Evaluation of Efficiency of Liposome-Entrapped Iridium(III) Complexes Inhibiting Tumor Growth In Vitro and In Vivo

IF 6.8 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry Pub Date : 2024-09-12 DOI:10.1021/acs.jmedchem.4c01026

Huiyan Hu, Jing Chen, Fan Zhang, Zhujun Sheng, Yan Yang, Yufeng Xie, Lin Zhou, Yunjun Liu

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Abstract

In this paper, three new iridium(III) complexes: [Ir(piq)₂(DFIPP)]PF₆ (piq = deprotonated 1-phenylisoquinoline, DFIPP = 3,4-difluoro-2-(1H-imidazo[4,5-f][1,10]phenenthrolin-2-yl)phenol, 3a), [Ir(bzq)₂(DFIPP)]PF₆ (bzq = deprotonated benzo[h]quinoline, 3b), and [Ir(ppy)₂(DFIPP)]PF₆ (ppy = deprotonated 1-phenylpyridine, 3c), were synthesized and characterized. The complexes were found to be nontoxic to tumor cells via 3-(4,5-dimethylthiazole-2-yl)-diphenyltetrazolium bromide (MTT) assay. Surprisingly, its liposome-entrapped complexes 3alip, 3blip, and 3clip on B16 cells showed strong cytotoxicity (IC₅₀ = 13.6 ± 2.8, 9.6 ± 1.1, and 18.9 ± 2.1 μM). Entry of 3alip, 3blip, and 3clip into B16 cells decreases mitochondrial membrane potential, regulates Bcl-2 family proteins, releases cytochrome c, triggers caspase family cascade reaction, and induces apoptosis. In addition, we also found that 3alip, 3blip, and 3clip triggered ferroptosis and autophagy. In vivo studies demonstrated that 3blip inhibited melanoma growth in C57 mice with a high inhibitory rate of 83.95%, and no organic damage was found in C57 mice.

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评价脂质体包裹的铱(III)复合物在体外和体内抑制肿瘤生长的效率

本文提出了三种新的铱(III)配合物：[Ir(piq)2(DFIPP)]PF6（piq = 去质子化的 1-苯基异喹啉，DFIPP = 3,4-二氟-2-(1H-咪唑并[4,5-f][1,10]苯乙烯-2-基)苯酚，3a）、合成并表征了[Ir(bzq)2(DFIPP)]PF6（bzq = 去质子化苯并[h]喹啉，3b）和[Ir(ppy)2(DFIPP)]PF6（ppy = 去质子化 1-苯基吡啶，3c）。通过 3-(4,5-二甲基噻唑-2-基)-二苯基溴化四氮唑（MTT）试验发现，这些复合物对肿瘤细胞无毒。令人惊讶的是，其脂质体包裹复合物 3alip、3blip 和 3clip 对 B16 细胞显示出很强的细胞毒性（IC50 = 13.6 ± 2.8、9.6 ± 1.1 和 18.9 ± 2.1 μM）。3alip、3blip 和 3clip 进入 B16 细胞后会降低线粒体膜电位，调节 Bcl-2 家族蛋白，释放细胞色素 c，引发 caspase 家族级联反应，诱导细胞凋亡。此外，我们还发现 3alip、3blip 和 3clip 能引发铁变态反应和自噬。体内研究表明，3blip能抑制C57小鼠黑色素瘤的生长，抑制率高达83.95%，且在C57小鼠体内未发现任何器质性损伤。

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来源期刊

Journal of Medicinal Chemistry 医学-医药化学

CiteScore

4.00

自引率

11.00%

发文量

804

审稿时长

1.9 months

期刊介绍： The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents. The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.

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