Wang Meng, Cao Guoxiu, Zhou Junjie, Cai Jinyuan, Ma Xianjie, Liu Zhikun, Huang Xiaochao, Wang Hengshan
State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences of Guangxi Normal University, Guilin 541004, China.
Jiangsu Key Laboratory of Regional Resource Exploitation and Medicinal Research, Huaiyin Institute of Technology, Huai'an 223003, China.
J Med Chem. 2023 Oct 12;66(19):13587-13606. doi: 10.1021/acs.jmedchem.3c00922. Epub 2023 Sep 27.
Developing multitarget platinum(IV) prodrugs is an important strategy to attenuate cisplatin (CDDP) resistance in tandem with reduced toxicity. Herein, six novel ligustrazine-derived chalcones-modified platinum(IV) complexes were synthesized and evaluated for their anti-proliferative activities. Among them, displayed higher cytotoxicity toward the tested cancer cell lines and lower cytotoxicity toward the human normal cells than CDDP or the combined group. Mechanistic studies revealed that efficiently induced DNA damage and initiated a mitochondria-dependent apoptosis pathway. Besides, significantly triggered ferroptosis by down-regulating expression levels of nuclear factor erythroid 2-related factor 2, glutathione peroxidase 4, and solute carrier family 7 member 11. Further, obtained superior in vivo anti-tumor efficiency than CDDP in CDDP-resistant pancreatic cancer xenograft models but showed no significant side effects. In summary, our study suggested that acts via a different anti-cancer mechanistic pathway than CDDP and may therefore encompass a novel practical strategy for cancer treatment.
开发多靶点铂（IV）前药是一种重要策略，可在降低毒性的同时减轻顺铂（CDDP）耐药性。在此，合成了六种新型川芎嗪衍生的查尔酮修饰的铂（IV）配合物，并评估了它们的抗增殖活性。其中，与CDDP或联合组相比，其对测试癌细胞系表现出更高的细胞毒性，对人正常细胞表现出更低的细胞毒性。机制研究表明，其能有效诱导DNA损伤并启动线粒体依赖性凋亡途径。此外，通过下调核因子红细胞2相关因子2、谷胱甘肽过氧化物酶4和溶质载体家族7成员11的表达水平，显著引发铁死亡。此外，在顺铂耐药的胰腺癌异种移植模型中，其体内抗肿瘤效率优于CDDP，但未显示出明显的副作用。总之，我们的研究表明，其通过与CDDP不同的抗癌机制途径发挥作用，因此可能为癌症治疗提供一种新的实用策略。
