Agouridas Vangelis, Blazejewski Jean-Claude, Cleeren Anny, Laïos Ioanna, Leclercq Guy, Magnier Emmanuel
Institut Lavoisier de Versailles (ILV), UMR CNRS 8180, Université de Versailles, Versailles Cedex, France.
Steroids. 2008 Mar;73(3):320-7. doi: 10.1016/j.steroids.2007.11.002. Epub 2007 Nov 22.
The concern of this work was to try to delineate factors, inherent to fluorination, susceptible to influence estradiol binding to the estrogen receptor alpha (ERalpha). For this purpose, fluorinated chains were linked at 11beta position of the steroid (i.e., C(6)F(13), CH(2)CH(2)C(4)F(9), CH(2)CH(2)C(8)F(17)). Relative binding affinity (RBA) for ERalpha of these compounds and of other related fluorinated derivatives was compared to those of non-fluorinated analogs. Despite being relatively well accepted by the receptor, investigated compounds exhibited lower RBA values at 0 degrees C than their non-fluorinated counterparts. Nevertheless, heavily fluorinated chains were tolerated in so far as they are not too long (C-4) and insulated from the steroidal core by a two methylene spacer unit. Increase of the temperature of our binding assay (25 degrees C) failed to change the RBA values of two selected polyfluorohexyl derivatives while it drastically enhanced the value of the corresponding non-fluorinated analogs. Rigidity of the chain induced by fluorination as well as the oleophilic (fluorophobic) nature of the estradiol binding cavity of ERalpha is proposed to explain these properties.
本研究旨在试图阐明氟化过程中固有的、可能影响雌二醇与雌激素受体α（ERα）结合的因素。为此，将氟化链连接在甾体的11β位（即C(6)F(13)、CH(2)CH(2)C(4)F(9)、CH(2)CH(2)C(8)F(17)）。将这些化合物及其他相关氟化衍生物对ERα的相对结合亲和力（RBA）与非氟化类似物的RBA进行比较。尽管所研究的化合物相对容易被受体接受，但在0℃时，它们的RBA值低于其非氟化对应物。然而，只要氟化链不太长得（C-4）并且通过两个亚甲基间隔单元与甾体核心隔开，重氟化链就能被耐受。将我们结合试验的温度提高到25℃，未能改变两种选定的多氟己基衍生物的RBA值，而相应的非氟化类似物的RBA值则大幅提高。氟化引起的链刚性以及ERα雌二醇结合腔的亲油性（憎氟性）被认为可以解释这些特性。
