Specific interactions between the macrocycle backbone, solvent and counter anions control configurational interconversions of novel organoruthenium(II) metallamacrocycles [Ru(eta 6-p-cymene)(mu 2-m-bitmb)Cl]2 center dot 2X, m-bitmb = 1,3,5-trimethyl-2,4-di(imidazole-1-ylmethyl)benzene, X =Cl-(12Cl), NO3-(12NO3), CF3SO3-(12CF3SO3), PF6-(12PF6), or BF4-(12BF4). X-ray crystal structures reveal 12Cl in boat and chair conformations, 12NO3 in twist-boat and chair conformations, and 12CF3SO3 in a chair conformation. Chair/boat isomers of mono-and bis-DMSO adducts from 12Cl, 12CF3SO3 or 12NO3 in DMSO/H2O were separated and characterized. Slow anion-dependent interconversion of configurational isomers was observed in solution. Ligand field molecular mechanics and density functional theory calculations suggest an unusual macrochelate ring-opening isomerization mechanism. Such dynamic stimuli-responsive configurational changes offer scope for design of metallocycles for induced-fit recognition of biological targets. (c) 2025 Published by Elsevier B.V. on behalf of Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.

Electronic absorption, emission, high field multinuclear NMR, and DFT studies of Ga( iii ) hydroxyquinolinate complexes reveal interesting features of their solution and solid state behaviour relevant to their anticancer and antimicrobial properties.

Photoactive Pt(IV) complexes conjugated to amino acid methyl esters trans,trans,trans-[Pt(py)2(N3)2(OH)(succinate-amino acid methyl ester)] (amino acid = L-leucine (1), glycine (2), L-tyrosine (3) and L-tryptophan (4)) have been synthesised and characterised. Complexes 1-4 showed high dark stability, but were activated upon irradiation with blue light to generate azidyl and hydroxyl radicals and Pt(II) species. Interestingly, conjugated tryptophan in 4 quenched the formation of azidyl and hydroxyl radicals and Pt-guanosine 5'-monphosphate adducts, while the amino acids in complexes 1-3 showed no significant effects on the formation of their photoproducts. Improved photocytotoxicity but lower dark cellular Pt accumulation in A2780 human ovarian cancer cells were observed for 1-4, with 50 % inhibition of cell viability (IC50) values of 1.4-7.0 μM) compared with the parent complex FM-190 (trans, trans, trans-[Pt(py)2(N3)2(OH)2]). Significant enhancement in Pt accumulation for 3 and 4 after irradiation probably contributes to their promising photocytotoxicity, especially for the tryptophan-conjugated complex 4.

Classical structure-activity relationships for square-planar Pt(II) anticancer complexes were based on the activity of cis-[PtCl2(NH3)2] (cisplatin) and inactivity of the trans isomer. Many other families of cis-diamine complexes and analogous octahedral Pt(IV) prodrugs are active. Here, we report the chemical and biological activities of isomeric photoactivatable cis,trans,cis- and all-trans-[Pt(N3)2(OH)2(MNZ)2] complexes (MNZ = metronidazole, 1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole). While both are relatively nontoxic in the ground state, only the all-trans isomer is cytotoxic toward bladder cancer cells on excitation with visible light and under hypoxia. Studies of DNA interstrand cross-links and photocytotoxicity toward wild-type and nucleotide-excision-repair deficient cells suggest that, unlike cisplatin, DNA is not the major target site of these isomers. Differences in photoactivation pathways were also explored using time-dependent DFT calculations. The key differences between the isomers on irradiation are the more rapid photoactivation of the all-trans complex, generation of azidyl radicals, retention of its metronidazole ligands, higher accumulation in cancer cells, binding to DNA, RNA, and proteins, and induction of apoptosis and mitochondrial membrane damages. These findings provide a basis for the design of future photochemotherapeutic platinum anticancer prodrugs.

