Estrogen-derived steroidal metal complexes: Agents for cellular delivery of metal centers to estrogen receptor-positive cells
Estrogen-derived steroidal metal complexes: Agents for cellular delivery of metal centers to estrogen receptor-positive cells
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DOI：
10.1021/ic010152a
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发表时间：
2001-07-30
影响因子：
4.6
通讯作者：
Hannon, MJ
中科院分区：
文献类型：
--
作者：
Jackson, A;Davis, J;Hannon, MJ
将药物靶向细胞递送至特定组织是生物医学化学的一个重要目标。实现这一目标需要利用和应用所需组织类型中普遍存在（或特定于）的分子水平识别事件。富含雌激素受体（ER）的组织（包括多种类型的乳腺癌）会积累与这些受体具有高结合亲和力的分子。因此，(i) 与 ER 结合、(ii) 具有良好的细胞转运特性、(iii) 包含第二种功能（例如可用于诊断成像或医学治疗的中心）的分子是药物递送领域令人兴奋的合成靶标。为此，我们制备了一系列基于 17α-乙炔雌二醇的金属雌激素，并检查了它们作为分离受体和全细胞测定（ER 阳性 MCF-7 细胞）与 ER 的结合。用金属结合单元功能化的雌激素是通过钯催化的交叉偶联反应制备的，并且很容易引入多种金属中心。所有制备和测试的化合物均表现出与雌激素受体的有效结合，并穿过细胞膜递送至 MCF-7 细胞中。在全细胞测定中，尽管具有单阳离子性质，但制备的钯和铂络合物与其相应的中性游离配体相比表现出相似（甚至增强）的受体结合亲和力。与不含金属的配体相比，阳离子复合物具有更高的 ER 结合亲和力，这是前所未有的。
Targeted cellular delivery of drugs to specific tissues is an important goal in biomedical chemistry. Achieving this requires harnessing and applying molecular-level recognition events prevalent in (or specific to) the desired tissue type. Tissues rich in estrogen receptors (ERs), which include many types of breast cancer, accumulate molecules that have high binding affinities for these receptors. Therefore, molecules that (i) bind to the ER, (ii) have favorable cellular transport properties, and (iii) contain a second functionality (such as a center that may be used for diagnostic imaging or medical therapy) are exciting synthetic targets in the field of drug delivery. To this end, we have prepared a range of metallo-estrogens based on 17 alpha -ethynylestradiol and examined their binding to the ER both as isolated receptor and in whole cell assays (ER positive MCF-7 cells). Estrogens functionalized with metal binding units are prepared by palladium-catalyzed cross-coupling reactions and a wide range of metal centers introduced readily. All the compounds prepared and tested exhibit effective binding to the estrogen receptor and are delivered across the cell membrane into MCF-7 cells. In the whole cell assays, despite their monocationic nature, the palladium and platinum complexes prepared exhibit similar (and even enhanced) receptor binding affinities compared to their corresponding neutral free ligands. It is unprecedented for a higher ER binding affinity to be observed for a cationic complex than for its metal-free ligand.