Miriam Caviglia , Fabio Del Bello , Carlo Santini , Sofia Migani , Wilma Quaglia , Jo’ Del Gobbo , Federica Matteucci , Maria Beatrice Morelli , Laura Zeppa , Cristina Aguzzi , Giuseppina Bozzuto , Annarita Stringaro , Chiara Battocchio , Giovanna Iucci , Iole Venditti , Carlo Meneghini , Simone Amatori , Alessandro Dolmella , Maura Pellei
{"title":"美金刚功能化双(吡唑-1-酰)醋酸酯配体支持的铜配合物的合成、结构表征和抗胶质母细胞瘤活性的研究","authors":"Miriam Caviglia , Fabio Del Bello , Carlo Santini , Sofia Migani , Wilma Quaglia , Jo’ Del Gobbo , Federica Matteucci , Maria Beatrice Morelli , Laura Zeppa , Cristina Aguzzi , Giuseppina Bozzuto , Annarita Stringaro , Chiara Battocchio , Giovanna Iucci , Iole Venditti , Carlo Meneghini , Simone Amatori , Alessandro Dolmella , Maura Pellei","doi":"10.1016/j.jinorgbio.2025.113035","DOIUrl":null,"url":null,"abstract":"<div><div>The new ligand bis(1H-pyrazol-1-yl)acetyl-3,5-dimethyladamantane-1-amide (L<sup>Mem</sup>) was synthesized by conjugating the drug memantine with the bifunctional species bis(pyrazol-1-yl)acetic acid and used as supporting ligand of copper(II) and copper(I) complexes <strong>1–7</strong>. In the synthesis of the Cu<sup>I</sup> complexes, the lipophilic triphenylphosphine (PPh<sub>3</sub>) and hydrophilic 1,3,5-triaza-7-phosphaadamantane (PTA) were selected as co-ligands, in order to stabilize copper in +1 oxidation state and to confer different solubility properties to the corresponding metal complexes. The electronic and molecular structures of Cu<sup>I</sup> and Cu<sup>II</sup> coordination compounds were investigated by high resolution Synchrotron Radiation-induced X-ray Photoelectron Spectroscopy (SR-XPS), Near Edge X-ray Absorption Fine Structure (NEXAFS) spectroscopy. The local structure around the copper ion sites was studied combining Density Functional Theory (DFT) modelling and X-ray Absorption Fine Structure (XAFS) spectroscopy, in both X-ray Absorption Near Edge Spectroscopy (XANES) and Extended X-ray Absorption Fine Structures (EXAFS) regions. X-ray diffraction (XRD) studies were carried out on suitable crystals to describe the molecular structure and the intermolecular contacts of the L<sup>Mem</sup> ligand. Among all Cu complexes tested, compounds <strong>4</strong> and <strong>5</strong> exhibited potent antiproliferative and cytotoxic effects in U87, T98, and U251 glioma cell lines. These effects were associated with increased reactive oxygen species (ROS) production and mitochondrial dysfunction, as evidenced by mitochondrial depolarization and altered intracellular distribution. Furthermore, the cytotoxic activity of these compounds was shown to be Cu-dependent, as it was effectively inhibited by the Cu chelator tetrathiomolybdate, confirming the essential role of copper in their mechanism of action.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"273 ","pages":"Article 113035"},"PeriodicalIF":3.2000,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Synthesis, structural characterization, and investigation of anti-glioblastoma activity of copper complexes supported by bis(pyrazol-1-yl)acetate ligands functionalized with memantine\",\"authors\":\"Miriam Caviglia , Fabio Del Bello , Carlo Santini , Sofia Migani , Wilma Quaglia , Jo’ Del Gobbo , Federica Matteucci , Maria Beatrice Morelli , Laura Zeppa , Cristina Aguzzi , Giuseppina Bozzuto , Annarita Stringaro , Chiara Battocchio , Giovanna Iucci , Iole Venditti , Carlo Meneghini , Simone Amatori , Alessandro Dolmella , Maura Pellei\",\"doi\":\"10.1016/j.jinorgbio.2025.113035\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>The new ligand bis(1H-pyrazol-1-yl)acetyl-3,5-dimethyladamantane-1-amide (L<sup>Mem</sup>) was synthesized by conjugating the drug memantine with the bifunctional species bis(pyrazol-1-yl)acetic acid and used as supporting ligand of copper(II) and copper(I) complexes <strong>1–7</strong>. In the synthesis of the Cu<sup>I</sup> complexes, the lipophilic triphenylphosphine (PPh<sub>3</sub>) and hydrophilic 1,3,5-triaza-7-phosphaadamantane (PTA) were selected as co-ligands, in order to