title: Novel estrogen receptor ligands based on an anthranylaldoxime structure: role of the phenol-type pseudocycle in the binding process.
abstract: The 3,4-diphenylsalicylaldoxime system 1 is an estrogen receptor (ER) ligand of unusual structure, having a hydrogen-bonded pseudocyclic A'-ring in place of the paradigmatic phenolic A-ring that is characteristic of most estrogens. We have investigated the role played by the pseudocycle A' in binding to the ER by preparing 3,4-diphenylbenzaldoxime (4), a compound that completely lacks this ring but still preserves all of the other features of the original molecule 1, as well as a series of 3,4-diphenylanthranylaldoximes (5a-c) in which the nature of the heteroatom participating in the formation of pseudoring A' has been changed from an oxygen (1) to a nitrogen that is either unsubstituted (5a) or substituted with small alkyl groups (a methyl in 5b, or an ethyl in 5c). The importance of hydrogen-bonded pseudocycle A' in the binding process was confirmed by the fact that benzaldoxime 4 showed a greatly reduced binding affinity compared to salicylaldoxime 1. Moreover, the binding affinity improved considerably when the A'-ring contained either an unsubstituted nitrogen (5a) or an N-Me group (5b). On the other hand, the N-Et-substituted anthranyl derivative 5c showed a marked drop in binding affinity. Molecular modeling docking studies on ERalpha confirmed that compounds 5a and 5b fit nicely in the ligand binding pocket, with an especially comfortable fit for the N-Me group of 5b in a small hydrophobic pocket surrounded by nonpolar residues. The limited size of this pocket does not allow accommodation of N-substituents larger than a methyl group, which is consistent with the low binding affinity of the N-Et compound 5c.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: Minutolo
authors.forename: Michela
authors.initials: M
authors.lastname: Antonello
authors.forename: Simone
authors.initials: S
authors.lastname: Bertini
authors.forename: Gabriella
authors.initials: G
authors.lastname: Ortore
authors.forename: Giorgio
authors.initials: G
authors.lastname: Placanica
authors.forename: Simona
authors.initials: S
authors.lastname: Rapposelli
authors.forename: Shubin
authors.initials: S
authors.lastname: Sheng
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Carlson
authors.forename: Benita S
authors.initials: BS
authors.lastname: Katzenellenbogen
authors.forename: John A
authors.initials: JA
authors.lastname: Katzenellenbogen
authors.forename: Marco
authors.initials: M
authors.lastname: Macchia
mesh_terms: D001555:Benzene Derivatives / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D001665:Binding Sites; D001667:Binding, Competitive; D004305:Dose-Response Relationship, Drug; D016889:Endometrial Neoplasms / Q000378:metabolism; D004958:Estradiol / Q000737:chemistry / Q000378:metabolism; D005260:Female; D017930:Genes, Reporter / Q000235:genetics; D006801:Humans; D006860:Hydrogen Bonding; D008024:Ligands; D008958:Models, Molecular; D010091:Oximes / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D010636:Phenols / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D011869:Radioligand Assay; D011960:Receptors, Estrogen / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D001555:Benzene Derivatives; D008024:Ligands; D010091:Oximes; D010636:Phenols; D011960:Receptors, Estrogen; D004958:Estradiol