Developing an Arene Binuclear Ruthenium(II) Complex to Induce Ferroptosis and Activate the cGAS-STING Pathway: Targeted Inhibiting Growth and Metastasis of Triple Negative Breast Cancer

IF 6.8 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry Pub Date : 2024-10-22 DOI:10.1021/acs.jmedchem.4c01908

Gang Xu, Qiongyue Liang, Lijuan Gao, Shihang Xu, Weicong Luo, Qiuming Wu, Jingyuan Li, Zhenlei Zhang, Hong Liang, Feng Yang

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Abstract

To effectively inhibit the growth and metastasis of triple-negative breast cancer (TNBC), we developed a high-efficiency and low-toxicity arene ruthenium (Ru) complex based on apoferritin (AFt). To achieve this, we optimized a series of Ru(II) 1,10-phenanthroline-2,9-diformaldehyde thiosemicarbazone complexes by studying their structure−activity relationships to obtain an arene binuclear Ru(II) complex (C5) with significant cytotoxicity and high accumulation in the mitochondria of tumor cells. Subsequently, a C5-AFt nanoparticle (NPs) delivery system was constructed. We found that the C5/C5-AFt NPs effectively inhibited TNBC growth and metastasis with few side effects. The C5-AFt NPs improved the anticancer and targeting abilities of C5 in vivo. Moreover, we confirmed the mechanism by which C5/C5-AFt NPs inhibit tumor growth and metastasis via mitochondrial damage-mediated ferroptosis and activation of the cGAS-STING pathway.

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开发烯双核钌(II)配合物以诱导铁变态反应并激活 cGAS-STING 通路：靶向抑制三阴性乳腺癌的生长和转移

为了有效抑制三阴性乳腺癌（TNBC）的生长和转移，我们开发了一种基于阿朴铁蛋白（AFt）的高效、低毒的炔钌 (Ru) 复合物。为此，我们通过研究一系列 1,10-菲罗啉-2,9-二甲醛硫代氨基甲酸钌（II）配合物的结构-活性关系，优化了这些配合物，从而获得了一种具有显著细胞毒性并能在肿瘤细胞线粒体中大量蓄积的芳香族双核钌（II）配合物（C5）。随后，我们构建了一种 C5-AFt 纳米粒子（NPs）递送系统。我们发现，C5/C5-AFt NPs 能有效抑制 TNBC 的生长和转移，且副作用小。C5-AFt NPs提高了C5在体内的抗癌和靶向能力。此外，我们还证实了 C5/C5-AFt NPs 通过线粒体损伤介导的铁凋亡和 cGAS-STING 通路的激活抑制肿瘤生长和转移的机制。

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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.