stabilize copper in +1 oxidation state and to confer different solubility properties to the corresponding metal complexes. The electronic and molecular structures of Cu<sup>I</sup> and Cu<sup>II</sup> coordination compounds were investigated by high resolution Synchrotron Radiation-induced X-ray Photoelectron Spectroscopy (SR-XPS), Near Edge X-ray Absorption Fine Structure (NEXAFS) spectroscopy. The local structure around the copper ion sites was studied combining Density Functional Theory (DFT) modelling and X-ray Absorption Fine Structure (XAFS) spectroscopy, in both X-ray Absorption Near Edge Spectroscopy (XANES) and Extended X-ray Absorption Fine Structures (EXAFS) regions. X-ray diffraction (XRD) studies were carried out on suitable crystals to describe the molecular structure and the intermolecular contacts of the L<sup>Mem</sup> ligand. Among all Cu complexes tested, compounds <strong>4</strong> and <strong>5</strong> exhibited potent antiproliferative and cytotoxic effects in U87, T98, and U251 glioma cell lines. These effects were associated with increased reactive oxygen species (ROS) production and mitochondrial dysfunction, as evidenced by mitochondrial depolarization and altered intracellular distribution. Furthermore, the cytotoxic activity of these compounds was shown to be Cu-dependent, as it was effectively inhibited by the Cu chelator tetrathiomolybdate, confirming the essential role of copper in their mechanism of action.</div></div>\",\"PeriodicalId\":364,\"journal\":{\"name\":\"Journal of Inorganic Biochemistry\",\"volume\":\"273 \",\"pages\":\"Article 113035\"},\"PeriodicalIF\":3.2000,\"publicationDate\":\"2025-08-13\",\"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/S0162013425002156\",\"RegionNum\":2,\"RegionCategory\":\"化学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Inorganic Biochemistry","FirstCategoryId":"99","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0162013425002156","RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
Synthesis, structural characterization, and investigation of anti-glioblastoma activity of copper complexes supported by bis(pyrazol-1-yl)acetate ligands functionalized with memantine
The new ligand bis(1H-pyrazol-1-yl)acetyl-3,5-dimethyladamantane-1-amide (LMem) was synthesized by conjugating the drug memantine with the bifunctional species bis(pyrazol-1-yl)acetic acid and used as supporting ligand of copper(II) and copper(I) complexes 1–7. In the synthesis of the CuI complexes, the lipophilic triphenylphosphine (PPh3) and hydrophilic 1,3,5-triaza-7-phosphaadamantane (PTA) were selected as co-ligands, in order to stabilize copper in +1 oxidation state and to confer different solubility properties to the corresponding metal complexes. The electronic and molecular structures of CuI and CuII coordination compounds were investigated by high resolution Synchrotron Radiation-induced X-ray Photoelectron Spectroscopy (SR-XPS), Near Edge X-ray Absorption Fine Structure (NEXAFS) spectroscopy. The local structure around the copper ion sites was studied combining Density Functional Theory (DFT) modelling and X-ray Absorption Fine Structure (XAFS) spectroscopy, in both X-ray Absorption Near Edge Spectroscopy (XANES) and Extended X-ray Absorption Fine Structures (EXAFS) regions. X-ray diffraction (XRD) studies were carried out on suitable crystals to describe the molecular structure and the intermolecular contacts of the LMem ligand. Among all Cu complexes tested, compounds 4 and 5 exhibited potent antiproliferative and cytotoxic effects in U87, T98, and U251 glioma cell lines. These effects were associated with increased reactive oxygen species (ROS) production and mitochondrial dysfunction, as evidenced by mitochondrial depolarization and altered intracellular distribution. Furthermore, the cytotoxic activity of these compounds was shown to be Cu-dependent, as it was effectively inhibited by the Cu chelator tetrathiomolybdate, confirming the essential role of copper in their mechanism of action.
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.