Synthesis And Evaluation Of 17 Alpha-Triazolyl And 9 Alpha-Cyano Derivatives Of Estradiol

A variety of 17 alpha-triazolyl and 9 alpha-cyano derivatives of estradiol were prepared and evaluated for binding to human ER13 in both a TR-FRET assay, as well as ER13 and ER alpha agonism in cell-based functional assays. 9 alpha Cyanoestradiol (5) was nearly equipotent as estradiol as an agonist for both ER13 and ER alpha. The potency of the 17 alpha-triazolylestradiol analogs is considerably more variable and depends on the nature of the 4-substituent of the triazole ring. While rigid protein docking simulations exhibited significant steric clashing, induced fit docking providing more protein flexibility revealed that the triazole linker of analogs 2d and 2e extends outside of the traditional ligand binding domain with the benzene ring located in the loop connecting helix 11 to helix 12.