title: Design, synthesis, and biological evaluation of cyclopropyl analogues of stilbene with raloxifene side chain as subtype-selective ligands for estrogen receptor.
abstract: We have designed the cyclopropane analog of stilbene as subtype-selective ligands for estrogen receptor based on the bioisosterism that cyclopropane could act as alkene bioisoster. Three cyclopropane analogs were prepared efficiently starting from 4-benzyloxybenzaldehyde, and evaluated for their binding to estrogen receptors ERα and ERβ. These cyclopropane analogs were also found to be full agonists in estrogen receptor-mediated gene transcription assay. Compared to the stilbene analogs such as tamoxifen and raloxifene, the three cyclopropane analogs showed lower binding affinity for estrogen receptor, but higher subtype selectivity for ERα. The structure-activity relationship revealed from this study might provide clues for improving subtype selectivity for ERα.
authors.affiliation: College of Pharmacy, Sookmyung Women's University, Seoul, 141-742, Korea.
authors.forename: Hye Lim
authors.initials: HL
authors.lastname: Yeo
authors.forename: Yoon Sun
authors.initials: YS
authors.lastname: Song
authors.forename: Jae-Ha
authors.initials: JH
authors.lastname: Ryu
authors.forename: Hee-Doo
authors.initials: HD
authors.lastname: Kim
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D002460:Cell Line; D002522:Chlorocebus aethiops; D003521:Cyclopropanes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D047628:Estrogen Receptor alpha / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D047629:Estrogen Receptor beta / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015914:Estrogen Replacement Therapy / Q000009:adverse effects; D004967:Estrogens / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D017930:Genes, Reporter / Q000187:drug effects; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D020849:Raloxifene Hydrochloride / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D020218:Response Elements / Q000187:drug effects; D020845:Selective Estrogen Receptor Modulators / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013267:Stilbenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D003521:Cyclopropanes; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; D008024:Ligands; D011994:Recombinant Proteins; D020845:Selective Estrogen Receptor Modulators; D013267:Stilbenes; D020849:Raloxifene Hydrochloride