There are currently fewer than ten antifungal drugs in clinical development, but new fungal strains, which are resistant to most current antifungals are spreading rapidly across the world. To prevent a second resistance crisis, new classes of antifungal drugs are urgently needed. Metal complexes have proven to be promising candidates for novel antibiotics, but so far, few compounds have been explored for their potential application as antifungal agents. In this work we report the evaluation of 1039 metal-containing compounds that were screened by the Community for Open Antimicrobial Drug Discovery (CO-ADD). We show that 20.9% of all metal compounds tested have antimicrobial activity against two representative Candida and Cryptococcus strains, compared with only 1.1% of the >300,000 purely organic molecules tested through CO-ADD. We identified 90 metal compounds (8.7%) that show antifungal activity while not displaying any cytotoxicity against mammalian cell lines or haemolytic properties at similar concentrations. The structures of 21 metal complexes which display high antifungal activity (MIC ≤ 1.25 µM) are discussed and evaluated further against a broad panel of yeasts. Most of these have not been evaluated for antifungal activity. Eleven of these metal complexes were tested for toxicity in the Galleria mellonella moth larvae model, revealing that only one compound showed signs of toxicity at the highest injected concentration. Lastly, we demonstrated that the organo-Pt(II) cyclooctadiene complex Pt1 significantly reduces fungal load in an in vivo G. mellonella infection model. These findings showcase that the structural and chemical diversity of metal-based compounds can be an invaluable tool in the development of new drugs against infectious diseases.

Capture of greenhouse gases, especially CO2, can reduce the effects of global warming and generate valuable minerals as feedstock for industry. Herein, the mineral products formed by capture of atmospheric CO2 by potassium hydroxide (KOH) in aqueous, aqueous‐ethanol, and aqueous‐acetone solutions, and aqueous‐acetone enriched using solid CO2 are studied. A multimodal analysis combining single‐crystal X‐ray diffraction (SCXRD), powder X‐ray diffraction (PXRD), with Pawley and Rietveld refinements, and 850 MHz, 1 GHz, and 1.2 GHz 1H, as well as 13C, and 39K nuclear magnetic resonance (NMR), is used to analyze the composition of the mineral products. SCXRD identifies KHCO3 in space group P21/n (transformable to P21/a) as a product from all reactions. PXRD and NMR data show the presence of both crystalline and amorphous phases in products, predominantly as mixtures of KHCO3 and K2CO3 and its hydrates, with KOH as a minor component, except for aqueous‐ethanol which gives KHCO3 in high purity. Analysis of complex 1H NMR data is aided by 2D nuclear Overhauser effect spectroscopy (1 GHz), which characterizes COH···OC interactions. Revealing K2CO3 hydration is aided by deconvolution of ultrahigh‐field 28.2 T (56 MHz) 39K spectra. This multimodal approach provides new insights into the speciation of potassium minerals from CO2 capture.

Photoactivatable metal complexes offer the prospect of novel drugs with low side effects and new mechanisms of action to combat resistance to current therapy. We highlight recent progress in the design of platinum, ruthenium, iridium, gold and other transition metal complexes, especially for applications as anticancer and anti-infective agents. In particular, understanding excited state chemistry related to identification of the bioactive species (excited state metallomics/pharmacophores) is important. Photoactivatable metallodrugs are classified here as photocatalysts, photorelease agents and ligand-activated agents. Their activation wavelengths, cellular mechanisms of action, experimental and theoretical metallomics of excited states and photoproducts are discussed to explore new strategies for the design and investigation of photoactivatable metallodrugs. These photoactivatable metallodrugs have potential in clinical applications of Photodynamic Therapy (PDT), Photoactivated Chemotherapy (PACT) and Photothermal Therapy (PTT).

Normal functioning of the human brain is dependent on adequate regulation of essential metal nutrients. However, it is also highly sensitive to metal-mediated toxicity, linked to various neurodegenerative disorders. Exposure to environmental metal sources (especially to particulate air pollution) can stimulate toxicity and neuropathologic effects, which is particularly evident in populations chronically exposed to high levels of air pollution. Identifying the sources of metal-rich deposits in the human brain is important in not only distinguishing the effects of environmentally acquired metals from endogenous metal dysregulation, but also for tracing pollutant sources which may be subject to exposure control. This perspective reviews evidence for key physicochemical properties (size/morphology, chemical composition, oxidation state, magnetic properties, and isotopic composition) concerning their capacity to distinguish sources of metals in the brain. The scope for combining analytical techniques to study properties in tandem is also discussed.

Photoactive diazido Pt(iv) complexes display in vivo anticancer efficacy towards oesophageal tumours, a worldwide common cancer. Here we explore the use of optical coherence tomography (OCT) as a new method for detecting tissue penetration and damage produced by the photoactivatable anticancer complex trans,trans,trans-[Pt(pyridine)2(N3)2(OH)2] (FM190). Dehydration of the sample and a change in refractive index were observed for swine oesophageal tissue treated with FM190 and blue laser light (445 nm) using an OCT system. In contrast, tissues treated with FM190 or laser light alone showed no apparent damage.

We report the synthesis and characterization of ten novel half‐sandwich Rh(III) azopyridine complexes as potential anticancer agents, with the general formula [(η 5 ‐Cp x )Rh(4‐R 2 ‐phenylazopy‐5‐R 1 )Cl]PF 6 , where Cp x = Cp*, Cp xPh or Cp xPhPh , R 1 = H, Br, or CF 3 , and R 2 = H, OH or NMe 2 . X‐ray crystallographic data for complex 2 (R 1 = Br, R 2 = OH, Cp x = Cp xPh ) and complex 3 (R 1 = CF 3 , R 2 = OH, Cp x = Cp xPh ) confirm their typical half‐sandwich “piano‐stool” geometry. The substituents have a major influence on the cytotoxicity of these complexes toward human ovarian (A2780 and cisplatin‐resistant A2780cis), lung (A549) and prostate (PC‐3) cancer cells, and non‐cancerous human lung fibroblasts (MRC‐5). Potencies range from sub‐micromolar to inactive (>50 µM). They were non‐cross‐resistant with cisplatin, and complex 9 (R 1 = H, R 2 = NMe 2 , Cp x = Cp * ) showed some selectivity (>3x) for A549 cancer cells versus normal cells. The highly active, lipophilic complex 2 was strongly accumulated by cells and catalyzed the oxidation of NADH (reduced nicotinamide adenine dinucleotide) to NAD + , and GSH (glutathione) to GSSG. Notably, complex 2 is almost an order of magnitude less toxic toward zebrafish in vivo than cisplatin, despite being 10‐fold more active in A549 cells. These studies demonstrate how the chemical and biological activities of this series of half‐sandwich organorhodium(III) complexes can be finely tuned by the choice of substituents on the cyclopentadienyl and azopyridine ligands. The complexes appear to have an unusual mechanism of anticancer activity, associated not only with Rh(III) but also with the phenylazopyridine, cyclopentadienyl, and the chlorido ligands.

The accumulation of amyloid plaques and increased brain redox burdens are neuropathological hallmarks of Alzheimer's disease. Altered metabolism of essential biometals is another feature of Alzheimer's, with amyloid plaques representing sites of disturbed metal homeostasis. Despite these observations, metal-targeting disease treatments have not been therapeutically effective to date. A better understanding of amyloid plaque composition and the role of the metals associated with them is critical. To establish this knowledge, the ability to resolve chemical variations at nanometer length scales relevant to biology is essential. Here, we present a methodology for the label-free, nanoscale chemical characterization of amyloid plaques within human Alzheimer's disease tissue using synchrotron X-ray spectromicroscopy. Our approach exploits a C-H carbon absorption feature, consistent with the presence of lipids, to visualize amyloid plaques selectively against the tissue background, allowing chemical analysis to be performed without the addition of amyloid dyes that alter the native sample chemistry. Using this approach, we show that amyloid plaques contain elevated levels of calcium, carbonates, and iron compared to the surrounding brain tissue. Chemical analysis of iron within plaques revealed the presence of chemically reduced, low-oxidation-state phases, including ferromagnetic metallic iron. The zero-oxidation state of ferromagnetic iron determines its high chemical reactivity and so may contribute to the redox burden in the Alzheimer's brain and thus drive neurodegeneration. Ferromagnetic metallic iron has no established physiological function in the brain and may represent a target for therapies designed to lower redox burdens in Alzheimer's disease. Additionally, ferromagnetic metallic iron has magnetic properties that are distinct from the iron oxide forms predominant in tissue, which might be exploitable for the in vivo detection of amyloid pathologies using magnetically sensitive imaging. We anticipate that this label-free X-ray imaging approach will provide further insights into the chemical composition of amyloid plaques, facilitating better understanding of how plaques influence the course of Alzheimer's disease.

