Metals exert various effects on all aspects of epigenetics. Yet, the effect metals expend on histone proteins has remained under the radar. The current review article presents histones as metal-coordinating proteins, i.e. histone metalation, with a particular focus on the redox biochemistry underlying histone metalation. Almost 60 years of research in the field compiling biochemical, structural and functional evidence is covered. We provide an overview of eighteen different metals which have been shown to be coordinated by histones: Mg, Ca, Cr, Mn, Fe, Co, Ni, Cu, Zn, As, Ru, Cd, Sn, W, Pt, Au, Hg, and Pb. Investigation on histone metalation have been hampered by the difficulty of various experimental challenges, and research has therefore mainly focused on histone peptide sequences. Nonetheless, we review evolutionary conserved metal coordination at the H2A C-tail (-S121HH124-) and H3-H3' (-C110AIH113-) dimerization interface as the two most likely coordination entities of the histone octamer. The functional implications this has on the biochemical transcription and DNA damage processes in the cell nucleus are debated. Besides, we suggest a working mechanism of histone metalation: in transcription initiation via metal accessible euchromatin sites. We discuss limitations of the current structural, biochemical and functional research which has been conducted and provide novel perspectives and opportunities. Finally, we address the remaining future challenges and open questions.

In this study, half-sandwich Ru(II)-p-cymene complexes containing L-borneol-based biguanide ligands were synthesized, characterized and evaluated for their biological properties. Lipophilicity (logP) and hydrolysis studies demonstrated that the biguanide moiety and its substituents significantly influence hydration behavior. UV-Vis analyses confirmed CT-DNA binding for all compounds, with the ligands showing higher affinity than the corresponding Ru(II) complexes. Viscosity measurements suggested that DNA binding occurs predominantly through a groove-binding mechanism rather than intercalation. Fluorescence spectroscopy studies showed that the complexes interacted strongly with HSA under physiological conditions, with KSV values of the order of 1.07-5.5 × 10[4] M[-1]. At the cellular level, cytotoxicity was compared in HUVEC and YKG-1 cells, and compounds 3a, 3b, 4a and 4b were found to exhibit selective antiproliferative effects against YKG-1 cells. Furthermore, compounds 4a and 4b had high radical scavenging capacity and exhibited strong antioxidant activity. Complex 4b was found to significantly suppress the colony formation and wound healing capacity of YKG-1 cells and to trigger apoptotic cell death mechanisms. This suggests that L-borneol-containing biguanide derivatives and their Ru(II) complexes may be promising candidates for treating glioblastoma. Molecular docking analyses were conducted for Complex 4b, the most active compound identified based on its in vitro HSA-binding, DNA-binding, and anticancer activities, to designate its molecular interaction profile with the selected biological target.

Macrocyclic scaffolds have become increasingly important in modern drug discovery owing to their structural preorganization, favorable pharmacological properties, and widespread incorporation into peptide- and amino acid-based therapeutics. In contrast, the integration of biologically relevant amino acid architectures into organometallic macrocycles remains largely unexplored, particularly for redox-active gold complexes. Herein, we report the design, synthesis, structural characterization, and biological evaluation of a new class of l-lysine-derived Au(III) bisphosphine macrocycles, exemplified by JH-121, together with related amino acid-expanded analogues. Incorporation of the flexible lysine backbone provides a distinct ligand environment that preserves the stability of the Au(III) center while imparting unique redox properties absent in conventional nitrogen-donor macrocycles. JH-121 exhibits potent antiproliferative activity across multiple breast cancer cell lines and inhibits breast cancer mammosphere growth under the experimental conditions examined. Spectroscopic, stability, and electrochemical studies demonstrate that the expanded amino acid backboned macrocycle has a distinct, irreversible, thiol-triggered Au(III)-Au(I) conversion, leading to the formation of an isolable Au(I) species that retains robust anticancer activity. These findings identify amino acid-derived bisphosphine macrocycles as a versatile platform for engineering the redox behavior of gold complexes and establish biologically inspired ligand design as a promising strategy for the development of next-generation gold-based anticancer therapeutics.

