State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, Ministry of Science and Technology of China, Guangxi Normal University, Guilin, Guangxi, China.
State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, Ministry of Science and Technology of China, Guangxi Normal University, Guilin, Guangxi, China.
J Inorg Biochem. 2018 Aug;185:10-16. doi: 10.1016/j.jinorgbio.2018.04.017. Epub 2018 Apr 25.
We synthesized and validated five Schiff base Pt(II) complexes derived from 2-hydroxy-1-naphthaldehyde benzoyl hydrazone and its derivatives, which are modified at the benzohydrazide structures (L1-L5). The complexes were [Pt(L1)(DMSO)Cl] (C1), [Pt(L2)(DMSO)Cl] (C2), [Pt(L3)(DMSO)Cl] (C3), [Pt(L4)(DMSO)Cl] (C4), and [Pt(L5)(DMSO)Cl] (C5). Crystal structures showed that the Pt centers of all complexes were tetra-coordinated with other atoms. The structure-activity relationships and anticancer mechanisms of the complexes were explored. These five Pt(II) complexes were toxic at micromolar doses and exhibited cytotoxicity similar to or somewhat higher than that of cisplatin, with IC values ranging from 4.38 μM to 25.16 μM. The complexes exerted chemotherapeutic effects via inhibition of telomerase by targeting the c-myc promoter and down-regulating the expression of human telomerase reverse transcriptase, consequently triggering cell apoptosis. In addition, Pt(II) complexes also caused cell cycle arrest at S-phase, leading to the down-regulation of cdc25 A, cyclin A2, and CDK2 and up-regulation of p53, p27, and p21 proteins. Other complex-associated events were reactive oxygen species production, transformation of the mitochondrial membrane potential (Δψ), release of cytochrome c, regulation of Bcl-2 family protein expression, facilitated release of apoptotic active substances, and activation of caspases to induce apoptosis.
我们合成并验证了五个源于 2-羟基-1-萘甲醛苯甲酰腙及其衍生物的席夫碱 Pt(II) 配合物，这些配合物在苯甲酰肼结构上进行了修饰（L1-L5）。这些配合物是[Pt(L1)(DMSO)Cl]（C1）、[Pt(L2)(DMSO)Cl]（C2）、[Pt(L3)(DMSO)Cl]（C3）、[Pt(L4)(DMSO)Cl]（C4）和[Pt(L5)(DMSO)Cl]（C5）。晶体结构表明，所有配合物的 Pt 中心均为四配位，与其他原子配位。研究了配合物的结构-活性关系和抗癌机制。这五个 Pt(II) 配合物在微摩尔剂量下具有毒性，并表现出与顺铂相似或略高的细胞毒性，IC 值范围为 4.38 μM 至 25.16 μM。这些配合物通过靶向 c-myc 启动子抑制端粒酶并下调人端粒酶逆转录酶的表达，从而触发细胞凋亡，发挥化疗作用。此外，Pt(II) 配合物还导致细胞周期在 S 期停滞，导致 cdc25A、细胞周期蛋白 A2 和 CDK2 的下调以及 p53、p27 和 p21 蛋白的上调。其他与复合物相关的事件包括活性氧物质的产生、线粒体膜电位（Δψ）的转化、细胞色素 c 的释放、Bcl-2 家族蛋白表达的调节、促进凋亡活性物质的释放以及 caspase 的激活，从而诱导细胞凋亡。
