Centro de Química Estrutural, Departamento de Química, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais 1, 1049-001, Lisbon, Portugal.
TUBITAK, Marmara Research Center, Genetic Engineering and Biotechnology Institute, Gebze/Kocaeli, Turkey.
Dalton Trans. 2019 Jun 28;48(24):8702-8716. doi: 10.1039/c9dt01193e. Epub 2019 May 24.
In the quest for therapeutic iron-based metallodrugs, two new mixed-ligand iron(iii) complexes bearing the tripodal aminobisphenolate ligand N,N-bis(3,5-dimethyl-2-hydroxybenzyl)-N-(2-pyridylmethyl)amine (HL) and hydroxyquinoline co-ligands, 8-hydroxyquinoline (8HQ) or 5-chloro-8-hydroxyquinoline (Cl8HQ), are synthesized, fully characterized and formulated as [Fe(L)(8HQ)] (1) and [Fe(L)(Cl8HQ)] (2), respectively. These high-spin Fe(iii) complexes are stable in aqueous solution in the presence of equimolar amounts of Bovine Serum Albumin (BSA), which indicates a likely binding interaction with the protein. In fact, binding constant log values at pH 7.4 for HSA of 5.08 and 6.35 were obtained for 1 and 2, respectively. Compounds 1 and 2 are cytotoxic against both human triple-negative breast adenocarcinoma (MDA-MB-231) and human cervical carcinoma (HeLa) cancer cells, and the activity is significantly improved by inclusion of the co-ligands 8HQ and Cl8HQ to the precursor complex Fe(L). Moreover, 1 and 2 are more active than 8HQ and Cl8HQ, particularly at lower incubation times tested, 24 and 48 h. Cells treated with the complexes display typical features of apoptosis as assessed by cellular morphology, DNA condensation and TUNEL analysis. COMET assays show that both drug candidates induce genomic damage in both cell lines. The complexes exhibit DNA cleavage activity and DNA damage that may be related to their ability to generate ROS. Overall, data supports that 1 and 2 are both active anticancer drug candidates within the low micromolar range. This is particularly interesting in the case of the breast MDA-MB-231 line, a model for triple-negative breast cancer that is an aggressive form of breast cancer, highly invasive and with limited treatment options and very poor prognosis. Furthermore, both complexes exhibited good anti-Mycobacterium tuberculosis activity, suggesting that 1 and 2 might have a wide spectrum of biological activity and justify further research.
在寻求治疗性铁基金属药物的过程中，合成了两种新的混合配体铁（III）配合物，它们带有三脚架氨基双苯并醇配体 N，N-双（3，5-二甲基-2-羟基苄基）-N-（2-吡啶基甲基）胺（HL）和羟基喹啉共配体 8-羟基喹啉（8HQ）或 5-氯-8-羟基喹啉（Cl8HQ），分别表示为[Fe（L）（8HQ）]（1）和[Fe（L）（Cl8HQ）]（2）。这些高自旋 Fe（III）配合物在存在等摩尔量牛血清白蛋白（BSA）的水溶液中稳定，这表明与蛋白质可能存在结合相互作用。实际上，在 pH 7.4 时，HSA 的结合常数 log 值分别为 5.08 和 6.35，对于 1 和 2。化合物 1 和 2对人三阴性乳腺癌（MDA-MB-231）和人宫颈癌（HeLa）癌细胞均具有细胞毒性，并且通过将 8HQ 和 Cl8HQ 掺入前体配合物 Fe（L），活性得到显著提高。此外，1 和 2 比 8HQ 和 Cl8HQ 更具活性，尤其是在测试的较低孵育时间 24 和 48 h 时。通过细胞形态，DNA 浓缩和 TUNEL 分析评估，用复合物处理的细胞显示出典型的细胞凋亡特征。COMET 测定表明，两种候选药物均在两种细胞系中诱导基因组损伤。该配合物具有 DNA 切割活性和 DNA 损伤，这可能与其生成 ROS 的能力有关。总体而言，数据表明 1 和 2 均为具有低微摩尔范围的活性抗癌候选药物。对于乳腺癌 MDA-MB-231 系，这是一种三阴性乳腺癌的模型，是一种侵袭性很强的乳腺癌，侵袭性很强，治疗选择有限，预后非常差，这一点尤其有趣。此外，两种配合物均表现出良好的抗结核分枝杆菌活性，这表明 1 和 2 可能具有广泛的生物学活性，值得进一步研究。
