优秀学术报告PPT示例(Ari-Koskinen)

ChemistryinBiomedicine,andDrugDiscovery,ProfessorAriKoskinenHelsinkiUniversityofTechnology,11.03.2005,AriKoskinenLaboratoryofOrganicChemistry,Numberapprovedby,FDA,0,24,0,21,7,18,6,16,2,15,5,13,7,12,5,11,8,9,4,8,2,7,6,6,5,5,8,4,$/No.,NewChemicalEntitiesvs.ROttenheijm,H.C.J.;Rees,D.Tetrahedron1996,52,4527-4554.,Frchtel,J.S.;Jung,G.Angew.Chem.,Int.Ed.Engl.1996,35,17-42.,Lowe,G.Chem.Soc.Rev.1995,24,309.Ellman,J.Chemtracts:OrganicChemistry1995,8,1-4.Pirrung,M.C.Chemtracts:OrganicChemistry1995,8,5-12.Czarnik,A.W.Chemtracts:OrganicChemistry1995,8,13-18.Mitscher,L.A.Chemtracts:OrganicChemistry1995,8,19-25.Dolle,R.E.;Nelson,K.H.J.Combinator.Chem.1999,1,235-282.,AriKoskinenLaboratoryofOrganicChemistry,1987,1989,1991,1993,1995,1997,1985,CombinatorialChemistryPublicationsCombinatorialChemistry140012001000,#,800600400200,PatentsPublications,0YearAriKoskinenLaboratoryofOrganicChemistry,SolidPhaseOrganicSynthesisPh,Ph,OPhOO,O,O,O,O,1.MeMgI2.H2O3.KOH4.H+,Ph,MeOH,CO2H,AtrolacticacidKawana,M.;Emoto,S.TetrahedronLett.1972,4855-4858.,O,O,Scrambledproductmustarisethroughintraresinreactions.Intraresinreactionsoccurevenatresinloadingsof0.5%(0.05,CH2OC(CH2)5COCEt3*,mmol/gresin!),O,O,O,O,O,*,*,Et3C,O,*,Resinboundester,Autocleavedester,Crowley,J.I.;Rapoport,H.Accts.Chem.Res.1976,9,135-144.AriKoskinenLaboratoryofOrganicChemistry,CombinatorialLibrary:SplitSynthesisMethod,Portioning-mixingFurka,A.etal.Int.J.Pept.ProteinRes.1991,37,487-493.Furka,A.etal.Bioorg.Med.Chem.Lett.1993,3,413-418.SplitSynthesisHruby,V.J.etal.Nature,1991,354,82-84.Divide,CoupleandRecombineHoughten,R.A.etalNature1991,354,84-86.AriKoskinenLaboratoryofOrganicChemistry,a,A,b,B,c,A,B,ConstructionofanEncodedSyntheticLibrary,Tagsa,b,andcareattachedtothesame,beadsasthegrowingoligomerchain.Theoverallstructureofthehitoligomercanthenbereadfromthetaginformation.Dower,W.J.etal.PCTAppl.WO93/06121.Needels,M.N.etal.PNAS1993,90,10700.,CTagsshouldhavehighinformationcontent,beamenbletohighsensitivitydetectionanddecoding,andmustbechemicallyorthogonaltotheoligomerprotocol.CSingle-strandedoligonucleotides,coupledwithPCRamplification:8.2x105syntheticpeptides.,a,b,c,also:Lerner,R.;etalPCTAppl.WO93/20242.,Nielsen,J.etal.JACS1993,115,9812-9813.POOL,a,A,b,B,c,C,AA,AB,AC,BA,BB,BC,CA,CB,CC,a,a,a,b,a,c,b,a,b,b,b,c,c,a,c,b,c,c,AriKoskinenLaboratoryofOrganicChemistry,SpatiallyAddressableParallelSynthesis,h,Mask1,X,X,X,X,X,X,X,X,A,A,X,X,NH,NH,NH,NH,Deprotect,NH2,NH2,NH,NH,X-A,NH,NH,NH,NH,CouplehMask2,X,X,E,E,F,F,A,A,X,X,X,X,X,X,C,C,D,D,NH,NH,NH,NH,X-B,A,A,B,B,Repeat,A,A,B,B,CoupleFodor,S.P.A.;Read,J.L.;Pirrung,M.C.;Stryer,L.;Yu,A.T.;Solas,D.Science1991,251,767.Jacobs,J.W.;Fodor,S.P.A.TrendsBiotechnol.1994,12,19-26.AriKoskinenLaboratoryofOrganicChemistry,SpatiallyAddressableChemicalLibraries,Fodor,S.P.A.;Read,J.L.;Pirrung,M.C.;Stryer,L.;Yu,A.T.;Solas,D.Science1991,251,767.,Jacobs,J.W.;Fodor,S.P.A.TrendsBiotechnol.1994,12,19-26.Pirrung,M.C.;Read,J.L.;Fodor,S.P.A.;Stryer,L.U.S.Pat5,143,854,1992.Holmes,C.P.;Fodor,S.P.A.InInnovationandPerspectivesinSolidPhaseSynthesisandComplementary,Technologies;Epton,R.,Ed.,Intercept,UK,1994.,AriKoskinenLaboratoryofOrganicChemistry,HydroxylamineResinOHON,Ph,O,Ph,O,Ph,Cl,NEt3/DMF,Ph,ON,Omax1792and1743cm-1,N2H4/THF,PhONH2PhTetrahedronLett.1997,38,7233-7236AriKoskinenLaboratoryofOrganicChemistry,SuccinylAmideLibraryOO,PhPh,ONH2,OTHF,PhPh,ONH,O,O,OH,RNH2,DCC/HOBtDMF,rt,HONH,O,O,NHR,HCO2H/THF,PhPh,ONH,O,O,NHR,Ph,Ph,O,OMe,O,OMe,TetrahedronLett.1997,38,7233-7236AriKoskinenLaboratoryofOrganicChemistry,PeptidicandPeptidomimeticLibraries,O,R1,PhPh,ONH2,OO10a,b,c,HONH,O,R1,O,HN,R2,+,HONH,O,R1,O,HN,R2,4,11,Compound10,11,12,12,entryR1=,aMePh,bPh,cBn,d,Ph,R2=,O,OMe,O,OMe,Ph,Ph,Reagentsandconditions:a)60C,6h,THF;b)(S)-phenylethylamineoraminoacideaterhydrochloride/triethylamine,HOBt,DCC(5-foldexcess),DMF,6h;c)HCO2H/THF(1:3),1hScheme3TetrahedronLett.1997,38,7233-7236AriKoskinenLaboratoryofOrganicChemistry,CrudeNMR80,70,HO,NH,O,O,HN,O,OMe,605040O30NOHO20100,10,9,8,7,6,5,4,3,2,1,(ppm)TetrahedronLett.1997,38,7233-7236AriKoskinenLaboratoryofOrganicChemistry,Analysis,Monitorconversiononbead(e.g.Kaisertestforfreeprimaryamines),Analysisofreactionproductsonbead,Analysisofcombinatorialmixturesofproducts,AriKoskinenLaboratoryofOrganicChemistry,IRonBead,1971:resinbeadsofchloromethylpolystyreneoxidationproductsinKBrdisks(FrechetJ.M.J.Am.Chem.Soc.1971,93,492-496.),FT-IRmicrospectroscopy:singlebeadfromrxntoIRmicroscopy(Yan,R.J.Org.Chem.1995,60,5736-5738.,Downto100pmolesofmaterial,AriKoskinenLaboratoryofOrganicChemistry,IRonBeadFT-IRcanmonitorprogressofreactions:,O,O,O,OH,O,COCl4,O,4,N,DiffusereflectanceinfraredFouriertransformspectroscopy(DRIFTS):fast,nosamplepreparation(Chan,T.Y.TetrahedronLett.1997,38,2821-2824).AriKoskinenLaboratoryofOrganicChemistry,13C:,NMR,lowabundance,usuallylargesample,quantities,longpulsing19F,31Pusedalso,MAS:nanoprobesallowfor10mgresin(Sarkar,S.K.J.Am.Chem.Soc.1996,118,2305-2306.),AriKoskinenLaboratoryofOrganicChemistry,Massspectrometry,MALDI-TOFMS:femtomolesamples(Zambias,1994,TOF-SIMS(Brummel,C.L.Science1994,264,399-402),CE-ESIMS(Dunayevskiy,Y.M.Proc.Natl.Acad.Sci.1996,93,6152-6157),AriKoskinenLaboratoryofOrganicChemistry,Isitfeasibletomakeallpossibleinterestingmoleculescombinatorially?OnlyC,H,N,OAvgmolwtofpermeabledrugmoleculeca500;max750Avogadrosnumber6.1023Onlyonemoleculeeach10200moleculestotalmass:10173tonnesweightofEarth:6.1021tonnes!,WeightoftheUniverse:ca1084,500,Mr,tonnes!AriKoskinenLaboratoryofOrganicChemistry,ChallengesinCombinatorialChemistry,DevelopmentofdiversityasaconceptDevelopmentofsolidphasesynthesis,Developmentoffast,chemoselective,highyieldsolutionsynthesismethods,Developmentofhighspeedanalysis,Developmentofefficientscreeningstrategiesforminuteamountsofcompoundsinmixtures,AriKoskinenLaboratoryofOrganicChemistry,AriKoskinenLaboratoryofOrganicChemistry,AriKoskinenLaboratoryofOrganicChemistry,MoreSources,Reviews:,Dolle,R.E.;Kingsley,N.K.J.Combin.Chem.1999,1,235-282.Terrett,N.K.CombinatorialChemistryOUP1998,186pp.Thompson,AriKoskinenLaboratoryofOrganicChemistry,TargetOriented,MedicinalBurke,M.D.Angew.Chem.Int.Ed.2004,43,4658,AriKoskinenLaboratoryofOrganicChemistry,GeneratingSkeletalDiversity,SchreiberS.L.;Burke,M.D.Angew.Chem.Int.Ed.2004,43,4658,AriKoskinenLaboratoryofOrganicChemistry,SmallMoleculeDiscovery,SchreiberS.L.;Burke,M.D.Angew.Chem.Int.Ed.2004,43,4658,AriKoskinenLaboratoryofOrganicChemistry,AriKoskinenLaboratoryofOrganicChemistry,ComplexityofSyntheticTargets,Thisiswhereitstarted!,O,Erythromycinis.,HOHO,O,OHO,NMe2OH,O,O,sohopelesslydifficultthatitsconquestcannotbeconceivedwithintheforeseeablefuture(Woodward,1956),OOOMeOAcErythromycinAAriKoskinenLaboratoryofOrganicChemistry,TrendsinSyntheticMethodology,PERIOD,TREND,OBJECTIVE/OUTPUT,1950-1960,ClassicalsynthesisTargetconquest,Hardware,ofnaturalproductsMechanisms,Spectroscopy,1970-1980R.B.WoodwardNobel1965forhisoutstandingachievementsintheartoforganicsynthesis,Multistep,strategyandtransformationbasedsynthesis,Stereo/enantiocontrolSoftwareSyntheticmethods,1990-,DesignedmoleculesSelectivity,RecognitionFunction,IntelligenceContentE.J.CoreyNobel1990forhisdevelopmentofthetheoryandmethodologyoforganicsynthesisAriKoskinenLaboratoryofOrganicChemistry,AriKoskinen,Bindingmodel,J.Biol.Chem.1997,272,23312-23316LaboratoryofOrganicChemistry,OverlayofmodelChen.J.TetrahedronLett.1991,32,6977-6980.Pihko,P.M.;Koskinen,A.M.P.Synlett1999,1966-1968.,Pihko,P.M.;Koskinen,A.M.P.J.Org.Chem.1998,63,92-98.,SpiroketalModelStudies,SpiroketalModelStudies,Rauhala,V.;Nevalainen,M.;Koskinen,A.M.P.Tetrahedron2004,60,9199.,Me3Al,THF/CH2Cl,SpiroketalModelStudies,O95%,O,ONBni)Et3N,Bu2BOTfii)3-Benzyloxy-propionaldehyde,TBSO,OBn,+,ONOMe,OTBS,i)HNMe(OMe).HCl,1)BuLi,alkyne2)Weinrebamide297%TBSOOBnO79%ii)TBSOTf,ImH,CH2Cl2,O,ONOBnBn,OH,O,OBnOTBS,OBn,68%,OBn,OBn,1)CSA,MeOH2)PhH,p-TsOH3)TEA,BnO,O,O,BnO,O,O,O,O,90%(1:1)Aiguade,J.;Hao,J.;Forsyth,C.J.Org.Lett.2001,3,979-982Rauhala,V.;Nevalainen,M.;Koskinen,A.M.P.Tetrahedron2004,60,9199.,C9-C19Fragment,Karisalmi,K.;Koskinen,A.M.P.Synthesis2004,1331-1341.,C9-C19Fragment,Karisalmi,K.;Koskinen,A.M.P.Synthesis2004,1331-1341.,BoronaldolTSs,Bernardi,A.,Gennari,C.,Goodman,J.M.andPatersonI.Tetrahedron:Asymmetry1995,6,2613