title: Selenophenes: Introducing a New Element into the Core of Non-Steroidal Estrogen Receptor Ligands.
abstract: The importance of the heterocyclic core elements with peripheral phenolic and alkyl substituents as a dominant structural motif of ligands for the estrogen receptor (ER) has been well recognized. In this study we expanded the structural diversity of core elements by preparing selenium-containing heterocycles and exploring the activities of these selenophenes on the two ERs, ERα and ERβ. Careful structure-activity relationship (SAR) analysis of their ER binding affinities showed that most selenophenes are ERβ-selective, with the position of the phenol substituents on the selenophene core and the nature of these substituents having a marked effect on their binding affinities. The compound bis(2-fluoro-4-hydroxyphenyl)selenophene (2 f) has the highest relative binding affinity (RBA) of 24.3 for ERβ. In transcription assays, most selenophenes were found to exhibit partial to full agonist activity for both ER subtypes, with compounds bis(2-methyl-4-hydroxyphenyl)selenophene (2 b), bis(4-fluoro-3-hydroxyphenyl)3-bromoselenophene (6 f), and 2,3,5-tris(hydroxyphenyl)thiophenes (8 b and 8 d) profiling as superagonists for ERα; however, several compounds display a range of ERα or ERβ antagonistic activities. A few selenophenes exhibited antiproliferative activity, with compound 8 c showing antiproliferative effects similar to that of 4-hydroxytamoxifen in breast cancer MCF-7 cells while being nontoxic to normal VERO cells. These new ligands could act as models for the development of novel agents leading to improved therapeutics that target the estrogen receptor.
authors.affiliation: State Key Laboratory of Virology, Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Wuhan University, Ministry of Education, Wuhan University School of Pharmaceutical Sciences, 185 East Lake Road, Wuhan, 430071, P.R. China.
authors.forename: Silong
authors.initials: S
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Virology, Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Wuhan University, Ministry of Education, Wuhan University School of Pharmaceutical Sciences, 185 East Lake Road, Wuhan, 430071, P.R. China.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Virology, Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Wuhan University, Ministry of Education, Wuhan University School of Pharmaceutical Sciences, 185 East Lake Road, Wuhan, 430071, P.R. China.
authors.forename: Zhiye
authors.initials: Z
authors.lastname: Hu
authors.affiliation: College of Life Sciences, Wuhan University, No. 299 Bayi Road, Wuhan, 430072, P.R. China.
authors.forename: Changhao
authors.initials: C
authors.lastname: Li
authors.affiliation: State Key Laboratory of Virology, Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Wuhan University, Ministry of Education, Wuhan University School of Pharmaceutical Sciences, 185 East Lake Road, Wuhan, 430071, P.R. China.
authors.forename: Chu
authors.initials: C
authors.lastname: Tang
authors.affiliation: Department of Chemistry, University of Illinois, 600 South Mathews Avenue, Urbana, IL, 61801, USA.
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Carlson
authors.affiliation: State Key Laboratory of Virology, Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Wuhan University, Ministry of Education, Wuhan University School of Pharmaceutical Sciences, 185 East Lake Road, Wuhan, 430071, P.R. China.
authors.forename: Junjie
authors.initials: J
authors.lastname: Luo
authors.affiliation: State Key Laboratory of Virology, Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Wuhan University, Ministry of Education, Wuhan University School of Pharmaceutical Sciences, 185 East Lake Road, Wuhan, 430071, P.R. China.
authors.forename: Chune
authors.initials: C
authors.lastname: Dong
authors.affiliation: Department of Chemistry, University of Illinois, 600 South Mathews Avenue, Urbana, IL, 61801, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Katzenellenbogen
authors.affiliation: College of Life Sciences, Wuhan University, No. 299 Bayi Road, Wuhan, 430072, P.R. China.
authors.forename: Jian
authors.initials: J
authors.lastname: Huang
authors.affiliation: State Key Laboratory of Virology, Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Wuhan University, Ministry of Education, Wuhan University School of Pharmaceutical Sciences, 185 East Lake Road, Wuhan, 430071, P.R. China.|Institute of Pharmacy & Pharmacology, University of South China, Hengyang, 421001, China.
authors.forename: Hai-Bing
authors.initials: HB
authors.lastname: Zhou
mesh_terms: D000818:Animals; D001665:Binding Sites; D049109:Cell Proliferation / Q000187:drug effects; D002522:Chlorocebus aethiops; D047628:Estrogen Receptor alpha / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008024:Ligands; D061986:MCF-7 Cells; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D016566:Organoselenium Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D014709:Vero Cells
chemical_list: D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D008024:Ligands; D016566:Organoselenium Compounds
keywords: breast cancer; estrogen receptor; relative binding affinity; selenophenes; structural diversity