Estrogenic affinity labels: synthesis, irreversible receptor binding, and bioactivity of aziridine-substituted hexestrol derivatives.

Abstract

To develop an affinity label for the estrogen receptor that would be an estrogen agonist, rather than antagonist, we prepared several aziridine derivatives of the potent nonsteroidal estrogen hexestrol [3R,4S)-3,4-bis(4-hydroxyphenyl)hexane) bearing an aziridine function on the side chain. Three functional groups link the hexestrol ligand and the aziridine: a carbonyl group (ketone or ester), a thioether, or a methylene chain. The apparent competitive binding affinity of these derivatives for the estrogen receptor ranges from 1.8% to 25% that of estradiol, and most of them bind in a time-dependent, irreversible manner with the receptor, although the rate and efficiency of this binding vary widely, often with relatively small changes in structure. This is consistent with the irreversible attachment requiring a precise alignment of activating and reacting residues in the binding site of the receptor. The estrogenic and antiestrogenic activity of these aziridine derivatives was investigated in MCF-7 human breast cancer cells. Most of the compounds are agonists, with one being an antagonist. The derivative (6R,7S)-1-N-aziridinyl-6,7-bis(4-hydroxyphenyl)-5-nonanone (keto-nonestrol aziridine 3) appears to have the most ideal behavior of the estrogenic affinity labeling agents prepared: It is an agonist, and it binds to receptor irreversibly, efficiently, and quite rapidly.

• Authors: J A Zablocki, J A Katzenellenbogen, K E Carlson, M J Norman, B S Katzenellenbogen
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 30 Issue 5 Pg. 829-38 (May 1987) ISSN: 0022-2623 [Print] United States
• PMID: 3033242 (Publication Type: Comparative Study, Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Affinity Labels
• Aziridines
• Azirines
• Estrogen Antagonists
• Receptors, Estrogen
• Hexestrol

Topics

• Affinity Labels (chemical synthesis, metabolism, pharmacology)
• Animals
• Aziridines (pharmacology)
• Azirines (pharmacology)
• Binding, Competitive
• Breast Neoplasms (metabolism, pathology)
• Cell Division (drug effects)
• Cell Line
• Chemical Phenomena
• Chemistry
• Estrogen Antagonists (pharmacology)
• Female
• Hexestrol (analogs & derivatives, chemical synthesis, metabolism)
• Humans
• Receptors, Estrogen (metabolism)
• Sheep
• Structure-Activity Relationship
• Uterus (metabolism)