Reactivity and Antiproliferative Activity of Ferrocenyl-Tamoxifen Adducts with Cyclodextrins against Hormone-Independent Breast-Cancer Cell Lines
Reactivity and Antiproliferative Activity of Ferrocenyl-Tamoxifen Adducts with Cyclodextrins against Hormone-Independent Breast-Cancer Cell Lines
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DOI：
10.1002/chem.200800507
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发表时间：
2008-01-01
影响因子：
4.3
通讯作者：
Amatore, Christian
中科院分区：
文献类型：
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作者：
Buriez, Olivier;Heldt, Jan Martin;Amatore, Christian
羟基二茂铁类化合物是一类新的和有前途的二茂铁类乳腺癌候选药物。它们具有内分泌调节特性和细胞毒性活性，分别来自他莫昔芬骨架和二茂铁部分的存在。然而，它们在水中的溶解度降低，这对其最终的治疗用途提出了问题。在此，我们研究了羟基二茂铁化合物与环糊精（CD）的相互作用，以评估它们的电子转移氧化途径是否受到其包含的影响。已经证明这些包合物可溶于纯水，这表明CD可以用于递送这些生物活性分子。因此，一系列的这些化合物已被研究的循环伏安法在各种介质中的CD（β-CD和Me-β-CD）的存在下。在甲醇中，羟基二茂铁化合物表现出弱的相互作用与CD腔。这些相互作用随着添加的水的量增加而变得更强。如果CD被部分甲基化，则发现羟基二茂铁醚化合物与β-CD之间的络合作用更强，这可能是由于双环和/或芳环与甲氧基之间的疏水作用。此外，似乎羟基二茂铁化合物的结构影响它们的溶解度和它们的络合动力学。在吡啶存在下的调查表明，碱动力学有利于在电子转移步骤期间的二茂铁-CD复合物的解离，但不影响后续的反应性的电生成的二茂铁阳离子，这最终导致相应的醌甲基化物，如在CD的情况下报告的。因此，这些β-CD包封的有机金属配合物在非依赖于环糊精的乳腺癌细胞（MDA-MB 231）中的细胞毒性被证实与在不存在环糊精的情况下获得的细胞毒性相似。
Hydroxyferrocifen compounds are a new and promising class of ferrocifen-type breast-cancer drug candidates. They possess both endocrine-modulating properties and cytotoxic activity, which come from the tamoxifen skeleton and the presence of a ferrocene moiety, respectively. However, they suffer from reduced solubility in water, which presents a problem for their eventual therapeutic use. Herein, we examined the interactions of hydroxyferrocifen compounds with cyclodextrins (CDs) to evaluate whether or not their electron-transfer oxidation pathways were affected by their inclusion. It has been demonstrated that these inclusion complexes are soluble in pure water, which shows that CDs can be used to deliver these biologically active molecules. Therefore, a series of these compounds has been investigated by cyclic voltametry in various media in the presence of CDs (P-CD and Me-beta-CD). In methanol, the hydroxyferrocifen compounds exhibited a weak interaction with the CD cavity. These interactions became stronger as the amount of added water increased. The complexation effect between the hydroxyferrocifen compounds and beta-CD was found to be stronger if the CD was partially methylated, which is probably due to hydrophobic effects between the cyclopentadienyl ring and/or the aromatic rings and the methoxy groups. Moreover, it appears that the structure of the hydroxyferrocifen compounds affects both their solubility and their complexation dynamics. Investigations in the presence of pyridine show that the base kinetically favors the dissociation of the ferrocifen-CD complex during the electron transfer step, but does not affect the follow-up reactivity of the electrogenerated ferrocenium cation, which leads eventually to the corresponding quinone methide, as reported in the absence of CD. Accordingly, the cytotoxicity of these beta-CD-encapsulated organometallic complexes in hormone-independent breast-cancer cells (MDA-MB231) were confirmed to be similar to those obtained in the absence of cyclodextrin.