DFT calculations on a conjugate of ferrocene to an octahedral Pt( iv ) complex reveal Fe-to-Pt charge transfer, promoting longer-wavelength photoactivation, enhanced cellular accumulation, potent anticancer activity, and cell death via ferroptosis.

Cisplatin is a DNA-targeting chemotherapeutic. We have utilized a forward chemical genetics strategy to map 7585 cisplatin-damaged genes (CDGs) with a fold-enrichment of >12 from A549 human lung cancer cells. The highly associated signalling pathways of the CDGs include sperm motility, molecular mechanism of cancer, and protein kinase A signalling. Among the CDGs, there are 1330 enzyme, 747 transcription regulators and 486 transporter genes. Importantly, cisplatin targets 306 protein kinase genes, accounting for 59% of putative protein kinase genes in the human genome, and 92 protein phosphatase genes which account for 67.6% of all protein phosphatases in the human genome. This suggests that cisplatin can reprogram protein phosphorylation genome-wide, evidenced by cisplatin-induced reduction in expression of 7 protein kinase genes in the sperm motility signalling pathway, and by CRISPR/dCas9-mediated imaging, which showed that cisplatination on the PTPRN2 gene recruits HMGB1, but repels Smad3, a transcription factor. Silencing NCCIT testicular cancer cell SPAG9 , which expresses JIP-4 in testicular haploid germ cells to activate MAPK signalling, resulted in similar apoptosis-inducing activity to cisplatin, implicating SPAG9 as a potential target for precise testicular cancer therapy.### Competing Interest StatementWe have documented selected cisplatin-damaged genes as potential drug targets and biomarkers for cancer therapy in a Chinese patent application.

Bladder cancer is a common cancer globally that suffers from expensive treatment, drug and hypoxia resistance, and high recurrence rate. A series of six novel diazido Pt(iv) complexes with the general formula trans, trans, trans-[Pt(N-3)(2)(OH)(2)(L)(2)] and various equatorial N-heterocyclic amine ligands (L = pyridines: 1 and 3-6; or imidazole: 2) have been synthesised and characterised, including their X-ray crystal structures, and their photoactivation investigated. The L-substituents modify the photocytotoxicity of these complexes towards bladder cancer cells significantly. In general, strong electron-withdrawing substituents result in higher photocytotoxicity compared to unsubstituted trans, trans, trans-[Pt(N-3)(2)(OH)(2)(py)(2)] (FM190) and enhanced photocytotoxicity under hypoxia than normoxia, but higher dark cytotoxicity as well. Among them, the nitroimidazole complex 2, trans, trans, trans-[Pt(N-3)(2)(OH)(2)(1-methyl-5-nitroimidazole)(2)], exhibits low dark cytotoxicity and promising photocytotoxicity with blue-light irradiation IC50 values < 5 mu M towards a series of bladder cancer cell lines under both normoxia and hypoxia. Notably, its green-light photocytotoxicity was significantly enhanced (>15x) under hypoxia compared to normoxia. Low cytotoxicity (IC50 14.4-100 mu M) was observed towards normal bladder cells, even upon irradiation. Although photoinduced ROS generation, apoptosis and lipid peroxidation were observed for 2 under normoxia rather than hypoxia, high nuclear Pt accumulation, increased photoactivation in the medium, significantly enhanced cellular Pt accumulation and mitochondrial membrane potential changes upon irradiation under hypoxia were observed. These results suggest different mechanisms of action for 2 under normoxia and hypoxia. In addition, 2 exhibited high liver microsomal dark stability and photo-enhanced Pt accumulation in rat bladder. Based on these results, complex 2 is a promising candidate for phototherapeutic bladder cancer treatment.

