Key Laboratory of Computer-Aided Drug Design of Dongguan City, Guangdong Key Laboratory for Research and Development of Natural Drugs, School of Pharmacy, Guangdong Medical University, Dongguan, Guangdong 523808, P. R. China.
The Marine Biomedical Research Institute, Guangdong Medical University, Zhanjiang, Guangdong 524023, P. R. China.
Metallomics. 2024 Jan 5;16(1). doi: 10.1093/mtomcs/mfae002.
Currently, cisplatin resistance remains a primary clinical obstacle in the successful treatment of non-small cell lung cancer. Here, we designed, synthesized, and characterized two novel cyclometalated Ru(II) complexes, [Ru(bpy)2(1-Ph-7-OCH3-IQ)] (PF6) (bpy = 2,2'-bipyridine, IQ = isoquinoline, RuIQ7)and [Ru(bpy)2(1-Ph-6,7-(OCH3)2-IQ)] (PF6) (RuIQ8). As experimental controls, we prepared complex Ru(bpy)2(1-Ph-IQ) (RuIQ6) lacking a methoxy group in the main ligand. Significantly, complexes RuIQ6-8 displayed higher in vitro cytotoxicity when compared to ligands, precursor cis-[Ru(bpy)2Cl2], and clinical cisplatin. Mechanistic investigations revealed that RuIQ6-8 could inhibit cell proliferation by downregulating the phosphorylation levels of Akt and mTOR proteins, consequently affecting the rapid growth of human lung adenocarcinoma cisplatin-resistant cells A549/DDP. Moreover, the results from qRT-PCR demonstrated that these complexes could directly suppress the transcription of the NF-E2-related factor 2 gene, leading to the inhibition of downstream multidrug resistance-associated protein 1 expression and effectively overcoming cisplatin resistance. Furthermore, the relationship between the chemical structures of these three complexes and their anticancer activity, ability to induce cell apoptosis, and their efficacy in overcoming cisplatin resistance has been thoroughly examined and discussed. Notably, the toxicity test conducted on zebrafish embryos indicated that the three Ru-IQ complexes displayed favorable safety profiles. Consequently, the potential of these developed compounds as innovative therapeutic agents for the efficient and low-toxic treatment of NSCLC appears highly promising.
目前，顺铂耐药性仍然是非小细胞肺癌成功治疗的主要临床障碍。在这里，我们设计、合成并表征了两个新型的金属环配合物 Ru(II) 配合物，[Ru(bpy)2(1-Ph-7-OCH3-IQ)] (PF6) (bpy = 2,2'-bipyridine, IQ = isoquinoline, RuIQ7)和[Ru(bpy)2(1-Ph-6,7-(OCH3)2-IQ)] (PF6) (RuIQ8)。作为实验对照，我们制备了缺乏主配体中一个甲氧基的配合物Ru(bpy)2(1-Ph-IQ) (RuIQ6)。值得注意的是，与配体、前体顺式-[Ru(bpy)2Cl2]和临床顺铂相比，配合物 RuIQ6-8 表现出更高的体外细胞毒性。机制研究表明，RuIQ6-8 通过下调 Akt 和 mTOR 蛋白的磷酸化水平，从而影响人肺腺癌细胞 A549/DDP 的快速生长，抑制细胞增殖。此外，qRT-PCR 的结果表明，这些配合物可以直接抑制 NF-E2 相关因子 2 基因的转录，从而抑制下游多药耐药相关蛋白 1 的表达，有效地克服顺铂耐药性。此外，还深入研究和讨论了这三个配合物的化学结构与其抗癌活性、诱导细胞凋亡能力以及克服顺铂耐药性的能力之间的关系。值得注意的是，对斑马鱼胚胎的毒性试验表明，这三种 Ru-IQ 配合物具有良好的安全性。因此，这些开发的化合物作为治疗非小细胞肺癌的高效低毒治疗的新型治疗剂具有很高的应用前景。
