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1、第八部分第八部分复杂分子的多样性问题复杂分子的多样性问题------CombinatorialChemistry&CombinatorialChemistry&NaturalProductNaturalProduct--LikeChemistryLikeChemistryCombinatorialChemistry:Reviews1.APracticalGuidetoCombinatorialChemistry；Czarnik,A.W.andDeWitt,S.H.,Eds.;ACS:WashingtonDC,1997.2.Molecul
2、arDiversityandCombinatorialChemistry:LibraryandDrugDiscovery;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.19
3、96,96,555.5.Gallop,M.A.,etal.ApplicationsofCombinatorialTechnologiestoDrugDiscovery,1.BackgroundandPeptideCombinatorialLibraries.J.Med.Chem.1994,37,1233.6.Gordon,E.M.,etal.ApplicationsofCombinatorialTechnologiestoDrugDiscovery,2.CombinatorialOrganicSynthesis,LibraryScree
4、ningStrategies,andFutureDirections.J.Med.Chem.1994,37,1385.SolidPhasePeptideSynthesis(SPPS)ClR1O•Attach1stAminoAcidtoNHCbz(Chloromethylated)PolymerOR1ObeadONHCbzN•Deprotect(HBr),CoupleHOR2(DCC),Cap(aceticanhydride)R1OR3OHONNHCbzNNHH•RepeatcouplingcycleOR2OR4R1OR3OHHONNH2
5、NN•Deprotect,Saponify,PurifyHHOR2OR4•Allowexcessofreagentsandreactantstoforcereactiontocompletion.•Removalofreagents,reactantsandbyproductsbyfiltration.Merrifield,R.B.JACS1963,85,2149.(1984NobelPrize)Tea-BagMethod•10to20mgof248different13-residuepeptides.Seal•Sequence1.D
6、eprotectMesh2.WashOpening3.Couple4.WashResin5.HFCleaveXXXCodeHoughten,R.A.etal.Proc.Natl.Acad.Sci.USA1985,82,5131.MultipinPeptideSynthesisPin•Synthesizeonpolyacrylate-graftedpolyethylenerods.•UtilizeconventionalReagentssolidphasereactantsGrowinginwellssynthesismethods.Pe
7、ptideonaPin•Preparationofupto10,000spatiallyseparatedIndividualpinscompoundsusingwithcrowns(1to7umolinexpensiveloadingcapacity)96-WellPlateequipmentandreadilyavailableGeysen,etal.PNAS1984,81,3998.automation.Zuckerman,etal.BMCL1993,3,463.SplitandMixSolidPhaseSynthesis•Sol
8、idsupportisdividedA13AA2beforeeachcouplingcycle•EquimolarmixtureofA123AApeptides-MixB13-SplitB2B•Cannot
