Chemically reactive estrogens: synthesis and estrogen receptor interactions of hexestrol ether derivatives and 4-substituted deoxyhexestrol derivatives bearing alkylating functions

• Published in: Journal of medicinal chemistry Vol. 24; no. 4; pp. 435 - 450
• Main Authors: Katzenellenbogen, John A, McGorrin, Robert J, Tatee, Tochiro, Kempton, Robert J, Carlson, Kathryn E, Kinder, David H
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 01.04.1981
• Subjects: Affinity Labels - pharmacology; Alkylating Agents - chemical synthesis; Alkylating Agents - pharmacology; Binding Sites; Estrogens - chemical synthesis; Estrogens - metabolism; Estrogens - pharmacology; Hexestrol - chemical synthesis; Hexestrol - metabolism; Photolysis; Receptors, Estrogen - drug effects; Receptors, Estrogen - metabolism; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00136a013

A series of chemically reactive derivatives of the nonsteroidal estrogen hexestrol have been synthesized as potential affinity labels for the estrogen receptor or as cytotoxic agents with selective activity against receptor-containing cells. These compounds are hexestrol ethers with halo ketone, halohydrin, or epoxide functions or 4-substituted deoxyhexestrols with halo ketone, benzyl halide, nitro, azide, sulfonyl fluoride, or sulfonyl azide groups. The alkylating activity of the electrophilic derivatives was measured using the colorimetric reagent nitrobenzylpyridine, the bromo derivatives being considerably more reactive than the chloro ones. Their reversible binding to the lamb uterine estrogen receptor was measured by competitive binding assays, and their irreversible reaction with receptor was measured by exchange assays that determine the rate and extent of receptor inactivation. In general, monoetherification of hexestrol or substitution of deoxyhexestrol produces compounds with relatively low affinity for the estrogen receptor (0.3-10% that of estradiol). Most of the electrophilic derivatives are rapid and effective inactivators of receptor (24-70% inactivation within 0.5-5 h at 25 degrees C). Of the photosensitive derivatives, 4-azidodeoxyhexestrol appears to be the most efficient receptor inactivator (49%). The high reactivity of these compounds toward the estrogen receptor and the lack of interference by their reaction with other cellular nucleophiles suggest that these compounds may be useful as affinity-labeling agents or as selective cytotoxic agents in intact systems.