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Debate over the electronic structure of Cu^III complexes has intensified in recent years, focusing primarily on whether the [Cu(CF₃)₄]^- moiety should be described as a classical Werner-type 3d⁸ Cu^III complex or as a 3d¹⁰ Cu^I inverted ligand field framework. The copper periodate complex [Cu(HIO₆)₂]^5-, discovered in 1937, has long been regarded as a 3d⁸ Cu^III species and sometimes used as a reference 3d⁸ Cu^III complex in oxidation state assignments for Cu-containing metalloenzymes. Nevertheless, its detailed electronic structure remains unexplored. Herein, we revisit the oxidation state of [Cu(HIO₆)₂]^5- by means of X-ray photoelectron spectroscopy, X-ray absorption spectroscopy, and density functional theory calculations. The obtained results show that the oxidation state of the Cu center in [Cu(HIO₆)₂]^5- lies at the boundary between the classical Werner-type and inverted ligand field regimes. This study thus demonstrates that categorizing the oxidation state of Cu^III complexes as either 3d⁸ or 3d¹⁰ configurations is often inadequate; instead, the existence of electronic states at the boundary between these two limiting cases should be recognized. Show less

The oxygen evolution reaction under neutral conditions remains a significant challenge due to sluggish kinetics and catalyst instability, largely stemming from inefficient proton management. Inspired by the proton-coupled electron transfer (PCET) networks in the oxygen-evolving complex of photosystem II, we report the rational design of two bioinspired cubane-type tetranuclear copper catalysts, Cu₄(L_Gly)₄ and Cu₄(L_Glu)₄, functionalized with amino acid derivatives. Electrochemical studies reveal that the glutamate-modified Cu₄(L_Glu)₄ outperforms its glycine counterpart, achieving a remarkable turnover frequency (TOF) of 9.64 ± 0.07 s^-1 at a low overpotential of 0.63 V in phosphate buffer solution (pH 7.30). Differential pulse voltammetry and mechanistic investigations indicate a PCET nature for the copper redox transitions. Density functional theory calculations demonstrate that the carboxylate group of the glutamate residue acts as an intrinsic proton relay, significantly lowering the energy barrier for the critical O-O bond formation step. Furthermore, a photovoltaic-electrocatalytic (PV-EC) device utilizing the Cu₄(L_Glu)₄ anode achieves a solar-to-hydrogen (STH) conversion efficiency of 10.24% under neutral conditions, one of the highest reported values without a strong alkaline environment. This work underscores the critical role of second-sphere proton-transfer functionality in designing efficient molecular catalysts for PCET-driven energy conversion reactions. Show less

Despite the widespread use of chemotherapeutic agents, their reliance on apoptosis often limits therapeutic efficacy and leads to drug resistance. To overcome these challenges, alternative cell death mechanisms such as cuproptosis have gained significant attention. While previous studies have primarily focused on incorporation of Cu into nanostructures, this work presents the first example of a molecular tripodal Cu(II) complex as a potent cuproptosis inducer. Herein, a series of tripodal Cu(II) complexes were chemically synthesized and biologically evaluated. The most promising compound demonstrated remarkable cytotoxicity in the low micromolar to nanomolar range. Mechanistic studies revealed that the compound catalytically produced hydroxyl radicals in the mitochondria of cancerous cells, causing protein oligomerization and the disruption of iron-sulfur cluster proteins, ultimately triggering cell death by cuproptosis. Contrary to traditional chemotherapeutic agents that cause reduction in tumor size, this compound induced the fragmentation of three-dimensional tumor spheroids. Show less

Three cytotoxic copper(ii) complexes – [Cu2(bipy)2L4] (1), [Cu2(phen)2L4] (2) and [Cu2(dmphen)2L4]·2H2O (3) – were synthesized based on 5-methyltetrazole (HL) and 2,2′-bipyridine/1,10-phenanthroline derivatives. Show less