Despite the success of the three platinum-based drugs approved worldwide by the Food and Drug Administration (cisplatin, oxaliplatin, and carboplatin), there has been over the years intense research to identify new metal-based anticancer drugs with enhanced and/or a broader spectrum of activity and a lower toxicity. To this aim, the interest in natural products has increased since they are relatively safe. Several studies report that cinnamic acid exhibits antioxidant, antimicrobial, anticancer, neuroprotective, anti-inflammatory, and antidiabetic properties. Thus, in this study we aimed to bind two trans-cinnamate residues to a Pt(II) complex with the aim to develop a potential multifunctional prodrug capable to release two pharmacologically active moieties after hydrolysis in the tumor cells. We synthesized three new Pt(II) complexes with ethylenediamine (en, 1), 1R,2R-diaminocyclohexane (1R,2R-DACH, 2) and cis-1,3-diaminocyclohexane (cis-1,3-DACH, 3) as carrier ligands and two trans-cinnamate as leaving ligands. Interestingly, complexes 1 and 2 underwent a transformation into the corresponding organometallic complexes in methanol. All the compounds were fully characterized by electrospray ionization mass spectrometry and nuclear magnetic resonance spectroscopy. Finally, as an initial stage of biological evaluation, the in vitro cytotoxic activity of the newly synthesized Pt(II) complexes was assessed against a selected panel of human cancer cell lines. In parallel, preliminary mechanistic studies were conducted to better elucidate the underlying cellular and molecular processes responsible for their anticancer effects and to gain deeper insight into their possible mode of action.

Fluorescent protein-based metal ion sensors have played central roles in elucidating the dynamics, trafficking, and homeostasis of metals across biological systems. Many of these platforms have combined proteins from the green fluorescent protein (GFP) family and mFruits with metal-sensitive binding domains like calmodulin or zinc fingers. These sensors have often been well-optimized and widely used but given their reliance on GFPs they cannot be applied in living systems under low oxygen conditions. GFPs and mFruits contain an intrinsic fluorophore that requires oxygen to form. Alternative oxygen-independent cofactor-binding fluorescent proteins utilize extrinsic chromophores that do not require oxygen to bind and impart fluorescence. This review will focus on using flavin- and bilin-based fluorescent proteins as platforms for metal ion sensors that do not require oxygen. We organize these oxygen-independent metal sensors into three categories, those based on green-emitting flavin-based fluorescent proteins, far-red/near-infrared-emitting biliverdin IXα-based fluorescent proteins, and orange fluorescent phycoerythrobilin-binding cyanobacteriochrome-based fluorescent proteins. The aim of this review is to provide a detailed compilation and analysis of the utility of each of these groups of fluorescent proteins for developing metal ion biosensors. We describe the background and highlight protein engineering efforts underlying each category of proteins and then examine metal ion sensors that have been developed, in our work and by others, using these flavin- and bilin-based fluorescent proteins. We also discuss challenges and directions for future studies, drawing inspiration from the GFP toolbox of metal ion sensors and including routes for developing and applying advanced cofactor-binding fluorescent protein-based metal sensors.