.,C9-C19FragmentC41O31C4,C3,C2,C1,O10,C5,O6,C11,C16,C8,C9,C7,C21,C12,C13,C14,C15,C9-C19Fragment,crotylsilylation:Chemler,S.R.;Roush,W.R.J.Org.Chem.2003,68,1319.,Karisalmi,K.;Koskinen,A.M.P.TetrahedronLett.2004,45,8245.,ConclusionsonI.A.I.,5-ringinductionusuallymorepredictablethan6-ring,Naturalproductsremainarichsourceforchallenges,Internalasymmetricinductionoftenpreferabletoe.g.chiralcatalysis,AriKoskinenLaboratoryofOrganicChemistry,R.L.StrausbergandS.L.SchreiberScience,2003,300,294.,AriKoskinen,LaboratoryofOrganicChemistry,-Turns,SECONDARYSTRUCTURALMOTIFSOFGLOBULARPROTEINS,Features:,4residueturns,ii+3,C=OitoN-Hi+3,AriKoskinenLaboratoryofOrganicChemistry,-Turnmimics,OURGOAL,Synthesisofsmallpeptidespossessingahighpopulationof-turnstructureinsolution,HN,Pro-GlyMOTIFStrongturninducerinpeptidesandproteins,R,NN,OOHNOH,OR,R,R,Xaa-Pro-Gly-Xaadrawnin-turnconformationAriKoskinenLaboratoryofOrganicChemistry,N,H,-TurnmimicsOURGOALLockedconformationoftheprolinering,COOHConformationallyconstrainedpeptidemimic,SidechaincontrolStructuralstudyinsolution(NMR)ElucidationofrequirementsforrecongnitionandbindingNewclassofDNA-cleavingagentsAriKoskinenLaboratoryofOrganicChemistry,-TurnmimicsON,Pt/C,Boc,80%,O,N1,CHOBoc,COOMePh3P2CH2Cl2,O,N3,COOMeBocE/Z96:472%,DIBALTol,-50oC,O,N4,Boc,88%,OH,H2H2,RaneyNiMeOH,5a,O,N,Boc,5b,OH,PPh3,CX4,O,N,Boc,X6aX=Cl,AcOH80%,HO,XNHBoc7aX=Cl48%(from5b),1)PhCOCl,Py2)Recryst.Hex/Et2O,trans/cis86:1495%,6bX=Br90%1)1NHCl,7bX=Br91%Jones,BzO,X,KHMDS,100oC,O,NHBoc8aX=Cl8bX=Br,THF,0oC71%,NBoc9,OBz,2)dioxane,10%Na2CO3,Fmoc-Cl,NFmoc10,acetoneOH59%96%,NFmoc,COOH11,Nevalainen,M.J.Org.Chem.2001,66,2061-2066.,AriKoskinen,LaboratoryofOrganicChemistry,ProlinesinTurns,Arg-Val-Asp-Val3,AlaLeuGlyAlaAlaProGlyAlacAlaMPGlyAlatAlaMPGlyAlaMP=N,Val-Asp-Val-Arg3,OKrische,M.J.AriKoskinenLaboratoryofOrganicChemistry,SynthesisofTetrapeptides,Ala,X,Gly,Ala,Cbz,OH,H2N,OtBu,Cbz,OH,H2N,OMe,CbzCbz,OtBuOH,CbzH2N,OMeOMe,X=Leu,Pro,4-MePro,CbzCbz,OMeNHMe,Krische,M.J.AriKoskinenLaboratoryofOrganicChemistry,-,-,-,-,ProlineConformationsFigure4d,x4,H,O,CH,N,x1,C,Cx2,x3CHH,O,CH,N,CC,CH,RamachandranA,RamachandranB,x1:0-30x2:+15-+50x3:-15-30x4:+5-+25,x1:x2:x3:x4:,+20-30+20-5,+35-40+35-20,Krische,M.J.;OConnell,J.AriKoskinenLaboratoryofOrganicChemistry,NMRof4-AlkylProlineTetrapeptides,Figure4b:Trans4-MethylProlinePeptide-ProlineSpinSystemAnalysisDMSO,Figure4c:Cis4-MethylProlinePeptide-ProlineSpinSystemAnalysisDMSO,O,(1.95)1,6.3(4.2),(2.41),6.99.5,(3.71)1,O,(7.23)1,Me,(3.01)1,(8.2),3.1,-12.5,9.5,6.6,(3.6),-10.3,(4.1),6.6,3.1,9.9,-9.9,(4.53),8.7,2(1.62),Me(0.97),2(3.14),(4.23),9.3,2(2.23),7.0,2(3.95),x1:x2:x3:,JC=8.7Jt=5.1JC=6.3Jt=-5.3JC=6.9Jt=5.9,x=21x=+13x=37x=-13x=34x=+14,MarkedlyNon-PlanarStronglyPrefersBForm(i.e.Equatorial4-