Guangxi Key Laboratory of Agricultural Resources, Chemistry and Biotechnology, College of Chemistry and Food Science, Yulin Normal University, 1303 Jiaoyudong Road, Yulin 537000, China.
Guangxi Key Laboratory of Agricultural Resources, Chemistry and Biotechnology, College of Chemistry and Food Science, Yulin Normal University, 1303 Jiaoyudong Road, Yulin 537000, China; School of food and chemical engineering, Liuzhou Institute of Technology, Liuzhou, Guangxi 545000, China.
J Inorg Biochem. 2024 Oct;259:112659. doi: 10.1016/j.jinorgbio.2024.112659. Epub 2024 Jul 4.
Ruthenium(II/III) coordination compounds have gained widespread attention as chemotherapy drugs, photosensitizers, and photodynamic therapy reagents. Herein, a family of 11 novel coumarin-coordinated 8-hydroxyquinoline ruthenium(II/III) compounds, i.e., [Ru(μ-Cl)(QL1a)(DMSO)] (YNU-4a = Yulin Normal University-4a), [Ru(μ-Cl)(QL1b)(DMSO)] (YNU-4b), [Ru(μ-Cl)(QL1c)(DMSO)] (YNU-4c), [Ru(μ-Cl)(QL1d)(DMSO)]⋅2CHOH (YNU-4d), [Ru(QL1e)(DMSO)] (YNU-4e), [Ru(QL1e)(QL3a)] (YNU-4f), [Ru(QL1e)(QL3b)] (YNU-4g), [Ru(QL1e)(QL3c)] (YNU-4h), [RuCl(H-QL3a)(DMSO)] (YNU-4i), [RuCl(H-QL3b)(DMSO)] (YNU-4j), and [RuCl(H-QL3c)(DMSO)] (YNU-4k), featuring the coligands 5,7-diiodo-8-hydroxyquinoline (H-QL1a), 5,7-dichloro-8-quinolinol (H-QL1b), 5-chloro-7-iodo-8-hydroxyquinolin (H-QL1c), 5,7-dibromo-8-hydroxyquinoline (H-QL1d), and 5,7-dichloro-8-hydroxy-2-methylquinoline (H-QL1e) and the main ligands 6,7-dichloro-3-pyridin-2-yl-chromen-2-one (H-QL3a), 6-bromo-3-pyridin-2-yl-chromen-2-one (H-QL3b), and 6-chloro-3-pyridin-2-yl-chromen-2-one (H-QL3c), respectively. The structure of compounds YNU-4a-YNU-4k was fully confirmed by conducting various spectroscopic analyses. The anticancer activity of YNU-4a-YNU-4k was evaluated in cisplatin-resistant A549/DDP lung cancer cells (LC549) versus normal embryonic kidney (HEK293) cells. Notably, compound YNU-4f bearing QL1e and QL3a ligands showed a more pronounced antiproliferative effect against LC549 cells (IC = 1.75 ± 0.09 μM) with high intrinsic selectivity toward LC549 cancer cells than YNU-4a-YNU-4e, H-QL1a-H-QL1e, cisplatin (PDD), YNU-4g-YNU-4k, and H-QL3a-H-QL3c. Additionally, a colocalization assay analysis of YNU-4e and YNU-4f showed that these two ruthenium(II/III) compounds were subcellularly accumulated in the mitochondria and other regions of the cytoplasm, where they induce mitophagy, adenosine triphosphate (ATP) reduction, mitochondrial respiratory chain complex I/IV(RC1/RC4) inhibition, and mitochondrial dysfunction. Accordingly, compounds YNU-4a-YNU-4k can be regarded as mitophagy inductors for the eradication of cisplatin-resistant LC549 cancer cells.
钌（II/III）配合物作为化疗药物、光增敏剂和光动力治疗试剂已经引起了广泛的关注。在此，我们介绍了一类 11 种新型香豆素配位的 8-羟基喹啉钌（II/III）化合物，即[Ru(μ-Cl)(QL1a)(DMSO)]（YNU-4a=玉林师范学院-4a）、[Ru(μ-Cl)(QL1b)(DMSO)]（YNU-4b）、[Ru(μ-Cl)(QL1c)(DMSO)]（YNU-4c）、[Ru(μ-Cl)(QL1d)(DMSO)]·2CHOH（YNU-4d）、[Ru(QL1e)(DMSO)]（YNU-4e）、[Ru(QL1e)(QL3a)]（YNU-4f）、[Ru(QL1e)(QL3b)]（YNU-4g）、[Ru(QL1e)(QL3c)]（YNU-4h）、[RuCl(H-QL3a)(DMSO)]（YNU-4i）、[RuCl(H-QL3b)(DMSO)]（YNU-4j）和[RuCl(H-QL3c)(DMSO)]（YNU-4k），这些化合物的配体为 5,7-二碘-8-羟基喹啉（H-QL1a）、5,7-二氯-8-喹啉醇（H-QL1b）、5-氯-7-碘-8-羟基喹啉（H-QL1c）、5,7-二溴-8-羟基喹啉（H-QL1d）和 5,7-二氯-8-羟基-2-甲基喹啉（H-QL1e），主配体为 6,7-二氯-3-吡啶-2-基香豆素-2-酮（H-QL3a）、6-溴-3-吡啶-2-基香豆素-2-酮（H-QL3b）和 6-氯-3-吡啶-2-基香豆素-2-酮（H-QL3c）。通过各种光谱分析，充分证实了化合物 YNU-4a-YNU-4k 的结构。在顺铂耐药 A549/DDP 肺癌细胞（LC549）与正常胚胎肾（HEK293）细胞中，评估了 YNU-4a-YNU-4k 的抗癌活性。值得注意的是，化合物 YNU-4f 具有 QL1e 和 QL3a 配体，对 LC549 细胞表现出更明显的增殖抑制作用（IC=1.75±0.09μM），与 YNU-4a-YNU-4e、H-QL1a-H-QL1e、顺铂（PDD）、YNU-4g-YNU-4k 和 H-QL3a-H-QL3c 相比，对 LC549 癌细胞具有更高的内在选择性。此外，YNU-4e 和 YNU-4f 的共定位分析表明，这两种钌（II/III）化合物在亚细胞水平上积聚在线粒体和细胞质的其他区域，在这些区域诱导自噬、三磷酸腺苷（ATP）减少、线粒体呼吸链复合物 I/IV（RC1/RC4）抑制和线粒体功能障碍。因此，化合物 YNU-4a-YNU-4k 可被视为用于根除顺铂耐药 LC549 癌细胞的自噬诱导剂。
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