Ling-Qi Du , Yan Yang , Li Ruan , Song Sun , Dong-Yin Mo , Jin-Yuan Cai , Hong Liang , Sai Shu , Qi-Pin Qin
{"title":"Insights into the antineoplastic activity and mechanisms of action of coumarin-coordinated 8-hydroxyquinoline ruthenium(II/III) compounds","authors":"Ling-Qi Du , Yan Yang , Li Ruan , Song Sun , Dong-Yin Mo , Jin-Yuan Cai , Hong Liang , Sai Shu , Qi-Pin Qin","doi":"10.1016/j.jinorgbio.2024.112659","DOIUrl":null,"url":null,"abstract":"<div><p>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<sup>II</sup><sub>2</sub>(<em>μ</em><sub>2</sub>-Cl)<sub>2</sub>(QL1a)<sub>2</sub>(DMSO)<sub>4</sub>] (<strong>YNU-4a</strong> = Yulin Normal University-4a), [Ru<sup>II</sup><sub>2</sub>(<em>μ</em><sub>2</sub>-Cl)<sub>2</sub>(QL1b)<sub>2</sub>(DMSO)<sub>4</sub>] (<strong>YNU-4b</strong>), [Ru<sup>II</sup><sub>2</sub>(<em>μ</em><sub>2</sub>-Cl)<sub>2</sub>(QL1c)<sub>2</sub>(DMSO)<sub>4</sub>] (<strong>YNU-4c</strong>), [Ru<sup>II</sup><sub>2</sub>(<em>μ</em><sub>2</sub>-Cl)<sub>2</sub>(QL1d)<sub>2</sub>(DMSO)<sub>4</sub>]⋅2CH<sub>3</sub>OH (<strong>YNU-4d</strong>), [Ru<sup>II</sup>(QL1e)<sub>2</sub>(DMSO)<sub>2</sub>] (<strong>YNU-4e</strong>), [Ru<sup>III</sup>(QL1e)<sub>2</sub>(QL3a)] (<strong>YNU-4f</strong>), [Ru<sup>III</sup>(QL1e)<sub>2</sub>(QL3b)] (<strong>YNU-4g</strong>), [Ru<sup>III</sup>(QL1e)<sub>2</sub>(QL3c)] (<strong>YNU-4h</strong>), [Ru<sup>II</sup>Cl<sub>2</sub>(H-QL3a)<sub>2</sub>(DMSO)<sub>2</sub>] (<strong>YNU-4i</strong>), [Ru<sup>II</sup>Cl<sub>2</sub>(H-QL3b)<sub>2</sub>(DMSO)<sub>2</sub>] (<strong>YNU-4j</strong>), and [Ru<sup>II</sup>Cl<sub>2</sub>(H-QL3c)<sub>2</sub>(DMSO)<sub>2</sub>] (<strong>YNU-4k</strong>), 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 <strong>YNU-4a</strong>–<strong>YNU-4k</strong> was fully confirmed by conducting various spectroscopic analyses. The anticancer activity of <strong>YNU-4a</strong>–<strong>YNU-4k</strong> was evaluated in cisplatin-resistant A549/DDP lung cancer cells (LC549) versus normal embryonic kidney (HEK293) cells. Notably, compound <strong>YNU-4f</strong> bearing QL1e and QL3a ligands showed a more pronounced antiproliferative effect against LC549 cells (IC<sub>50</sub> = 1.75 ± 0.09 μM) with high intrinsic selectivity toward LC549 cancer cells than <strong>YNU-4a</strong>–<strong>YNU-4e</strong>, H-QL1a–H-QL1e, cisplatin (PDD), <strong>YNU-4g</strong>–<strong>YNU-4k</strong>, and H-QL3a–H-QL3c. Additionally, a colocalization assay analysis of <strong>YNU-4e</strong> and <strong>YNU-4f</strong> 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 <strong>YNU-4a</strong>–<strong>YNU-4k</strong> can be regarded as mitophagy inductors for the eradication of cisplatin-resistant LC549 cancer cells.</p></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":null,"pages":null},"PeriodicalIF":3.8000,"publicationDate":"2024-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Inorganic Biochemistry","FirstCategoryId":"99","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0162013424001831","RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
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., [RuII2(μ2-Cl)2(QL1a)2(DMSO)4] (YNU-4a = Yulin Normal University-4a), [RuII2(μ2-Cl)2(QL1b)2(DMSO)4] (YNU-4b), [RuII2(μ2-Cl)2(QL1c)2(DMSO)4] (YNU-4c), [RuII2(μ2-Cl)2(QL1d)2(DMSO)4]⋅2CH3OH (YNU-4d), [RuII(QL1e)2(DMSO)2] (YNU-4e), [RuIII(QL1e)2(QL3a)] (YNU-4f), [RuIII(QL1e)2(QL3b)] (YNU-4g), [RuIII(QL1e)2(QL3c)] (YNU-4h), [RuIICl2(H-QL3a)2(DMSO)2] (YNU-4i), [RuIICl2(H-QL3b)2(DMSO)2] (YNU-4j), and [RuIICl2(H-QL3c)2(DMSO)2] (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 (IC50 = 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.
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.
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