Copper speciation plays a central role in modulating redox reactivity and biological responses under oxidative stress conditions, for example in soybean (Glycine max (L.) Merr.) under salt stress. In this study, a series of Cu(II)-amino acid complexes (Cu(aa)2) containing glycine, serine, histidine, tryptophan and tyrosine were synthesized and characterized by elemental analysis, infrared spectroscopy, mass spectrometry, and ultraviolet-visible spectroscopy. Their reactivity toward superoxide was evaluated using the riboflavin-nitro blue tetrazolium assay and potassium superoxide kinetic assays as chemical models of reactive oxygen species (ROS) interaction. The complexes displayed ligand-dependent superoxide reactivity, with Cu(His)2 showing the highest kinetic response toward KO2-derived superoxide species. Selected compounds were subsequently evaluated in soybean plants subjected to acute salt stress to investigate the relationship between the copper coordination environment and physiological responses. Histochemical analyses revealed marked differences among treatments: whereas CuCl2 promoted increased ROS accumulation and phytotoxicity, Cu(aa)2 complexes reduced superoxide and hydrogen peroxide levels while maintaining lower toxicity. Among the evaluated compounds, Cu(His)2 exhibited the most consistent behavior, combining high chemical reactivity with effective ROS reduction in planta and moderate copper accumulation in leaf tissues. These findings demonstrate that ligand coordination strongly influences copper behavior, decoupling in vitro reactivity from biological outcome under stress conditions. Overall, the results establish a structure-reactivity-biological response relationship for Cu(II)-amino acid complexes and highlight the importance of copper speciation in the design of safer redox-active compounds for biological applications.

The emission of toxic metals into the global environment poses threats to ecosystems and human health that are incompletely understood. Since Ni is widely used for the manufacturing of alloys used in the high-tech industry, certain human populations are exposed to this carcinogenic and neurotoxic metal near mines and manufacturing sites. After Ni[2+] is absorbed from the gastrointestinal tract into the bloodstream, it is distributed to target organs by poorly understood bioinorganic processes which ultimately define its exposure-response relationship. To gain insight, we have employed size exclusion chromatography (SEC) using a 25 mM Tris buffer (pH 7.4) mobile phase hyphenated to a flame atomic absorption spectrometer (FAAS) as the Ni-specific detector. The chromatography of a Ni-human serum albumin (HSA) complex on this SEC-FAAS system revealed the elution of the intact complex. To delineate the role of small molecular weight ligands in plasma in the translocation of Ni[2+] from its HSA binding sites to target organs, we then chromatographed the HSA-Ni complex with mobile phases containing 2.0 mM L-cysteine, L-glutathione, N-acetyl-L-cysteine, DL-homocysteine, L-methionine, L-histidine (His) or taurine. Since His most effectively mobilized Ni[2+] from HSA, we also chromatographed the HSA-Ni complex with 1.5, 1.0 and 0.5 mM His mobile phases and observed a mobilization event. The latter results are of physiological relevance as histidinemia is a human condition in which plasma His concentrations can reach up to 1.4 mM. Accordingly, the perturbation of the metabolism of Ni[2+] in the blood-organ system of histidinemia patients may contribute to the disease outcome.

Responsive MRI probes are a powerful platform for the non-invasive detection of enzymatic activity in biological tissues. Herein, two series of DO3A-based molecular probes, LnL[1] and LnL[2] (Ln = Gd[3+], Tb[3+] and Tm[3+]), capable of responding to enzyme tyrosinase (TYR), were designed and evaluated. Ligands L[1-2] feature either an ester group (L[1]) or a carboxylic group (L[2]) on their side arms. Luminescence lifetimes of the Tb[3+] complexes in H2O and D2O revealed that both complexes have one water molecule in the inner-hydration sphere. UV-Vis studies revealed that both GdL[1] and GdL[2] undergo oxidative polymerization to form melanin-like polymers upon incubation with TYR, leading to a significant increase in longitudinal relaxivity. The Tm[3+] complexes exhibited chemical exchange saturation transfer (CEST) effect. Although [1]H NMR results indicated that both complexes predominantly adopt the SAP configuration, the hydrophilic carboxylic group and hydrophobic ester group impart subtle structural variations. These structural modulations consequently underlie the marked differences observed in CEST effect and relaxivity behaviors upon enzyme catalysis, which paves the way to design desirable MRI agents via minor structural modification.

