Iridium(III) and rhenium(I) complexes containing an IDO inhibitor induce apoptosis and pyroptosis

IF 3.1 2区化学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Inorganic Biochemistry Pub Date : 2026-04-01 Epub Date: 2026-01-05 DOI:10.1016/j.jinorgbio.2026.113216

Hou Zhu , Yong-Sheng Yang , Lin-Yuan Zhu, Chun-Rong Jiang, Zheng Zhang, Meng-Ting Xu, Rong-Tao Li, Rui-Rong Ye

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Abstract

Four novel Ir(III)/Re(I)-1-methyl-D-tryptophan conjugates (Ir-MT-1–2 and Re-MT-1–2) were designed and synthesized for the first time, among which 1-methyl-D-tryptophan (1-MT) is an indoleamine 2,3-dioxygenase (IDO) inhibitor. Three (Ir-MT-1–2 and Re-MT-1) of the metal-conjugates showed high-efficient anti-tumor activities against human cervical cancer HeLa cells, with IC₅₀ values of 5.2, 7.1, and 4.4 μM, respectively, and significantly inhibited IDO expression. Mechanistic investigations revealed that these complexes selectively localized to mitochondria, inducing mitochondrial membrane potential (MMP) depolarization, elevating intracellular reactive oxygen species (ROS) levels, activating mitochondrial apoptotic pathways, and simultaneously inducing the cleavage of pyroptosis marker (GSDME) to cause pyroptosis. These results demonstrate the potential of combing transition metals with IDO inhibitors for cancer treatment.

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含有IDO抑制剂的铱（III）和铼(I)配合物可诱导细胞凋亡和焦亡

首次设计合成了4种新型Ir(III)/Re(I)-1-甲基-d -色氨酸缀合物（Ir- mt -1- 2和Re- mt -1- 2），其中1-甲基-d -色氨酸（1-MT）是吲哚胺2,3-双加氧酶（IDO）抑制剂。其中3个金属偶联物（Ir-MT-1-2和Re-MT-1）对人宫颈癌HeLa细胞表现出高效的抗肿瘤活性，IC50值分别为5.2、7.1和4.4 μM，并显著抑制IDO表达。机制研究表明，这些复合物选择性定位于线粒体，诱导线粒体膜电位（MMP）去极化，提高细胞内活性氧（ROS）水平，激活线粒体凋亡途径，同时诱导焦亡标记物（GSDME）裂解导致焦亡。这些结果证明了将过渡金属与IDO抑制剂结合治疗癌症的潜力。

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来源期刊

Journal of Inorganic Biochemistry 生物-生化与分子生物学

CiteScore

7.00

自引率

10.30%

发文量

336

审稿时长

41 days

期刊介绍： The Journal of Inorganic Biochemistry is an established international forum for research in all aspects of Biological Inorganic Chemistry. Original papers of a high scientific level are published in the form of Articles (full length papers), Short Communications, Focused Reviews and Bioinorganic Methods. Topics include: the chemistry, structure and function of metalloenzymes; the interaction of inorganic ions and molecules with proteins and nucleic acids; the synthesis and properties of coordination complexes of biological interest including both structural and functional model systems; the function of metal- containing systems in the regulation of gene expression; the role of metals in medicine; the application of spectroscopic methods to determine the structure of metallobiomolecules; the preparation and characterization of metal-based biomaterials; and related systems. The emphasis of the Journal is on the structure and mechanism of action of metallobiomolecules.