Hillard Elizabeth, Vessières Anne, Le Bideau Franck, Plazuk Damian, Spera Daniela, Huché Michel, 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.
ChemMedChem. 2006 May;1(5):551-9. doi: 10.1002/cmdc.200500035.
We recently reported that a ferrocenyl diphenol butene derivative showed a very strong cytotoxic effect on both hormone-dependent and -independent breast cancer cell lines. In order to obtain more information about the structure-activity relationship in the cytotoxicity of small ferrocene compounds, we have prepared a series of simple unconjugated ferrocenyl diphenol complexes (ortho,para; meta,para; para,para). These compounds retain a reasonable to good affinity for both estrogen receptor types, with higher values for the beta form, and superior binding for the para,para diphenol complex (RBA=28%). In vitro these complexes exhibit significant cytotoxic effects on hormone-independent prostate (PC3) and breast cancer cell lines (MDA-MB231), with IC50 values between 2.5 and 4.1 microM. This effect is more marked with PC3, the ortho,para diphenol complex proving the most effective. On the hormone-dependent MCF7 breast cancer cell line, the observed effect seems to be the result of two components, one cytotoxic (antiproliferative), the other estrogenic (proliferative). Electrochemical studies show that the cytotoxic effect of the complexes correlates with the ease of oxidation of the ferrocene group. All these complexes are much less cytotoxic than the ferrocenyl diphenol butene derivative.
我们最近报道，一种二茂铁基二酚丁烯衍生物对激素依赖性和非激素依赖性乳腺癌细胞系均显示出非常强的细胞毒性作用。为了获取更多关于二茂铁小分子化合物细胞毒性构效关系的信息，我们制备了一系列简单的非共轭二茂铁基二酚配合物（邻位，对位；间位，对位；对位，对位）。这些化合物对两种雌激素受体类型均保持合理至良好的亲和力，对β型受体的亲和力更高，且对位，对位二酚配合物具有更强的结合能力（相对结合活性=28%）。在体外，这些配合物对非激素依赖性前列腺癌细胞系（PC3）和乳腺癌细胞系（MDA-MB231）表现出显著的细胞毒性作用，半数抑制浓度（IC50）值在2.5至4.1微摩尔之间。这种作用在PC3细胞系中更为明显，邻位，对位二酚配合物被证明是最有效的。在激素依赖性MCF7乳腺癌细胞系中，观察到的作用似乎是由两个成分导致的，一个是细胞毒性（抗增殖），另一个是雌激素样（增殖）。电化学研究表明，配合物的细胞毒性作用与二茂铁基团氧化的难易程度相关。所有这些配合物的细胞毒性均远低于二茂铁基二酚丁烯衍生物。
