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1、COMMUNICATIONSClickChemistryInSitu:Acetylcholinesteraseofconnectingreactions:formationofhydrazoneorSchiffasaReactionVesselfortheSelectiveAssemblybaseadducts,disulfidebondformation,alkylationoffreeofaFemtomolarInhibitorfromanArrayofthiolsoramines,epoxidering-opening,orolefinmetathe-sis.
2、[5,6,8,11,15±19]MostcloselyrelatedtotheworkdescribedBuildingBlocks**hereinisthegenerationofcarbonicanhydraseinhibitorsbyWarrenG.Lewis,LukeG.Green,FlavioGrynszpan,usingtheSN2reactionofathiolwithana-chloroketoneintheZoranRadic¬,PaulR.Carlier,PalmerTaylor,presenceoftheenzymetarget.[16]M.G
3、.Finn,*andK.BarrySharpless*Mostoftheabovestrategiessharethelimitationthatthereactivegroupsontheligandprobes(buildingblocks),beingThegenerationand/oroptimizationofleadcompoundsbyeitherelectrophilesornucleophiles,arelikelytoreactincombinatorialmethodshasbecomewidelyacceptedinundesiredway
4、swithinbiochemicalsystems.Analternativeismedicinalchemistry,andisthesubjectofcontinuedimprove-offeredbythe™creamofthecrop∫among™clickreac-ment.[1±3]However,mostcombinatorialstrategiesremain[20]tions∫–theHuisgen1,3-dipolarcycloadditionofazidesanddependentuponiterativecyclesofsynthesisan
5、dscreening.acetylenestogive1,2,3-triazoles[Eq.(1)].[21±23]Thiswater-Thedirectinvolvementofthetarget,usuallyareceptororenzyme,intheselection,evolution,andscreeningofdrugcandidatescanacceleratethediscoveryprocessbyshort-circuitingitstraditionallystepwisenature.[4±11]Theuseofanenzymetarge
6、ttoselectbuildingblocksandsynthesizeitsowninhibitorisarelativelyunexploredoption.Thisapproachdependsonthesimultaneousbindingoftwoligands,decoratedwithcomplementaryreactivegroups,toadjacentsitesontheprotein;theirco-localizationisthentolerantreactionemploysfunctionalgroupsthataregenerall
7、y[12]likelytoacceleratethereactionthatconnectsthem.Whencompatiblewithenzymesunderphysiologicalconditions[24,25]thecatalysisofsuchbondformationisblockedbyproductandarereadilyincorporatedintodiverseorganicbuildinginhibition,thehigheraffinityproducts[12±14]thenserveasleadblocks.Itsdepen
