title: Synthesis of anthranylaldoxime derivatives as estrogen receptor ligands and computational prediction of binding modes.
abstract: N-Me-anthranylaldoximes possess a hydrogen-bonded pseudocyclic A' ring in place of the typical phenolic A-ring that is characteristic of most estrogen receptor (ER) ligands. We have investigated the role played by substituents introduced into either one or both of the peripheral 3- and 4-phenyl rings in modulating ER binding affinity. An efficient synthetic strategy was employed for the preparation of differentially substituted 3- and 4-aryl derivatives that involved exploiting the different reactivity of bromo- versus chloro-aryl groups in palladium-catalyzed cross-couplings. The binding data showed that ERalpha affinity could be improved by a single p-OH group in the 4-phenyl ring, whereas the same substitution on the 3-phenyl ring caused a dramatic reduction of ERbeta affinity. The most ERalpha-selective compound was the one with two p-OH groups on both phenyl substituents. To rationalize these results, ligand docking followed by molecular mechanics Poisson-Boltzmann/surface area (MM-PBSA) studies were carried out. These analyses suggested a molecular basis for the interaction of these compounds with the ERs and enabled the development of models able to predict the mode of ligand binding.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy.
authors.forename: Tiziano
authors.initials: T
authors.lastname: Tuccinardi
authors.forename: Simone
authors.initials: S
authors.lastname: Bertini
authors.forename: Adriano
authors.initials: A
authors.lastname: Martinelli
authors.forename: Filippo
authors.initials: F
authors.lastname: Minutolo
authors.forename: Gabriella
authors.initials: G
authors.lastname: Ortore
authors.forename: Giorgio
authors.initials: G
authors.lastname: Placanica
authors.forename: Giovanni
authors.initials: G
authors.lastname: Prota
authors.forename: Simona
authors.initials: S
authors.lastname: Rapposelli
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Carlson
authors.forename: John A
authors.initials: JA
authors.lastname: Katzenellenbogen
authors.forename: Marco
authors.initials: M
authors.lastname: Macchia
mesh_terms: D001555:Benzene Derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D001667:Binding, Competitive; D047628:Estrogen Receptor alpha / Q000737:chemistry* / Q000378:metabolism*; D047629:Estrogen Receptor beta / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D010091:Oximes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D001555:Benzene Derivatives; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D008024:Ligands; D010091:Oximes