Synthesis and biological evaluation of mixed-ligand cyclometalated iridium(III)–quinoline complexes
Synthesis and biological evaluation of mixed-ligand cyclometalated iridium(III)–quinoline complexes
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混合配体环金属化铱(III)-喹啉配合物的合成及生物学评价
DOI：
10.1039/d1dt02416g
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发表时间：
2021
影响因子：
4
通讯作者：
Hong Liang
中科院分区：
文献类型：
--
作者：
Yan Yang;Cheng-Ming Wang;Feng-Hua Pan;Qi-Pin Qin;Qiu-Ji Xie;Qing Chen;Hong Liang
为了更好地研究Ir(III)环化配合物的细胞凋亡机制和体内药效，合成了6个新的Ir(III)-喹啉配合物[Ir(1a)(2pq)2](2a)，[Ir(1b)(2pq)2](2b)，[Ir(1c)(2pq)2](2c)，[Ir(1d)(2pq)2](2d)，[Ir(1e)(2pq)2](2e)，[Ir(1e)(2pq)2](2e)，以5，7-二卤代-8-羟基喹啉配体(1a-1f)和[Ir(2pq)2Cl]2为前驱体合成了[Ir(1f)(2pq)2](2f)(2pq=2-苯基异喹啉)，并进行了表征。化合物2a-2f对顺铂耐药的SK-OV-3/DDP和A549/DDP细胞表现出较强的抗癌活性(IC_(50)=0.11-1.83μM)，其顺序为2e>；2f>；2b>；2c>；2d>；2a。共聚焦显微镜图像显示，2e和2b可以作为红色探针用于特定的细胞成像，并有效地启动线粒体、细胞质和细胞核中的凋亡和自噬。Beclin1、caspase-9、细胞色素c、LC3II和APAF-1的过表达，p62、细胞周期蛋白D1、细胞周期蛋白A2和细胞周期蛋白CDK2的抑制，以及大量的快速积累，表明自噬、DNA损伤和线粒体应激诱导的细胞死亡是一种类似的模式。此外，2E在10.0 mg kg−-1浓度下对A549/DDP肿瘤生长的抑制率为64.1%，明显高于顺铂。根据生物活性测定，环金属Ir(III)-喹啉配合物2E具有比2b更强的抗癌作用，这可能与2E的1E配体甲基的电子效应有关。
With the aim of gaining new insight into the underlying apoptosis mechanisms and in vivo efficacy of cyclometalated Ir(III) complexes as metalodrugs, six new cyclometalated Ir(III)–quinoline complexes, [Ir(1a)(2pq)2] (2a), [Ir(1b)(2pq)2] (2b), [Ir(1c)(2pq)2] (2c), [Ir(1d)(2pq)2] (2d), [Ir(1e)(2pq)2] (2e), and [Ir(1f)(2pq)2] (2f) (2pq = 2-phenylisoquinoline), have been synthesized using 5,7-dihalo-8-hydroxylquinoline ligands (1a–1f) and [Ir(2pq)2Cl]2 precursors and characterized. Complexes 2a–2f have shown potent anticancer activity against cisplatin-resistant SK-OV-3/DDP and A549/DDP cells (IC50 = 0.11–1.83 μM), following the order 2e > 2f > 2b > 2c > 2d > 2a. Confocal microscopy images suggest that 2e and 2b could act as red-color probes for specific cell imaging and efficiently initiate apoptosis and autophagy in the mitochondria, cell cytosol, and nucleus. Overexpression of beclin1, caspase-9, cytochrome c, LC3II, and apaf-1; inhibition of p62, cyclin D1, cyclin A2, and CDK2; and a substantial rapid accumulation suggest a paraptotic mode of cell death induced by autophagy, DNA damage, and mitochondrial stress. In addition, the inhibitory rate of 2e on A549/DDP tumor growth was 64.1% at a concentration of 10.0 mg kg−1, which is clearly higher than that of cisplatin. According to the biological assay, the cyclometalated Ir(III)–quinoline complex 2e exhibited a higher anticancer effect than 2b, which may be associated with the electronic effect of the methyl group of the 1e ligand of 2e playing a key role in the mechanism.