The challenging design of artificial metalloenzymes can be achieved by bioconjugation based on the targeted insertion of synthetic metal coordination motif on a peptide that can subsequently be covalently attached to a protein scaffold. The Spy system, consisting of a protein domain, SpyCatcher, which reacts spontaneously with a short peptide, SpyTag, forming a covalent isopeptide bond, can be used for this purpose. In this work, a SpyTag peptide functionalized with a histidine-based domain is engineered to bind hemin both as a free peptide and after assembly with SpyCatcher. The binding between SpyTag and hemin occurs successfully with micromolar affinity, but the coordination of hemin with reconstituted Spy protein (the SpyTag/SpyCatcher adduct) is not maintained with the same strength. The hemin-SpyTag peptide complex displays enhanced reactivity towards the activation of hydrogen peroxide in oxidative reactions, while the SpyTag/SpyCatcher adduct does not significantly affect hemin reactivity. Neither system exhibits substantial catalase-like activity. All tested components act as ROS scavengers, likely due to oxidative modifications undergone by the peptide/protein backbone. Overall, the study provides a solid experimental and methodological basis and highlights the need to improve hemin binding within the Spy system for future optimization and development of more advanced artificial hemoproteins.

Adamantane-based compounds have gained significant interest in drug discovery due to their versatile therapeutic potential and hydrophobic character, which allows for structural modifications across a wide range of drug classes. Their distinct structural and physicochemical properties continue to make them valuable assets in the design and development of new pharmaceuticals. Herein, we report the synthesis of three new metal complexes derived from an adamantane-appended tridentate koneramine ligand (L[kAd]), coordinated with Cu(II), Zn(II), and Fe(III). These complexes exhibit good stability and have been thoroughly characterized using ESI-MS, Nuclear Magnetic Resonance spectroscopy, and single-crystal X-ray diffraction (SCXRD) analysis. The crystal structures of the [Cu(L[kAd])Cl2], [Zn(L[kAd])Cl2], and [Fe(L[kAd])Cl3] complexes revealed that Cu(II) and Zn(II) ions occupy distorted trigonal bipyramidal and distorted square pyramidal geometries, respectively, while Fe (III) adopts a distorted octahedral coordination environment. All the three metal complexes were evaluated for their antiproliferative activities against one human cancer cell line, human triple negative breast cancer cells MDA-MB-231 and non-cancerous human embryonic kidney cells (HEK-293).

This focussed review provides the authors' perspective on how H2O2-induced, heme-mediated hole hopping in heme peroxidases expands their substrate diversity and hence physiological roles. First, the reported substrate diversity and functions of heme peroxidases are reviewed and an overview of hole hopping in oxidoreductases is provided. Following a concise introduction to peroxidase Compound I formation, regulation of hole donation to the polypeptide by residues surrounding the heme is considered. Studies from the literature of substrate oxidation by lactoperoxidase and lignin peroxidase are then briefly discussed with a focus on increased substrate diversity through hole hopping. Lastly, we recap our extensive mapping of hole hopping in yeast mitochondrial cytochrome c peroxidase (CCP) based largely on characterization of its oxidized proteoforms by mass spectrometry. Our unexpected findings on recombinant CCP and that isolated from yeast cells reveal how hole hopping unlocks unprecedented physiological functions for this heme peroxidase.

