Elemental isomerism: a boron-nitrogen surrogate for a carbon-carbon double bond increases the chemical diversity of estrogen receptor ligands
Date
2007
Authors
Zhou, H.
Nettles, K.
Bruning, J.
Kim, Y.
Joachimiak, A.
Sharma, S.
Carlson, K.
Stossi, F.
Katzenellenbogen, B.
Greene, G.
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Journal article
Citation
Chemistry and Biology, 2007; 14(6):659-669
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Hai-Bing Zhou, Kendall W. Nettles, John B. Bruning, Younchang Kim, Andrzej Joachimiak, Sanjay Sharma, Kathryn E. Carlson, Fabio Stossi, Benita S. Katzenellenbogen, Geoffrey L. Greene, and John A. Katzenellenbogen
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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.
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Copyright © 2007 Elsevier Ltd. All rights reserved.