Hillard Elizabeth Anne, Pigeon Pascal, Vessières Anne, Amatore Christian, Jaouen Gérard
Laboratoire de Chimie et Biochimie des Complexes Moléculaires, UMR CNRS 7576, Ecole Nationale Supérieure de Chimie de Paris, 11 rue Pierre et Marie Curie, 75231, Paris, Cedex 05, France.
Dalton Trans. 2007 Nov 21(43):5073-81. doi: 10.1039/b705030e. Epub 2007 Sep 28.
The ferrocenyl compound 2-ferrocenyl-1,1-bis(4-hydroxyphenyl)-but-1-ene (), is very cytotoxic against breast cancer cells (IC(50) = 0.44 microM against MDA-MB-231). We now report the synthesis of a new series of para- and meta- substituted mono- and di- ferrocenyl phenols [2-ferrocenyl-1-(3-hydroxyphenyl)-1-phenyl-but-1-ene (), 2-ferrocenyl-1-(3-hydroxyphenyl)-1-(4-hydroxyphenyl)-but-1-ene (), 1,2-di-ferrocenyl-1-(4-hydroxyphenyl)-but-1-ene (), and 1,2-di-ferrocenyl-1-(3-hydroxyphenyl)-but-1-ene ()] and their electrochemical and biochemical properties, especially in comparison to the previously reported "standard" compounds [2-ferrocenyl-1-(4-hydroxyphenyl)-1-phenyl-but-1-ene () and ()]. We also report the synthesis and characterization of the diphenyl analogue, 2-ferrocenyl-1,1-diphenyl-but-1-ene (). This structure-activity relationship study was motivated by our hypothesis that the cytotoxicity of is related to its ability to form a quinone methide structure after two in situ 1-electron oxidations, a process which requires the presence of at least one p-phenol. The mono-ferrocenyl compounds (including those previously reported) are reasonably well recognized by the oestrogen receptors alpha (RBAs = 0.9-9.6%) and beta (RBAs = 0.28-16.3%), although the bulkier di-ferrocenyl compounds show very little affinity. In vitro, the cytotoxic effects of the phenolic complexes are related to the positioning of the hydroxyl group (para- superior to meta-), and to the number of ferrocenyl groups (one superior to two), with IC(50) values against the MDA-MB-231 cell line ranging from 0.44-3.5 microM. On the hormone-dependent breast cancer cell line MCF-7, the observed effect seems to be the result of two components, one cytotoxic (antiproliferative) and one estrogenic (proliferative). Electrochemical studies show that only the compounds with a p-phenol engage in proton-coupled intramolecular electron transfer.
二茂铁基化合物2-二茂铁基-1,1-双（4-羟基苯基）-丁-1-烯（）对乳腺癌细胞具有很强的细胞毒性（对MDA-MB-231细胞的IC(50) = 0.44微摩尔）。我们现在报告一系列新的对位和间位取代的单二茂铁基和二二茂铁基苯酚的合成[2-二茂铁基-1-（3-羟基苯基）-1-苯基-丁-1-烯（）、2-二茂铁基-1-（3-羟基苯基）-1-（4-羟基苯基）-丁-1-烯（）、1,2-二二茂铁基-1-（4-羟基苯基）-丁-1-烯（）和1,2-二二茂铁基-1-（3-羟基苯基）-丁-1-烯（）]及其电化学和生化性质，特别是与先前报道的“标准”化合物[2-二茂铁基-1-（4-羟基苯基）-1-苯基-丁-1-烯（）和（）]进行比较。我们还报告了二苯基类似物2-二茂铁基-1,1-二苯基-丁-1-烯（）的合成与表征。这项构效关系研究是基于我们的假设，即的细胞毒性与其在两次原位单电子氧化后形成醌甲基化物结构的能力有关，这一过程需要至少一个对苯酚的存在。单二茂铁基化合物（包括先前报道的那些）能被雌激素受体α（相对结合亲和力 = 0.9 - 9.6%）和β（相对结合亲和力 = 0.28 - 16.3%）较好地识别，尽管体积更大的二二茂铁基化合物显示出很小的亲和力。在体外，酚类配合物的细胞毒性作用与羟基的位置（对位优于间位）以及二茂铁基的数量（一个优于两个）有关，对MDA-MB-231细胞系的IC(50)值范围为0.44 - 3.5微摩尔。在激素依赖性乳腺癌细胞系MCF-7上，观察到的效应似乎是两种成分的结果，一种是细胞毒性（抗增殖），一种是雌激素样（增殖）。电化学研究表明，只有具有对苯酚的化合物参与质子耦合的分子内电子转移。
