A synthesis of 7 alpha-substituted estradiols: synthesis and biological evaluation of a 7 alpha-pentyl-substituted BODIPY fluorescent conjugate and a fluorine-18-labeled 7 alpha-pentylestradiol analog.
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 7 alpha-substituted estradiols. The key step in the synthesis involves a copper-catalyzed, alpha-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 7 alpha-pentenyl androgen gave the 7 alpha-pentenylestradiol in good yields. The alpha-stereoselectivity of this addition in the testosterone series, compared with the 19-nortestosterone series, is significantly improved by the presence 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.
French
A N
AN
Department of Chemistry, University of Illinois, Urbana 61801.
Wilson
S R
SR
Welch
M J
MJ
Katzenellenbogen
J A
JA
D001896:Boron Compounds / Q000138:chemical synthesis*; D001965:Bromides; D003300:Copper; D003460:Crystallization; D004958:Estradiol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics; D005456:Fluorescent Dyes; D005462:Fluorine Radioisotopes; D008274:Magnesium; D013050:Spectrometry, Fluorescence; D014018:Tissue Distribution; D014961:X-Ray Diffraction
D001896:Boron Compounds; D001965:Bromides; D005456:Fluorescent Dyes; D005462:Fluorine Radioisotopes; C081187:7-(5-fluoropentyl)estradiol; C081186:7-(5-(4,4-difluoro-5,7-dimethyl-4-bora-3,4-diaza-3-indacenepropionyl)aminopentyl)estradiol; D004958:Estradiol; D003300:Copper; D008274:Magnesium