Identification and Structure–Activity Relationships of a Novel Series of Estrogen Receptor Ligands Based on 7-Thiabicyclo[2.2.1]hept-2-ene-7-oxide

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1、Articlepubs.acs.org/jmcIdentificationandStructure−ActivityRelationshipsofaNovelSeriesofEstrogenReceptorLigandsBasedon7-Thiabicyclo[2.2.1]hept-2-ene-7-oxide††§§‡†PengchengWang,JianMin,JeromeC.Nwachukwu,ValerieCavett,KathrynE.Carlson,PuGuo,†††,‡§ManghongZhu,YangfanZhen

2、g,ChuneDong,JohnA.Katzenellenbogen,*KendallW.Nettles,,†andHai-BingZhou*†StateKeyLaboratoryofVirology,LaboratoryofCombinatorialBiosynthesisandDrugDiscovery,WuhanUniversity,MinistryofEducation,WuhanUniversitySchoolofPharmaceuticalSciences,Wuhan430072,China‡Departmentof

3、Chemistry,UniversityofIllinois,600SouthMathewsAvenue,Urbana,Illinois61801,UnitedStates§DepartmentofCancerBiology,TheScrippsResearchInstituteFlorida,130ScrippsWay,Jupiter,Florida33458,UnitedStates*SSupportingInformationABSTRACT:Todevelopestrogenreceptor(ER)ligandshav

4、ingnovelstructuresandactivities,wehaveexploredcompoundsinwhichthecentralhydrophobiccorehasamorethree-dimensionaltopologythantypicallyfoundinestrogenligandsandthusexploitstheunfilledspaceintheligand-bindingpocket.Here,webuilduponourpreviousinvestigationsof7-oxabicyclo

5、[2.2.1]heptenecoreligands,byreplacingtheoxygenbridgewithasulfoxide.Thesenew7-thiabicyclo[2.2.1]hept-2-ene-7-oxideswereconvenientlypreparedbyaDiels−Alderreactionof3,4-diarylthiopheneswithdienophilesinthepresenceofanoxidantandgivecycloadductswithendostereochemistry.Sev

6、eralnewcompoundsdemonstratedhighbindingaffinitieswithexcellentERαselectivity,butunlikeoxabicycliccompounds,whicharetranscriptionalantagonists,mostthiabicycliccompoundsarepotent,ERα-selectiveagonists.Modelingsuggeststhatthegaininactivityofthethiabicycliccompoundsarise

7、sfromtheirendostereochemistrythatstabilizesanactiveERconformation.Further,thedispositionofmethylsubstituentsinthephenylgroupsattachedtothebicycliccoreunitcontributestotheirbindingaffinityandsubtypeselectivity.■INTRODUCTIONthree-dimensionaltopologythaniscommonlyfoundi

8、nbothEstrogensareknowntoplayimportantrolesinthedevelop-steroidalandnonsteroidalERligands.Thisdesignstrategywasmentandmaintenanceofb