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1、©2004YZJ-SIOC第八部分复杂分子的多样性问题---CombinatorialChemistry&NaturalProduct-LikeChemistry1©2004YZJ-SIOCCombinatorialChemistry:Reviews1.APracticalGuidetoCombinatorialChemistry；Czarnik,A.W.andDeWitt,S.H.,Eds.;ACS:WashingtonDC,1997.2.MolecularDiversityandCombinatorialChemistry:Libr
2、aryandDrugDiscovery;Chaiken,I.N.,Janda,K.D.,Eds.;ACS:WashingtonDC,1996.3.Balkenhol,F.,etal.CombinatorialSynthesisofSmallMolecules.Angew.Chem.Int.Ed.Engl.1996,35,2288.4.Ellman,J.A.,etal.SynthesisofSmallMoleculeLibraries.Chem.Rev.1996,96,555.5.Gallop,M.A.,etal.Applications
3、ofCombinatorialTechnologiestoDrugDiscovery,1.BackgroundandPeptideCombinatorialLibraries.J.Med.Chem.1994,37,1233.6.Gordon,E.M.,etal.ApplicationsofCombinatorialTechnologiestoDrugDiscovery,2.CombinatorialOrganicSynthesis,LibraryScreeningStrategies,andFutureDirections.J.Med.
4、Chem.1994,37,1385.2©2004YZJ-SIOCSolidPhasePeptideSynthesis(SPPS)ClR1VAttach1stAminoAcidtoONHCbz(Chloromethylated)OR1OPolymerbeadONHCbzNHVDeprotect(HBr),CoupleOR2R1OR3O(DCC),Cap(aceticHONNHCbzanhydride)NNHHOR2OR4VRepeatcouplingcycleR1OR3OHHONNH2VDeprotect,Saponify,PurifyN
5、NHHOR2OR4•Allowexcessofreagentsandreactantstoforcereactiontocompletion.•Removalofreagents,reactantsandbyproductsbyfiltration.Merrifield,R.B.JACS1963,85,2149.(NobelPrize,1984)3©2004YZJ-SIOCTea-BagMethod•10to20mgof248different13-Sealresiduepeptides.•Sequence1.DeprotectMesh
6、Opening2.Wash3.CoupleResin4.WashXXXCode5.HFCleaveHoughten,R.A.etal.Proc.Natl.Acad.Sci.USA1985,82,5131.4©2004YZJ-SIOCMultipinPeptideSynthesisPin•Synthesizeonpolyacrylate-graftedpolyethylenerods.•UtilizeconventionalReagentssolidphasesynthesisreactantsGrowinginwellsmethods.
7、PeptideonaPin•Preparationofupto10,000spatiallyseparatedcompoundsIndividualpinsusinginexpensivewithcrowns(1to7umolequipmentandloadingcapacity)96-WellPlatereadilyavailableGeysen,etal.PNAS1984,81,3998.automation.Zuckerman,etal.BMCL1993,3,463.5©2004YZJ-SIOCSplitandMixSolidPh
8、aseSynthesis•SolidsupportisdividedbeforeA1A3eachcouplingcycleA2•EquimolarmixtureofpeptidesA1A2A3-Mix•Ca
