ClickChemistryisachemicalreactionbetweenpairsofreagents(namedclickchemistryreagents)toexclusivelyreactwitheachotherundermildconditionsandiseffectivelyinerttonaturallyoccurringfunctionalgroupssuchasaminegroups.Theterm"ClickChemistry"wasfirstcoinedbySharplessin2001inanefforttodesignamethodtoeasilysynthesizemoleculesundermildconditionsandtheproductcanbeeasilyisolated.
Broadpharm基础篇什么是点击化学（什么叫点击化学）
ClickChemistryreactionscanbecategorizedintothreegenerations:
(1)
ThefirstgenerationofClickChemistryinvolvedthereactionofazidewithalkynecatalyzedbyCu(I).Thecoppercatalystallowsforthisreactiontobecarriedoutefficientlyundermildconditionsinwaterwhereasthereactionwouldrequirehightemperatureandhighpressurewithoutthecoppercatalyst.CoppercatalyzedClickChemistryhasbeenfoundtohavethesecondfastestrateconstantof10-100M-1
-1
Duetothetoxicnatureofcoppertolivingstructuresandbiosystems,coppercatalyzedClickChemistryisnotaviablemethodofcarryingoutreactionsinlivingsystemswhichhasledtothedevelopmentofthefollowingtwogenerationsofClickChemistry.
(2)
DBCOreagentorBCNreagentcanbeusedtoperformClickChemistrywithazidemoleculeswithouttheneedofheavy-metalcatalysis.
Figure2:Strain-promotedAzide-DBCOClickChemistry
Thebondstraincreatedbythebondangleofthecyclooctyne(DBCOorBCN)requireslessenergyforthecyclooctynetoformthe(3+2)cycloadditionwhichreleasesenthalpicenergycausedbytheringstrainofthecyclooctyne.Thisgenerationdoesnotrequirecopperasacatalystanditcanbeusedincellsurfaceandinvivolabeling.Therateconstantis10-2
-1
-1
(3)
ThethirdgenerationofClickChemistryistheligationbetweentetrazinewithtrans-Cyclooctene(TCO).Themechanismforthisligationutilizesringstrainfromthetrans-CycloocteneandaninverseDiels-Alderreactionbetweentheelectronrichtrans-Cycloocteneandtheelectronpoortetrazine.ThisligationhasbeenfoundtobethefastestgenerationofClickChemistrythusfarwitharateconstantof1-106
-1
-1
ApplicationsofClickChemistry
ClickChemistryhasbeenwidelyusedindrugdiscovery,bioconjugation,labeling,andmaterialsciencesinthepharmaceuticalandbiotechindustryduetoitsmildconditionsandhighselectivity.
ClickChemistryinDrugDiscovery
ClickChemistryisutilizedintheformationofADClinkersinantibodydrugconjugates.Forexample,Trodelvy(SacituzumabGovitecan),alsoknownasIMMU-132(Figure4),isanimmunetargettherapymedicinefortriple-negativebreastcancerwhichcontainssacituzumabandSN-38boundwithalinker.ClickChemistryisusedintheformationofthelinkertoformatriazolethatlinksSMCCtoaPEG8moiety.
Figure4:
ClickChemistryinJointCartilageTherapy
ClickChemistryhasalsobeenusedincell-basedtherapytotreatdamageinjointcartilage,relievepain,andimprovefunction.Autologouschondrocytetransplantationtargetsapoptoticchondrocytesincartilagewhichcanbeidentifiedbyasixaminoacidpeptide,ApoPep-1,andbybindinginjectedhealthychondrocytesfromunaffectedcartilage.ApoPep-1carriesatrans-CycloocteneboundbyaPEGLinkertoapoptoticchondrocyteswhichcanthenbindhealthychondrocytesviaClickChemistrytotetrazinetoencouragecartilageregeneration(Figure5).
Figure5:
ClickChemistryTools
Asaleadingclickchemistyreagentsupplierworldwide,BroadPharmprovidesover500highpurityClickChemistryReagents(tools)andKitswithanarrayoffunctionalgroupssuchas:Azide,Alkyne,DBCO,TCO,Tetrazine,BCNtoempowerourclientsadvancedresearchanddrugdevelopment.
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