title: Synthesis, characterization and biological evaluation of 7 alpha-perfluoroalkylestradiol derivatives.
abstract: Linkage of a long CH(2 )side chain ('spacer') onto C-7 alpha of estradiol-17 beta (E(2)) does not abrogate the binding affinity of this hormone for its receptor. Our purpose was to assess whether the linkage of a CF(2 )side chain, which is more bulky and rigid, could also be accommodated by the estrogen receptor (ER). We describe here the synthesis of 7 alpha-perfluorohexylestradiol 7 by perfluoroalkylation of a key silylenolether 2 with FITS-6 (perfluorohexyl-phenyliodoniurn trifluoromethanesulfonate). 7 alpha-Trifluoromethylestradiol 10a was prepared as a fluorinated control compound by UV-light induced trifluoromethylation of 2 with Umemoto reagent (S-trifluoromethyldibenzo[b,d]thiophenium trifluoromethanesulfonate). Endocrine properties of these two E(2 )derivatives were tested on the MCF-7 breast cancer cell line. Our data reveal that rigidity of the side chain of 7 affected the association of its hormone moiety with the ER to the same extent as a long alkyl side chain. Rigidity also failed to abrogate estrogenicity, as demonstrated by the ability of 7 to enhance ERE-dependent transcription and cell growth. Compound retained the capacity of inducing down regulation of the receptor. Interestingly, no evidence of antiestrogenicity was recorded since this compound behaved like a weak estrogen, exerting a mitogenic effect at high concentration. Of note, control 10a displayed a higher binding affinity than 7 for ER and consequently acted like the latter, albeit with a higher efficiency. Selection of appropriate residues to be linked at the end of a long 7 alpha alkyl side chain is known to be essential for generating strong antiestrogenicity. One may hope that such a property may also hold for perfluorinated chains to produce antiestrogens with strong metabolic stability.
authors.affiliation: SIRCOB, ESA CNRS 8086, Université de Versailles, 45 Avenue des Etats-Unis, 78035 Versailles, France. jcblaz@chimie.uvsq.fr
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Blazejewski
authors.forename: Martin P
authors.initials: MP
authors.lastname: Wilmshurst
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Popkin
authors.forename: Claude
authors.initials: C
authors.lastname: Wakselman
authors.forename: Guy
authors.initials: G
authors.lastname: Laurent
authors.forename: Denis
authors.initials: D
authors.lastname: Nonclercq
authors.forename: Anny
authors.initials: A
authors.lastname: Cleeren
authors.forename: Yan
authors.initials: Y
authors.lastname: Ma
authors.forename: Hye-Sook
authors.initials: HS
authors.lastname: Seo
authors.forename: Guy
authors.initials: G
authors.lastname: Leclercq
mesh_terms: D000478:Alkylation; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001943:Breast Neoplasms / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D004958:Estradiol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000737:chemistry / Q000494:pharmacology; D005455:Fluorescent Antibody Technique / Q000379:methods; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011960:Receptors, Estrogen / Q000378:metabolism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D004965:Estrogen Antagonists; D006845:Hydrocarbons, Fluorinated; D011960:Receptors, Estrogen; D004958:Estradiol