Copper is a trace element which is essential for biological organisms, and its homeostatic balance is important for living organisms to maintain the normal function. When the copper homeostasis is disordered, the cellular function and structure will be disrupted. Excess copper cause oxidative stress and DNA damage in cells, thereby inducing regulated cell death such as apoptosis and necroptosis. Excess copper in mitochondria can bind to lipoylated proteins in the tricarboxylic acid (TCA) cycle and cause them to aggregate, resulting in proteotoxic stress and eliciting a novel cell death modality: cuproptosis. Cancer cells have a greater demand for copper compared to normal tissue, and high levels of copper ions are closely associated with tumour proliferation and metastasis. The anti-tumor mechanisms of copper include the production of oxidative stress, inhibition of the ubiquitin–proteasome system, suppression of angiogenesis, and induction of copper-dependent cell death. Targeting copper is one of the current directions in oncology research, including the use of copper ion carriers to increase intracellular copper levels to induce oxidative stress and cuproptosis, as well as the use of copper ion chelators to reduce copper bioavailability. However, copper complexes have certain toxicity, so their biosafety needs to be improved. Emerging nanotechnology is expected to solve this problem by utilizing copper-based nanomaterials (Cu-based NMs) to deliver copper ions and a variety of drugs with different functions, thereby improving the anti-tumor efficacy and reducing the side effects. Therefore, a thorough understanding of copper metabolic processes and the mechanism of cuproptosis will greatly benefit anti-tumor therapy. This review summarizes the processes of copper metabolism and the mechanism of cuproptosis. In addition, we discuss the current anti-tumor paradigms related to copper, we also discuss current nanotherapeutic approaches to copper mortality and provide prospective insights into the future copper-mediated cancer therapy. Show less

Copper(II), manganese(II), and mercury(II) complexes of 4-amino-5-(2-(1-pyridine-2-yl)ethylidene)hydrazinyl)-4H-1,2,4-triazole-3-thiol (H2TAP) were synthesized and characterized using CHN analysis, FT-IR, 1H-NMR, 13C-NMR, UV–Vis, ESR, MS, PXRD, magnetic moment measurements, molar conductance, and TG/DTA. DFT calculations indicate octahedral geometries and the neutral bidentate or tridentate chelating behavior of the ligand. Cyclic voltammetry revealed the complexes’ redox properties, and Job’s method elucidated stoichiometric compositions in solution. Biochemical assays demonstrated antimicrobial activity against Escherichia coli, Staphylococcus aureus, and Candida albicans. The MnII complex exhibited potent antitumor activity against HepG-2 cells. Antioxidant and DNA binding studies showed promising results, with docking investigations indicating strong interactions between the ligand/complexes and target proteins (PDB: 1YWN) and DNA (PDB: 8EC1), suggesting therapeutic potential. Show less

Abstract Complex compounds [CuL(phen)(H2O)(NO3)]NO3 (1), [CuL(bipy)(NO3)2]·2EtOH (2), [CuL2(H2O)2 (NO3)2] (2a), [CuL(dmbipy)(NO3)2]·3EtOH (3), and [CuL2(NO3)2] (3a), where L is 3-(5-phenyl-2H-tetrazol-2-yl)pyridine, phen is 1,10-phenanthroline, bipy is 2,2′-bipyridine, and dmbipy is 4,4′-dimethyl-2,2′-bipyridine, are obtained and structurally characterized. It is shown that L behaves as the monodentate ligand being coordinated by the nitrogen atom of the pyridine ring. The coordination polyhedron made of copper atoms is a square pyramid in complexes 1 and 3, a distorted octahedron and a distorted square in complexes 2a and 3a respectively. Complex 1 is characterized by the elemental analysis, powder X-ray diffraction, and IR spectroscopy. Furthermore, its cytotoxic properties are studied on human larynx carcinoma (Hep2), breast adenocarcinoma (MCF7), and non-tumor human fibroblast (MRC5) cell lines. Complex 1 is shown to exhibit the pronounced cytotoxic action (LC50(Hep2) = 4.1±0.4 µM and LC50(MCF7) = 4.9±0.1 µM), however, does not exhibit selectivity against tumor cell lines (LC50(MRC5) = = 3.06 ±0.02 µM). Show less

