title: Benzothiophene selective estrogen receptor modulators with modulated oxidative activity and receptor affinity.
abstract: The regulation of estrogenic and antiestrogenic effects of selective estrogen receptor modulators (SERMs) is thought to underlie their clinical use. Most SERMs are polyaromatic phenols susceptible to oxidative metabolism to quinoids, which are proposed to be genotoxic. Conversely, the redox reactivity of SERMs may contribute to antioxidant and chemopreventive mechanisms, providing a new approach to improve the therapeutic properties of SERMs. An improved synthetic strategy was developed to generate a family of benzothiophene SERMs. Using computational modeling methods and measurements of antioxidant activity and estrogen receptor (ER) ligand binding, this SERM family was shown to provide both a range of ERalpha/ERbeta selectivity from 1.2- to 67-fold and a range of redox activity. Antioxidant activity was successfully modulated by varying a substituent remote from the OH group; the source of the antioxidant capacity. An efficient synthetic procedure is reported yielding benzothiophene SERMs wherein redox activity and ER affinity are modulated.
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612-7231, USA.
authors.forename: Zhihui
authors.initials: Z
authors.lastname: Qin
authors.forename: Irida
authors.initials: I
authors.lastname: Kastrati
authors.forename: R Esala P
authors.initials: RE
authors.lastname: Chandrasena
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.forename: Ping
authors.initials: P
authors.lastname: Yao
authors.forename: Pavel A
authors.initials: PA
authors.lastname: Petukhov
authors.forename: Judy L
authors.initials: JL
authors.lastname: Bolton
authors.forename: Gregory R J
authors.initials: GR
authors.lastname: Thatcher
mesh_terms: D000975:Antioxidants / Q000138:chemical synthesis* / Q000737:chemistry; D047628:Estrogen Receptor alpha / Q000737:chemistry* / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D010084:Oxidation-Reduction; D010880:Piperidines / Q000737:chemistry; D011869:Radioligand Assay; D011994:Recombinant Proteins / Q000737:chemistry; D020845:Selective Estrogen Receptor Modulators / Q000138:chemical synthesis* / Q000737:chemistry; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D000975:Antioxidants; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D010880:Piperidines; D011994:Recombinant Proteins; D020845:Selective Estrogen Receptor Modulators; D013876:Thiophenes; C115121:LY 353381