Faculty of Chemistry, University of Belgrade, Studentski trg 12-16, 11000 Belgrade, Serbia.
ChemMedChem. 2010 Jun 7;5(6):881-9. doi: 10.1002/cmdc.201000058.
The present study describes the synthesis and anticancer activity of novel octahedral Pt(IV) complexes with cyclohexyl functionalized ethylenediamine-N,N'-diacetate-type ligands. Molecular mechanics calculations and density functional theory analysis revealed that s-cis is the preferred geometry of these Pt(IV) complexes with tetradentate-coordinated (S,S)-ethylenediamine-N,N'-di-2-(3-cyclohexyl)propanoate. The viability of cancer cell lines (U251 human glioma, C6 rat glioma, L929 mouse fibrosarcoma, and B16 human melanoma) was assessed by measuring mitochondrial dehydrogenase activity and lactate dehydrogenase release. Cell-cycle distribution, oxidative stress, caspase activation, and induction of autophagy were analyzed by flow cytometry using appropriate fluorescent reporter dyes. The cytotoxic activity of novel Pt(IV) complexes against various cancer cell lines (IC(50) range: 1.9-8.7 microM) was higher than that of cisplatin (IC(50) range: 10.9-67.0 microM) and proceeded through completely different mechanisms. Cisplatin induced caspase-dependent apoptosis associated with the cytoprotective autophagic response. In contrast, the new Pt(IV) complexes caused rapid, caspase-independent, oxidative stress-mediated non-apoptotic cell death characterized by massive cytoplasmic vacuolization, cell membrane damage, and the absence of protective autophagy.
本研究描述了新型八面体铂（IV）配合物的合成及其抗癌活性，这些配合物具有环己基功能化的乙二胺-N,N'-二乙酸型配体。分子力学计算和密度泛函理论分析表明，这些具有四配位（S,S）-乙二胺-N,N'-二-2-（3-环己基）丙二酸的铂（IV）配合物优先采用 s-cis 几何构型。通过测量线粒体脱氢酶活性和乳酸脱氢酶释放来评估癌细胞系（U251 人神经胶质瘤、C6 大鼠神经胶质瘤、L929 小鼠纤维肉瘤和 B16 人黑色素瘤）的活力。通过使用适当的荧光报告染料，通过流式细胞术分析细胞周期分布、氧化应激、半胱天冬酶激活和自噬诱导。新型铂（IV）配合物对各种癌细胞系的细胞毒性活性（IC50 范围：1.9-8.7 microM）高于顺铂（IC50 范围：10.9-67.0 microM），并且通过完全不同的机制进行。顺铂诱导与细胞保护自噬反应相关的半胱天冬酶依赖性细胞凋亡。相比之下，新的铂（IV）配合物引起快速的、半胱天冬酶非依赖性的、氧化应激介导的非凋亡性细胞死亡，其特征是大量细胞质空泡化、细胞膜损伤和缺乏保护性自噬。
