School of Chemistry, National University of Ireland, Galway H91 TK33, Ireland.
Anatomy, School of Medicine, National University of Ireland, Galway H91 TK33, Ireland.
Mol Pharm. 2020 Aug 3;17(8):3009-3023. doi: 10.1021/acs.molpharmaceut.0c00417. Epub 2020 Jul 15.
The design, synthesis, characterization, and biological activity of a series of platinum(IV) prodrugs containing the axial ligand 3-(4-phenylquinazoline-2-carboxamido)propanoate () are reported. is a derivative of the quinazolinecarboxamide class of ligands that binds to the translocator protein (TSPO) at the outer mitochondrial membrane. The cytotoxicities of ,,-[Pt(NH)Cl()(OH)] (), ,,-[Pt(NH)Cl()(BZ)] (), -[Pt(DACH)(OX)()(OH)] (), and -[Pt(DACH)(OX)()(BZ)] () (DACH: ,-diaminocyclohexane, BZ: benzoate, OX: oxalate) in MCF-7 breast cancer and noncancerous MCF-10A epithelial cells were assessed and compared with those of cisplatin, oxaliplatin, and the free ligand . Moreover, the cellular uptake, ROS generation, DNA damage, and the effect on the mitochondrial function, mitochondrial membrane potential, and morphology were investigated. Molecular interactions of in the TSPO binding site were studied using molecular docking. The results showed that complex is the most effective Pt(IV) complex and exerts a multimodal mechanism involving DNA damage, potent ROS production, loss of the mitochondrial membrane potential, and mitochondrial damage.
报告了一系列含有轴向配体 3-(4-苯基喹唑啉-2-甲酰胺基)丙酸盐 ()的铂(IV)前药的设计、合成、表征和生物活性。 是喹唑啉甲酰胺类配体的衍生物，与外膜上的转位蛋白 (TSPO) 结合。评估了 MCF-7 乳腺癌和非癌性 MCF-10A 上皮细胞中 、 、 、 和 ()(DACH： ，-二氨基环己烷，BZ：苯甲酸盐，OX：草酸盐)在 MCF-7 乳腺癌和非癌性 MCF-10A 上皮细胞中的细胞毒性，并与顺铂、奥沙利铂和游离配体进行了比较。此外，还研究了细胞摄取、ROS 生成、DNA 损伤以及对线粒体功能、线粒体膜电位和形态的影响。使用分子对接研究了 在 TSPO 结合位点的分子相互作用。结果表明，配合物 是最有效的铂(IV)配合物，它通过多种方式发挥作用，包括 DNA 损伤、产生大量 ROS、线粒体膜电位丧失和线粒体损伤。
