title: Elemental isomerism: a boron-nitrogen surrogate for a carbon-carbon double bond increases the chemical diversity of estrogen receptor ligands.
abstract: To increase the chemical diversity of bioactive molecules by incorporating unusual elements, we have examined the replacement of a C=C double bond with the isoelectronic, isostructural B-N bond in the context of nonsteroidal estrogen receptor (ER) ligands. While the B-N bond was hydrolytically labile in the unhindered cyclofenil system, the more hindered anilino dimesitylboranes, analogs of triarylethylene estrogens, were easily prepared, hydrolytically stable, and demonstrated substantial affinity for ERs. X-ray analysis of one ERalpha-ligand complex revealed steric clashes with the para methyl groups distorting the receptor; removal of these groups resulted in an increase in affinity, potency, and transcriptional efficacy. These studies define the structural determinants of stability and cellular bioactivity of a B-N for C=C substitution in nonsteroidal estrogens and provide a framework for further exploration of "elemental isomerism" for diversification of drug-like molecules.
authors.affiliation: Department of Chemistry, University of Illinois, Urbana, IL 61801, USA.
authors.forename: Hai-Bing
authors.initials: HB
authors.lastname: Zhou
authors.forename: Kendall W
authors.initials: KW
authors.lastname: Nettles
authors.forename: John B
authors.initials: JB
authors.lastname: Bruning
authors.forename: Younchang
authors.initials: Y
authors.lastname: Kim
authors.forename: Andrzej
authors.initials: A
authors.lastname: Joachimiak
authors.forename: Sanjay
authors.initials: S
authors.lastname: Sharma
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Carlson
authors.forename: Fabio
authors.initials: F
authors.lastname: Stossi
authors.forename: Benita S
authors.initials: BS
authors.lastname: Katzenellenbogen
authors.forename: Geoffrey L
authors.initials: GL
authors.lastname: Greene
authors.forename: John A
authors.initials: JA
authors.lastname: Katzenellenbogen
mesh_terms: D001895:Boron / Q000737:chemistry*; D002244:Carbon / Q000737:chemistry*; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004968:Estrogens, Non-Steroidal / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007536:Isomerism; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D009584:Nitrogen / Q000737:chemistry*; D011485:Protein Binding; D011869:Radioligand Assay; D011960:Receptors, Estrogen / Q000378:metabolism*
chemical_list: D004968:Estrogens, Non-Steroidal; D008024:Ligands; D011960:Receptors, Estrogen; D002244:Carbon; D009584:Nitrogen; D001895:Boron