Synthesis and biological assessment of a ruthenium(II) cyclopentadienyl complex in breast cancer cells and on the development of zebrafish embryos
Synthesis and biological assessment of a ruthenium(II) cyclopentadienyl complex in breast cancer cells and on the development of zebrafish embryos
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DOI：
10.1016/j.ejmech.2019.112030
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发表时间：
2020-02-15
影响因子：
6.7
通讯作者：
Castonguay, Annie
中科院分区：
文献类型：
--
作者：
Golbaghi, Golara;Pitard, Irene;Castonguay, Annie
钌基配合物目前吸引了极大的关注，因为它们有望取代铂基药物作为一线癌症治疗。尽管钌芳烃络合物是研究最多的物种，因为它们具有潜在的抗癌特性，但其他类型的钌络合物却被忽略了。在这里，我们报告的合成和表征的Ru（II）的钌（Cp），Ru（II）的cyclooctodienyl（COD）和Ru（III）的配合物轴承阿那曲唑或来曲唑配体，第三代芳香酶抑制剂目前用于治疗雌激素受体阳性（ER +）乳腺癌。在这些配合物中，Ru（II）Cp 2是唯一一个在DMSO和细胞培养基中显示出高稳定性的配合物，因此，唯一的配合物，在体外和体内的生物活性进行了研究。与单独的阿那曲唑不同，复合物2在人ER +乳腺癌（T47 D和MCF 7）、三阴性乳腺癌（TNBC）（MBA-MB-231）和肾上腺皮质癌（H295 R）细胞中具有相当大的体外细胞毒性（IC 50值< 1 μ M）。理论（对接模拟）和实验（芳香酶催化活性）的研究表明，2和芳香酶之间的相互作用是不可能发生的，并且PPh 3配体的体积可能是一个重要的因素，防止复杂的到达活性位点的酶。将斑马鱼胚胎暴露于浓度在其体外细胞毒性IC 50值（0.1-1 μ M）附近的复合物2在96小时内没有导致明显的毒性迹象，使其成为进一步体内研究的合适候选物。这项研究证实了Ru（II）Cp络合物用于乳腺癌治疗的潜力，更具体地说，对通常不响应目前使用的化疗药物的TNBC。(C)2020 Elsevier Masson SAS。All rights reserved.
Ruthenium-based complexes currently attract great attention as they hold promise to replace platinum-based drugs as a first line cancer treatment. Whereas ruthenium arene complexes are some of the most studied species for their potential anticancer properties, other types of ruthenium complexes have been overlooked for this purpose. Here, we report the synthesis and characterization of Ru(II) cyclopentadienyl (Cp), Ru(II) cyclooctadienyl (COD) and Ru(III) complexes bearing anastrozole or letrozole ligands, third-generation aromatase inhibitors currently used for the treatment of estrogen receptor positive (ER +) breast cancer. Among these complexes, Ru(II)Cp 2 was the only one that displayed a high stability in DMSO and in cell culture media and consequently, the only complex for which the in vitro and in vivo biological activities were investigated. Unlike anastrozole alone, complex 2 was considerably cytotoxic in vitro (IC50 values < 1 mu M) in human ER + breast cancer (T47D and MCF7), triple negative breast cancer (TNBC) (MBA-MB-231), and in adrenocortical carcinoma (H295R) cells. Theoretical (docking simulation) and experimental (aromatase catalytic activity) studies suggested that an interaction between 2 and the aromatase enzyme was not likely to occur and that the bulkiness of the PPh3 ligands could be an important factor preventing the complex to reach the active site of the enzyme. Exposure of zebrafish embryos to complex 2 at concentrations around its in vitro cytotoxicity IC50 value (0.1-1 mu M) did not lead to noticeable signs of toxicity over 96 h, making it a suitable candidate for further in vivo investigations. This study confirms the potential of Ru(II)Cp complexes for breast cancer therapy, more specifically against TNBCs that are usually not responsive to currently used chemotherapeutic agents. (C) 2020 Elsevier Masson SAS. All rights reserved.