Anticancer agents that exhibit catalytic mechanisms of action offer a unique multi-targeting strategy to overcome drug resistance. Nonetheless, many in-cell catalysts in development are hindered by deactivation by endogenous nucleophiles. We have synthesised a highly potent, stable Os-based 16-electron half-sandwich ('piano stool') catalyst by introducing a permanent covalent tether between the arene and chelated diamine ligand. This catalyst exhibits antiproliferative activity comparable to the clinical drug cisplatin towards triple-negative breast cancer cells and can overcome tamoxifen resistance. Speciation experiments revealed Os to be almost exclusively albumin-bound in the extracellular medium, while cellular accumulation studies identified an energy-dependent, protein-mediated Os accumulation pathway, consistent with albumin-mediated uptake. Importantly, the tethered Os complex was active for in-cell transfer hydrogenation catalysis, initiated by co-administration of a non-toxic dose of sodium formate as a source of hydride, indicating that the Os catalyst is delivered to the cytosol of cancer cells intact. The mechanism of action involves the generation of reactive oxygen species (ROS), thus exploiting the inherent redox vulnerability of cancer cells, accompanied by selectivity for cancerous cells over non-tumorigenic cells.

The 16e square-planar bis-thiolato-Au(iii) complexes [AuIII(1,2-dicarba-closo-dodecarborane-1,2-dithiolato)2][NBu4] (Au-1) and [AuIII(4-methyl-1,2-benzenedithiolato)2][NBu4] (Au-2) have been synthesized and fully characterized. Au-1 and Au-2 were encapsulated in the symmetrical triblock copolymer poloxamer (Pluronic (R)) P123 containing blocks of poly(ethylene oxide) and poly(propylene oxide), giving micelles AuMs-1 and AuMs-2. High electron flux in scanning transmission electron microscopy (STEM) was used to generate single gold atoms and gold nanocrystals on B/S-doped graphitic surfaces, or S-doped amorphous carbon surfaces from AuMs-1 and AuMs-2, respectively. Electron energy loss spectroscopy (EELS) data suggested strong interactions of gold atoms/nanocrystals with boron in the B/S-doped graphitic matrix. Density-functional theory (DFT) calculations, also supported the experimental findings, pointing towards strong Au-B bonds, depending on the charge on the Au-(B-graphene) fragment and the presence of further defects in the graphene lattice. Single Au atoms and Au nanocrystals on doped graphitic surfaces generated by beam irradiation of micelle-encapsulated Au complexes in an aberration-corrected scanning transmission electron microscope, exhibit strong Au-B interactions.

The novel hetero-dinuclear complex trans , trans , trans -[Pt IV (py) 2 (N 3 ) 2 (OH)(μ-OOCCH 2 CH 2 CONHCH 2 -bpyMe)Ir III (ppy) 2 ]Cl ( Pt-Ir ), exhibits charge transfer between the acceptor photochemotherapeutic Pt(IV) ( Pt-OH ) and donor photodynamic Ir(III) ( Ir-NH 2 ) fragments. It is stable in the dark, but undergoes photodecomposition more rapidly than the Pt(IV) parent complex ( Pt-OH ) to generate Pt(II) species, an azidyl radical and 1 O 2 . The Ir(III) * excited state, formed after irradiation, can oxidise NADH to NAD⋅ radicals and NAD + . Pt-Ir is highly photocytotoxic towards cancer cells with a high photocytotoxicity index upon irradiation with blue light (465 nm, 4.8 mW/cm 2 ), even with short light-exposure times (10–60 min). In contrast, the mononuclear Pt-OH and Ir-NH 2 subunits and their simple mixture are much less potent. Cellular Pt accumulation was higher for Pt-Ir compared to Pt-OH . Irradiation of Pt-Ir in cancer cells damages nuclei and releases chromosomes. Synchrotron-XRF revealed ca . 4× higher levels of intracellular platinum compared to iridium in Pt - Ir treated cells under dark conditions. Luminescent Pt-Ir distributes over the whole cell and generates ROS and 1 O 2 within 1 h of irradiation. Iridium localises strongly in small compartments, suggestive of complex cleavage and excretion via recycling vesicles (e.g. lysosomes). The combination of PDT and PACT motifs in one molecule, provides Pt-Ir with a novel strategy for multimodal phototherapy.

