A synthesis of 7α-substituted estradiols: synthesis and biological evaluation of a 7α-pentyl-substituted BODIPY fluorescent conjugate and fluorine 18-labeled 7α-pentylestradiol analog

Article abstract of DOI:10.1016/0039-128X(93)90063-S

In an effort to assist in the preparation of ligands for the study of the estrogen receptor (ER), we have developed a new synthesis of 7α-substituted estradiols.The key step in the synthesis involves a copper-catalyzed, α-selective, 1,6-conjugate addition of 4-pentenyl magnesium bromide to a suitably protected 6-dehydrotestosterone derivative.Desaturation and then reductive aromatization of the resulting 7α-pentenyl androgen gave the 7α-pentenylestradiol in good yields.The α-stereoselectivity of this addition in the testosterone series, compared with the 19-nortestosterone series, is significantly improved by the presense of the C-19 methyl group, which shields the beta face from attack.A key intermediate was functionalized further by substitution with fluorine-18 to provide a potential imaging agent for positron emission tomography, and by conjugation with a BODIPY (Molecular Probes Inc., Eugene, OR, USA fluorophore to make a fluorescent probe for the estrogen receptor.The synthesis and biological evaluation of these analogs is presented, as well as a discussion of the improvements in the synthetic procedure.Keywords: steroids; estrogen receptor; fluorescence; breast tumor imaging; fluorine-18; 7α-substituted estrogen