Three copper(II) complexes – [Cu2(bipy)2L4] (1), [Cu2(phen)2L4] (2) and [Cu2(dmphen)2L4]·2H2O (3) – were synthesized based on 5-methyltetrazole (HL) and 2,2′-bipyridine/1,10-phenanthroline derivatives. A crystallographic study revealed that complexes 1–3 have a binuclear structure with coordination polyhedron close to the square pyramid. Stability of the complexes in aqueous solution was studied by UV-Vis spectroscopy and conductometry. In vitro cytotoxicity study was carried out in 2D and 3D cell culture models and showed that complexes 2 and 3 possess cytotoxic activity against tumor cells (A549, Hep2, HepG2, MCF7) with LC50 values exceeding those of the medical drug cisplatin. At the same time, being less active, compound 1 has a selectivity index of 3.1 to hepatocellular carcinoma (HepG2 cell line) compared to non-tumor MRC5 cells. The Hoechst/Propidium iodide staining assay and ROS generation assay on Hep2 cells indicated that the cytotoxic effects of the complexes involved apoptosis induction without ROS accumulation. Show less

Oxidative stress appears to act globally and span body systems (e.g., nervous, immune, and endocrine). Currently, there is no single, generally-accepted measurement of oxidative stress. Many possible measurement approaches focus on the bottom-up analysis of individual molecules (e.g., reactive species, antioxidants, hormones or signaling molecules) or combinations of molecules (e.g., proteomics or metabolomics). Efforts to develop a global measurement of oxidative stress often detect a sample's ability to reduce a metal-ion (e.g., iron or copper) or quench a free radical. Here, we review results from a recently-developed iridium-reducing capacity assay (Ir-RCA) and suggest that this method offers several key benefits as a potential measurement of oxidative stress. First, the Ir-RCA employs simple optical and/or electrochemical measurements that can be extended to high throughput formats. Second, the Ir-RCA appears to be more sensitive than alternative global antioxidant assays. Third, the Ir-RCA measures stable molecular features of a sample. Fourth, the Ir-RCA has been "validated" by showing statistically significant differences in persons diagnosed with schizophrenia (N = 73) versus healthy controls (N = 45). Fifth, the Ir-RCA measurement of oxidative stress is "movable": psychosocial stressors can increase this measure of oxidative stress, while beneficial dietary interventions can decrease this measure of oxidative stress. Limitations and future directions for the Ir-RCA are discussed. Show less

Ferredoxins (FDXs) are evolutionarily conserved iron-sulfur (Fe-S) proteins that serve as master regulators of mitochondrial redox homeostasis, governing critical processes including electron transfer, energy metabolism, Fe-S cluster biogenesis, and steroidogenesis. In humans, the mitochondrial isoforms FDX1 and FDX2 exhibit specialized yet complementary functions: FDX1 directs steroidogenesis, protein lipoylation, and copper redox cycling, while FDX2 is a core factor in Fe-S cluster assembly. Crucially, dysregulation of these proteins disrupts mitochondrial integrity, impairs redox balance, and activates multiple programmed cell death (PCD) pathways such as cuproptosis, ferroptosis, apoptosis, and autophagic cell death. This review systematically analyzes their isoform-specific roles in mitochondrial electron transport, Fe-S cluster dynamics, metabolic regulation, and summarizes major advances in understanding how FDX1 and FDX2 orchestrate mitochondrial-PCD crosstalk. The work further examines their critical functions in PCD execution, including FDX1-mediated cuproptosis through Cu+-dependent aggregation of lipoylated proteins and FDX2-deficiency-driven ferroptosis via Fe-S cluster collapse and iron overload. Disease mechanisms across multiple pathologies, including cancer, neurodegeneration, cardiovascular disease, endocrine disorders, and genetic syndromes, are explored, highlighting links to FDX dysfunction, with emerging therapeutic strategies targeting FDXs also addressed. By elucidating the synergistic roles of FDX1 and FDX2 as metabolic-death gatekeepers, this review establishes a foundation for developing isoform-targeted therapies against diverse pathologies. Show less