Neuromelanin-pigmented neurons of the substantia nigra are selectively lost during the progression of Parkinson's disease. These neurons accumulate iron in the disease state, and iron-mediated neuron damage is implicated in cell death. Animal models of Parkinson's have evidenced iron loading inside the nucleoli of nigral neurons, however the nature of intranuclear iron deposition in the melanised neurons of the human substantia nigra is not understood. Here, scanning transmission x-ray microscopy (STXM) is used to probe iron foci in relation to the surrounding ultrastructure in melanised neurons of human substantia nigra from a confirmed Parkinson's case. In addition to the expected neuromelanin-bound iron, iron deposits are also associated with the edge of the cell nucleolus. Speciation analysis confirms these deposits to be ferric (Fe3+) iron. The function of intranuclear iron in these cells remains unresolved, although both damaging and protective mechanisms are considered. This finding shows that STXM is a powerful label-free tool for the in situ, nanoscale chemical characterisation of both organic and inorganic intracellular components. Future applications are likely to shed new light on incompletely understood biochemical mechanisms, such as metal dysregulation and morphological changes to cell nucleoli, that are important in understanding the pathogenesis of Parkinson's. Showcasing the application of scanning transmission x-ray microscopy to study the oxidation state of intranuclear iron in nigral neurons. Implications and potential future applications are discussed.

The development of catalytic metallodrugs is an emerging field that may offer new approaches to cancer chemotherapeutic design. By exploiting the unique properties of transition metal complexes, in-cell catalysis can be applied to modulate the cellular redox balance as part of a multi-targeting mechanism of action. We describe the synthesis and characterization of six coordinatively unsaturated iridium(III) diamine catalysts that are stable at physiological pH in aqueous solution. Reduction of the colorimetric substrate 2,6-dichlorophenolindophenol by transfer hydrogenation under biologically compatible conditions achieved turnover frequencies up to 63 +/- 2 h-1 and demonstrated that the source of hydride (sodium formate) is the limiting reagent, despite being in a 1000-fold excess of the catalyst. The catalyst showed low in vivo acute toxicity in zebrafish embryos and modest in vitro potency towards cancer cells. When administered alone, the catalyst generated oxidative stress in cells (an effect that was conserved in vivo), but co-treatment with a nontoxic dose of sodium formate negated this effect. Co-treatment with sodium formate significantly enhanced catalyst potency in cancer cells (A2780 ovarian and MCF7 breast cancer cells) and drug-resistant cells (A2780cis and MCF7-TAMR1) but not in non-tumorigenic cells (MRC5), demonstrating that a redox-targeting mechanism may generate selectivity for cancer cells. Modulation of cellular redox using an in-cell catalyst exploits an inherent vulnerability of cancer cells. Iridium sulfonamide catalysts generate oxidative stress in cells (an effect that is conserved in vivo), and potency is significantly enhanced upon coadministration of nontoxic sodium formate to initiate in-cell transfer hydrogenation. This redox-targeting mechanism can overcome drug resistance and shows selectivity for cancer cells over non-tumorigenic cells. image

HPLC-ICPMS with LC-MS allows identification of products from photoactivation of a diazido Pt( iv ) anticancer complex by visible light under physiologically-relevant conditions, including novel polyhyroxido Pt( iv ) species, potential pharmacophores.