Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming 650500, P. R. China.
Faculty of Chemistry and Chemical Engineering, Yunnan Normal University, Kunming 650500, P. R. China.
Metallomics. 2022 Sep 26;14(9). doi: 10.1093/mtomcs/mfac068.
A series of cyclometalated iridium(III) complexes with the formula Ir(C^N)2 L (C^N = 2-phenylpyridine (ppy, in Ir-1), 2-(2-thienyl)pyridine (thpy, in Ir-2), 2-(2,4-difluorophenyl)pyridine (dfppy, in Ir-3), L = 2-(1H-imidazo[4,5-f][1,10]phenanthrolin-2-yl)quinolin-8-ol) were designed and synthesized, which utilize 8-hydroxyquinoline derivative as N^N ligands to chelate the cofactor Fe2+ of the Jumonji domain-containing protein (JMJD) histone demethylase. As expected, the results of UV/Vis titration analysis confirm the chelating capabilities of Ir-1-3 for Fe2+, and molecular docking studies also show that Ir-1-3 can interact with the active pocket of JMJD protein, and treatment of cells with Ir-1-3 results in significant upregulation of trimethylated histone 3 lysine 9 (H3K9Me3), indicating the inhibition of JMJD activity. Meanwhile, Ir-1-3 exhibit much higher cytotoxicity against the tested tumor cell lines compared with the clinical chemotherapeutic agent cisplatin. And Ir-1-3 can block the cell cycle at the G2/M phase and inhibit cell migration and colony formation. Further studies show that Ir-1-3 can specifically accumulate in lysosomes, damage the integrity of lysosomes, and induce apoptosis and autophagy. Reduction of mitochondrial membrane potential and elevation of reactive oxygen species also contribute to the antitumor effects of Ir-1-3. Finally, Ir-1 can inhibit tumor growth effectively in vivo and increase the expression of H3K9Me3 in tumor tissues. Our study demonstrates that these iridium(III) complexes are promising anticancer agents with multiple functions, including the inhibition of JMJD and induction of apoptosis and autophagy.
一系列具有化学式Ir(C^N)2 L的金属铱(III)配合物被设计和合成，其中 C^N 代表 2-苯基吡啶（ppy，在 Ir-1 中）、2-(2-噻吩基)吡啶（thpy，在 Ir-2 中）、2-(2,4-二氟苯基)吡啶（dfppy，在 Ir-3 中），L 代表 2-(1H-咪唑[4,5-f][1,10]菲咯啉-2-基)喹啉-8-醇)，它们利用 8-羟基喹啉衍生物作为 N^N 配体螯合 Jumonji 结构域包含蛋白（JMJD）组蛋白去甲基酶的辅因子 Fe2+。正如预期的那样，紫外/可见滴定分析的结果证实了 Ir-1-3 对 Fe2+的螯合能力，分子对接研究也表明 Ir-1-3 可以与 JMJD 蛋白的活性口袋相互作用，并且用 Ir-1-3 处理细胞会导致三甲基化组蛋白 3 赖氨酸 9 (H3K9Me3)的显著上调，表明 JMJD 活性受到抑制。同时，与临床化疗药物顺铂相比，Ir-1-3 对测试的肿瘤细胞系表现出更高的细胞毒性。Ir-1-3 可以阻断细胞周期在 G2/M 期，并抑制细胞迁移和集落形成。进一步的研究表明，Ir-1-3 可以特异性地在溶酶体中积累，破坏溶酶体的完整性，并诱导细胞凋亡和自噬。线粒体膜电位的降低和活性氧的升高也有助于 Ir-1-3 的抗肿瘤作用。最后，Ir-1 可以有效地在体内抑制肿瘤生长，并增加肿瘤组织中 H3K9Me3 的表达。我们的研究表明，这些金属铱(III)配合物是具有多种功能的有前途的抗癌药物，包括抑制 JMJD 和诱导细胞凋亡和自噬。