Cuproptosis is a newly identified form of cell death induced by excessive copper (Cu) accumulation within cells. Mechanistically, cuproptosis results from Cu-induced aggregation of dihydrolipoamide S-acetyltransferase, correlated with the mitochondrial tricarboxylic acid cycle and the loss of iron–sulfur cluster proteins, ultimately resulting in proteotoxic stress and triggering cell death. Recently, cuproptosis has garnered significant interest in tumor research due to its potential as a crucial therapeutic strategy against cancer. In this review, we summarized the cellular and molecular mechanisms of cuproptosis and its relationship with other types of cell death. Additionally, we reviewed the current drugs or strategies available to induce cuproptosis in tumor cells, including Cu ionophores, small compounds, and nanomedicine. Furthermore, we targeted cell metabolism and specific regulatory genes in cancer therapy to enhance tumor sensitivity to cuproptosis. Finally, we discussed the feasibility of targeting cuproptosis to overcome tumor chemotherapy and immunotherapy resistance and suggested future research directions. This study suggested that targeting cuproptosis could open new avenues for developing tumor therapy. Show less

Copper is a necessary micronutrient for maintaining the well-being of the human body. The biological activity of organic ligands, especially their anticancer activity, is often enhanced when they coordinate with copper(I) and (II) ions. Copper and its compounds are capable of inducing tumor cell death through various mechanisms of action, including activation of apoptosis signaling pathways by reactive oxygen species (ROS), inhibition of angiogenesis, induction of cuproptosis, and paraptosis. Some of the copper complexes are currently being evaluated in clinical trials for their ability to map tumor hypoxia in various cancers, including locally advanced rectal cancer and bulky tumors. Several studies have shown that copper nanoparticles can be used as effective agents in chemodynamic therapy, phototherapy, hyperthermia, and immunotherapy. Despite the promising anticancer activity of copper-based compounds, their use in clinical trials is subject to certain limitations. Elevated copper concentrations may promote tumor growth, angiogenesis, and metastasis by affecting cellular processes. Show less

Abstract Ferroptosis is a new form of regulated cell death featuring iron‐dependent lipid peroxides accumulation to kill tumor cells. A growing body of evidence has shown the potential of ferroptosis‐based cancer therapy in eradicating refractory malignancies that are resistant to apoptosis‐based conventional therapies. In recent years, studies have reported a number of ferroptosis inducers that can increase the vulnerability of tumor cells to ferroptosis by regulating ferroptosis‐related signaling pathways. Encouraged by the rapid development of ferroptosis‐driven cancer therapies, interdisciplinary fields that combine ferroptosis, pharmaceutical chemistry, and nanotechnology are focused. First, the prerequisites and metabolic pathways for ferroptosis are briefly introduced. Then, in detail emerging ferroptosis inducers designed to boost ferroptosis‐induced tumor therapy, including metal complexes, metal‐based nanoparticles, and metal‐free nanoparticles are summarized. Subsequently, the application of synergistic strategies that combine ferroptosis with apoptosis and other regulated cell death for cancer therapy, with emphasis on the use of both cuproptosis and ferroptosis to induce redox dysregulation in tumor and intracellular bimetallic copper/iron metabolism disorders during tumor treatment is discussed. Finally, challenges associated with clinical translation and potential future directions for potentiating cancer ferroptosis therapies are highlighted. Show less

Understanding the functions of metal ions in biological systems is crucial for many aspects of research, including deciphering their roles in diseases and potential therapeutic use. Structural information about the molecular or atomic details of these interactions, generated by methods like X-ray crystallography, cryo-electron microscopy, or nucleic magnetic resonance, frequently provides details that no other method can. As with any experimental method, they have inherent limitations that sometimes lead to an erroneous interpretation. This manuscript highlights different aspects of structural data available for metal-protein complexes. We examine the quality of modeling metal ion binding sites across different structure determination methods, where different kinds of errors stem from, and how they can impact correct interpretations and conclusions.Many metalloproteins contain metal ions as integral components, while others bind them transiently in cellular processes like transport and signaling. Ions of metals like magnesium, iron, zinc, and copper are crucial components of enzymes, stabilizing their structure and providing their biological function, and each of them also plays multiple other roles in the body (Jomova et al., 2022). Calcium (Ca 2+ ) is the most abundant metal in the human body, most often associated with skeletal health, but it is also involved in muscle function, nerve transmission, and enzyme activity. Magnesium (Mg 2+ ) is also a cofactor in more than 300 enzymatic reactions and a multitude of cellular processes (Jahnen-Dechent & Ketteler, 2012). Working in concert, calcium and magnesium are essential for proper muscle contraction and relaxation (Potter et al., 1981), optimal nerve transmission and neuromuscular coordination (Kirkland et al., 2018), bone mineralization, and maintenance of normal bone (Rondanelli et al., 2021). It has been shown that stress can increase magnesium loss, and in turn, magnesium deficiency can further enhance susceptibility to stress, resulting in a magnesium and stress vicious circle (Pickering et al., 2020). Magnesium is also of interest for the potential prevention and treatment of numerous neurological disorders (Kirkland Show less

