Elemental isomerism: a boron-nitrogen surrogate for a carbon-carbon double bond increases the chemical diversity of estrogen receptor ligands.
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.
Zhou
Hai-Bing
HB
Department of Chemistry, University of Illinois, Urbana, IL 61801, USA.
Nettles
Kendall W
KW
Bruning
John B
JB
Kim
Younchang
Y
Joachimiak
Andrzej
A
Sharma
Sanjay
S
Carlson
Kathryn E
KE
Stossi
Fabio
F
Katzenellenbogen
Benita S
BS
Greene
Geoffrey L
GL
Katzenellenbogen
John A
JA
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*
D004968:Estrogens, Non-Steroidal; D008024:Ligands; D011960:Receptors, Estrogen; D002244:Carbon; D009584:Nitrogen; D001895:Boron