Synthesis and evaluation of 2-halogenated-1,1-bis(4-hydroxyphenyl)-2-(3-hydroxyphenyl)-ethylenes as potential estrogen receptor-targeted radiodiagnostic and radiotherapeutic agents

• Published in: Steroids 2015-04, Vol.96 (C), p.50-62
• Main Authors: Hanson, Robert N., Tongcharoensirikul, Pakamas, Barnsley, Kelton, Ondrechen, Mary Jo, Hughes, Alun, DeSombre, Eugene R.
• Format: Article
• Language: English
• Subjects: Animals; Auger; Chemistry Techniques, Synthetic; Estrogen Receptor alpha - chemistry; Estrogen Receptor alpha - metabolism; Ethylenes - chemical synthesis; Ethylenes - chemistry; Ethylenes - metabolism; Ethylenes - therapeutic use; Female; Halogenation; Ligands; Models, Molecular; Molecular Imaging; Nonsteroidal estrogens; Protein Structure, Tertiary; Radiopharmaceuticals - chemical synthesis; Radiopharmaceuticals - chemistry; Radiopharmaceuticals - metabolism; Radiopharmaceuticals - therapeutic use; Rats; Relative binding affinity; Synthesis; Uterotrophic growth
• ISSN: 0039-128X; 1878-5867
• DOI: 10.1016/j.steroids.2015.01.013

[Display omitted] •Synthesis of a small series of halogenated triarylethylene estrogens.•Compounds demonstrate high affinity and in vivo estrogenicity.•Preparation of stannylated precursor for radioiodination studies.•Molecular docking studies to identify interactions with receptor. A series of three 1,1-bis(4-hydroxyphenyl)-2-(3-hydroxyphenyl)-ethylene derivatives was prepared and evaluated as potential estrogen receptor imaging agents. The compounds display high binding affinity compared to estradiol, with the 2-iodo and 2-bromo-derivatives expressing higher affinity than the parent 2-nonhalogenated derivative. Evaluation in immature female rats also indicate that the compounds were all full estrogenic agonists with potencies in the same order of activity (I∼Br>H). Computational analysis of the interactions between the ligands and ERα-LBD demonstrated positive contribution of halide to binding properties. In preparation for studies using the radiohalogenated analogs, the corresponding protected 2-(tributylstannyl) derivative was prepared and converted to the corresponding 2-iodo-product.