Cuproptosis, a newly identified copper (Cu)-dependent form of cell death, stands out due to its distinct mechanism that sets it apart from other known cell death pathways. The molecular underpinnings of cuproptosis involve the binding of Cu to lipoylated enzymes in the tricarboxylic acid cycle. This interaction triggers enzyme aggregation and proteotoxic stress, culminating in cell death. The specific mechanism of cuproptosis has yet to be fully elucidated. This newly recognized form of cell death has sparked numerous investigations into its role in tumorigenesis and cancer therapy. In this review, we summarized the current knowledge on Cu metabolism and its link to cancer. Furthermore, we delineated the molecular mechanisms of cuproptosis and summarized the roles of cuproptosis-related genes in cancer. Finally, we offered a comprehensive discussion of the most recent advancements in Cu ionophores and nanoparticle delivery systems that utilize cuproptosis as a cutting-edge strategy for cancer treatment. Show less

Copper–organic compounds have gained momentum as potent antitumor drug candidates largely due to their ability to generate an oxidative burst upon the transition of Cu2+ to Cu1+ triggered by the exogenous-reducing agents. We have reported the differential potencies of a series of Cu(II)–organic complexes that produce reactive oxygen species (ROS) and cell death after incubation with N-acetylcysteine (NAC). To get insight into the structural prerequisites for optimization of the organic ligands, we herein investigated the electrochemical properties and the cytotoxicity of Cu(II) complexes with pyridylmethylenethiohydantoins, pyridylbenzothiazole, pyridylbenzimidazole, thiosemicarbazones and porphyrins. We demonstrate that the ability of the complexes to kill cells in combination with NAC is determined by the potential of the Cu+2 → Cu+1 redox transition rather than by the spatial structure of the organic ligand. For cell sensitization to the copper–organic complex, the electrochemical potential of the metal reduction should be lower than the oxidation potential of the reducing agent. Generally, the structural optimization of copper–organic complexes for combinations with the reducing agents should include uncharged organic ligands that carry hard electronegative inorganic moieties. Show less

Abstract The review is devoted to copper coordination compounds based on 2,2′-bipyridine / 1,10-phenanthroline and diverse N-, O-, S-donor ligands exhibiting cytotoxic properties. Therefore, they can be a starting platform for developing antitumor drugs. The review covers the structural aspects of the complexes, the features of their cytotoxic activity and its mechanism, as well as in vivo studies. Show less

Copper plays vital roles in numerous cellular processes and its imbalance can lead to oxidative stress and dysfunction. Recent research has unveiled a unique form of copper-induced cell death, termed cuproptosis, which differs from known cell death mechanisms. This process involves the interaction of copper with lipoylated tricarboxylic acid cycle enzymes, causing protein aggregation and cell death. Recently, a growing number of studies have explored the link between cuproptosis and cancer development. This review comprehensively examines the systemic and cellular metabolism of copper, including tumor-related signaling pathways influenced by copper. It delves into the discovery and mechanisms of cuproptosis and its connection to various cancers. Additionally, the review suggests potential cancer treatments using copper ionophores that induce cuproptosis, in combination with small molecule drugs, for precision therapy in specific cancer types. Show less

AbstractTransition metal chemistry is essential to life, where metal binding to DNA, RNA, and proteins underpins all facets of the central dogma of biology. In this context, metals in proteins are typically studied as static active site cofactors. However, the emergence of transition metal signaling, where mobile metal pools can transiently bind to biological targets beyond active sites, is expanding this conventional view of bioinorganic chemistry. This Minireview focuses on the concept of metalloallostery, using copper as a canonical example of how metals can regulate protein function by binding to remote allosteric sites (e.g., exosites). We summarize advances in and prospects for the field, including imaging dynamic transition metal signaling pools, allosteric inhibition or activation of protein targets by metal binding, and metal‐dependent signaling pathways that underlie nutrient vulnerabilities in diseases spanning obesity, fatty liver disease, cancer, and neurodegeneration. Show less

