Synthesis, characterization and biological evaluation of 7α-perfluoroalkylestradiol derivatives

Linkage of a long CH2 side chain ('spacer') onto C-7alpha of estradiol-17beta (E-2) does not abrogate the binding affinity of this hormone for its receptor. Our purpose was to assess whether the linkage of a CF2, side chain, which is more bulky and rigid, could also be accommodated by the estrogen receptor (ER). We describe here the synthesis of 7alpha-perfluorohexylestradiol 7 by perfluoroalkylation of a key silylenolether 2 with FITS-6 (perfluorohexyl-phenyliodonium trifluoromethanesulfonate). 7alpha-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 E2 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 7 retained the capacity of inducing down regulation of the receptor. Interestingly, no evidence of antiestrogervicity 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 7alpha alkyl side chain is known to be essential for generating strong antiestrogervicity. One may hope that such a property may also hold for perfluorinated chains to produce antiestrogens with strong metabolic stability. (C) 2002 Elsevier Science Ltd. All rights reserved.