemsidentifiedistheavailabilityofsystemsoftwaretointerpretanalyticaldataafteralotofyear
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