In this study, a new ligand, 5-(4-pyrimidinecarboxamido)-1H-tetrazol (4-H2pat), was synthesized by connecting the pyrimidine group and tetrazole group through an amide bond for the first time, aiming to construct new POM-based metal–organic complexes (POMOCs). By using the ligand 4-H2pat, two new POMOCs, [Cu4(4-pat)2(μ2-OH)(CrMo6(OH)6O18)(H2O)3]·2H2O (1) and [Cu2(4-pat)(β-Mo8O26)0.5(H2O)3] (2), were successfully synthesized under solvothermal and hydrothermal conditions, respectively. The structures were characterized by single crystal X-ray diffraction analysis, IR spectroscopy and powder X-ray diffraction (PXRD). In complex 1, the 1D [Cu4(μ2-OH)(4-pat)2]n3n+ metal–organic chains were connected by μ2-bridging [CrMo6(OH)6O18]3− (CrMo6) anions to construct a 2D layered structure. In complex 2, the 2D [Cu2(4-pat)]n2n+ metal–organic grid framework was consolidated by the μ4-bridging [β-Mo8O26]4− (Mo8) anions. The use of two different POM anion clusters results in the formation of two diverse 2D framework structures. Complexes 1 and 2 can effectively catalyze the oxidation of methyl phenyl sulfide as non-homogeneous catalysts with 97% and 95% conversions, respectively. They can also be used as electrocatalysts to prepare bulk-modified electrodes for detecting Cr(VI) and Fe(III) ions with low detection limits. In addition, the effects of different POMs on the structures and catalytic/electrocatalytic performances of the title complexes were discussed. Show less

Transition metal chemistry is essential to life, where metal binding to DNA, RNA, and proteins underpins all facets of the central dogma of biology. In this context, metals in proteins are typically studied as static active site cofactors. However, the emergence of transition metal signaling, where mobile metal pools can transiently bind to biological targets beyond active sites, is expanding this conventional view of bioinorganic chemistry. This Minireview focuses on the concept of metalloallostery, using copper as a canonical example of how metals can regulate protein function by binding to remote allosteric sites (e.g., exosites). We summarize advances in and prospects for the field, including imaging dynamic transition metal signaling pools, allosteric inhibition or activation of protein targets by metal binding, and metal-dependent signaling pathways that underlie nutrient vulnerabilities in diseases spanning obesity, fatty liver disease, cancer, and neurodegeneration. Show less

Herein, we present the synthesis, characterization, and in vitro investigation of cytotoxic activity against cancer (HepG-2, MCF-7) and non-cancerous (Hek-293, MRC-5) cell lines of six copper(II) complexes with 1H-tetrazole-5-acetic acid (H2L) and secondary ligands, such as olygopyridines (dmphen – 4,7-dimethyl-1,10-phenanthroline, phendione – 1,10 phenanthroline-5,6-dione, 5-Cl-phen – 5-chloro-1,10-phenanthroline, phen – 1,10 phenanthroline, dmbipy – 2,2′-bi-4-picoline, bipy – 2,2′-bipyridine). These compounds were characterized by powder X-ray diffraction, IR spectroscopy, elemental, and thermogravimetric analysis. The behavior of the complexes in solution was studied by optical spectroscopy, conductometry, and EPR. The DNA binding constant has been obtained for complex 5 using UV–vis spectroscopy. The antimicrobial activity of the complexes has been investigated against E. coli, S. aureus, P. italicum, and C. steinii. In addition, eight new crystal structures were obtained: [Cu(5-Cl-phen)L]n·0.5DMSO·1.5H2O (3a), [Cu(phen)L]n·2.5nH2O (4·2.5nH2O), [Cu3(phen)2(H2O)(HL)2L2]n·6nH2O (4a), [Cu(dmbipy)L]n (5), [Cu(dmbipy)(HL)2] (5a), [Cu3(dmpiby)2(HL)2L2]n·2nH2O·2nC2H5OH (5b), [Cu(bipy)L]n (6), and [Cu(bipy)(H2O)L] (6a). Show less