Synthesis and Biological Evaluation of 4-(Hydroxyalkyl)estradiols and Related Compounds

• Published in: Journal of medicinal chemistry 1997-11, Vol.40 (23), p.3756-3764
• Main Authors: Lovely, Carl J, Bhat, Abhijit S, Coughenour, Holly D, Gilbert, Nancy E, Brueggemeier, Robert W
• Format: Article
• Language: English
• Subjects: Adenocarcinoma - metabolism; Adenocarcinoma - pathology; Adenocarcinoma - ultrastructure; Antineoplastic agents; Biological and medical sciences; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Breast Neoplasms - ultrastructure; Cell Division - drug effects; Estradiol - analogs & derivatives; Estradiol - chemical synthesis; Estradiol - pharmacokinetics; Estradiol - pharmacology; Estrogens, Catechol - chemical synthesis; Estrogens, Catechol - pharmacology; General aspects; Humans; Kinetics; Medical sciences; Neoplasms, Hormone-Dependent - metabolism; Neoplasms, Hormone-Dependent - pathology; Neoplasms, Hormone-Dependent - ultrastructure; Pharmacology. Drug treatments; Receptors, Estrogen - metabolism; Structure-Activity Relationship; Tumor Cells, Cultured - drug effects
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm9701684

A series of synthetic estrogens containing hydroxyalkyl side chains at the C-4 position of the A ring were designed as metabolically stable analogs of 4-hydroxyestradiol, a catechol estrogen. These synthetic steroids would facilitate investigations on the potential biological role of catechol estrogens and also enable further examination of the structural and electronic constraints on the A ring in the interaction of estrogens with the estrogen receptor. Catechol estrogens are implicated as possible causative agents in estrogen-induced tumorigenesis. 4-Hydroxyestradiol has weaker affinity for the estrogen receptor and exhibits lower estrogenic activity in vivo; on the other hand, the catechol estrogens are prone to further oxidative metabolism and can form reactive intermediates. This report describes the synthesis and initial biochemical evaluation of 4-(hydroxyalkyl)estrogens and 4-(aminoalkyl)estradiols. The 4-(hydroxyalkyl)estrogens were prepared by oxidative hydroboration of 4-alkenylestradiols. The alkenylestradiols were obtained via a Stille cross-coupling between a MOM-protected 4-bromoestradiol and an alkenylstannane. The (4-aminoalkyl)estrogens were prepared from the hydroxyalkyl derivatives with phthalimide under Mitsunobu conditions. The substituted estradiols were evaluated for estrogen receptor binding activity in MCF-7 human mammary carcinoma cells, and 4-(hydroxymethyl)estradiol 1 exhibited the highest affinity with an apparent EC50 value of 364 nM. The relative activities for mRNA induction of the pS2 gene in MCF-7 cell cultures by the 4-(hydroxyalkyl)estrogens closely parallel the relative binding affinities. 4-(Hydroxymethyl)estradiol 1 did not stimulate the growth of MCF-7 cells at concentrations up to 1 μM. Thus, 4-(hydroxymethyl)estradiol 1 exhibited similar estrogen receptor affinity as the catechol estrogen, 4-hydroxyestradiol, and may prove useful in the examination of the biological effects of 4-hydroxyestrogens.