Synthesis, characterization and biological evaluation of 7α-perfluoroalkylestradiol derivatives
Synthesis, characterization and biological evaluation of 7α-perfluoroalkylestradiol derivatives
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DOI：
10.1016/s0968-0896(02)00457-1
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发表时间：
2003-02-06
影响因子：
3.5
通讯作者：
Leclercq, G
中科院分区：
文献类型：
--
作者：
Blazejewski, JC;Wilmshurst, MP;Leclercq, G
将长CH 2侧链（“间隔区”）连接到雌二醇-17 β（E-2）的C-7 α上不会消除该激素对其受体的结合亲和力。我们的目的是评估是否连接的CF2，侧链，这是更庞大和刚性，也可以容纳的雌激素受体（ER）。我们在此描述了通过用FITS-6（全氟己基-苯基碘鎓三氟甲磺酸盐）对关键的硅烯基醇醚2进行全氟烷基化来合成7 α-全氟己基亚乙基醚7。通过用Umemoto试剂（S-三氟甲基二苯并[B，d]噻吩鎓三氟甲磺酸盐）对2进行UV-光诱导的三氟甲基化，制备7 α-三氟甲基乙炔10a作为氟化对照化合物。在MCF-7乳腺癌细胞系上测试这两种E2衍生物的内分泌性质。我们的数据表明，刚性的侧链7影响其激素部分与ER的关联到相同的程度作为一个长的烷基侧链。刚性也未能废除雌激素，如7的能力，以提高ERE依赖的转录和细胞生长所证明的。化合物7保留了诱导受体下调的能力。有趣的是，没有记录到抗雌激素活性的证据，因为该化合物表现得像弱雌激素，在高浓度下发挥促有丝分裂作用。值得注意的是，对照10a对ER显示出比7更高的结合亲和力，因此表现得像后者，尽管效率更高。选择合适的残基连接在长的7 α-烷基侧链的末端是产生强抗雌激素活性的关键。人们可能希望这种性质也适用于全氟链，以产生具有强代谢稳定性的抗雌激素。(C)2002爱思唯尔科技有限公司。保留所有权利。
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.