Metal complexes possess unique spatial coordination frameworks and tunable biological functions, rendering them promising candidates for antitumor drug development. Herein, we rationally designed and synthesized a novel copper(II) complex Cu1 with the molecular formula Cu1(Cu(L)2(ClO4)2·2H2O, C36H26Br2Cl2CuN8O10S2, where the ligand L corresponds to 2-([2,2':6',2″-terpyridin]-4'-yl)-4-bromothiazole. We systematically characterized its antitumor potency toward triple-negative breast cancer (TNBC) and dissected the underlying immunomodulatory mechanisms. UV-vis absorption titration and viscosity assays validated that Cu1 binds tightly to duplex DNA primarily via an intercalative binding mode. In cellular experiments, Cu1 exhibited potent cytotoxicity against both MDA-MB-231 and 4T1 cells, accompanied by pronounced nuclear accumulation and DNA damage. Mechanistically, Cu1 triggered massive intracellular reactive oxygen species (ROS) accumulation, activated the cGAS-STING axis coupled with endoplasmic reticulum (ER) stress, and elicited canonical immunogenic cell death (ICD), as validated by calreticulin (CRT) membrane translocation, HMGB1 cytoplasmic release, and elevated extracellular ATP secretion. Furthermore, Cu1 initiated Caspase-1/GSDMD-mediated pyroptosis. In both tumor vaccination and 4T1 orthotopic tumor-bearing mouse models, Cu1 displayed robust in vivo antitumor activity by orchestrating systemic antitumor immunity: it promoted dendritic cell (DC) maturation, boosted intratumoral CD8+ T cell infiltration, diminished immunosuppressive Foxp3+ regulatory T cells (Tregs), and established long-lasting tumor-specific immune memory. Collectively, Cu1 represents a multifunctional copper coordination complex that integrates direct tumoricidal activity and immunoregulatory capacity. This work delivers comprehensive experimental evidence supporting the translational development of copper-based therapeutic agents for TNBC chemoimmunotherapy.

Artificial metalloenzymes, which are formed by inserting inorganic complexes into biological scaffolds, have attracted interest as a potential biotechnological alternative of natural enzymes. In this study, vanadium complexes were incorporated as artificial active sites for sulfoxidation catalysis within NikA, a bacterial Ni(II) import protein. Two of the designed metal complexes, namely VOL1 and VOL3, which are based on either an amino alcohol or an amino acid ligand, respectively, were spectroscopically and structurally characterized, demonstrating transformation of a VOL3 into a VO(L3)2 species. This study has highlighted the capacity of NikA to bind inorganic complexes at different sites. Unlike VOL3, VO(L3)2 complex is stabilized within the well-characterized natural binding site. Conversely, the planar structure of VOL1 prevents similar binding, instead allowing a novel binding mode within the protein. VOLX@NikA-based cross-linked enzyme crystals were then used as catalysts for sulfide oxidation. This work highlights the versatility of the NikA protein in binding inorganic complexes, as well as the different reactivities of VOLX-based cross-linked enzyme crystals (CLEC) in catalyzing oxidation reactions.

In modern science, metal ions are significant because they are essential in our biological processes and the environment. Chemosensors such as colorimetric and fluorescent material having heterocyclic based analogues such as pyrrole, furan, thiophene, pyridine, quinoline and pyrazole etc. have been designed in such a manner so that it can detect various metal ions with significant advantages like low-cost value, highly sensitive, higher binding constant and should be very convenient to handle. This review delivers an insight into the emerging findings on chemosensors and the number of strategies related to the sensing mechanisms. Chemosensors having heterocyclic analogues provides valuable information and inspire the development of more effective approaches toward chemosensors and their utilities in biological and environmental science.

A series of three water-soluble methylenetrimethylammonium α-N-heterocyclic thiosemicarbazones (TSCs) was synthesized and characterized, and their proton dissociation and complex formation equilibria with Cu(II), Fe(II), and Fe(III) were studied using UV-visible, NMR, and electron paramagnetic resonance spectroscopic methods. In addition, the structures of one ligand and one Cu(II) complex were determined by single-crystal X-ray diffraction, revealing that the Cu(II) complex adopts coordination of the Schiff base through an (N,N,S) donor set. The interaction of the most active Cu(II) complex with human serum albumin-stabilized gold nanoclusters was also investigated to explore the association of the two systems and the impact of this protein-based matrix on the stability of the complex. The effect of the -CH2-N(CH3)3[+] substituent in position 6 of the pyridine ring on the solution chemical properties and cytotoxicity was examined. At physiological pH, the positively charged species dominate for all compounds studied, providing excellent aqueous solubility. The -CH2-N(CH3)3[+] moiety resulted in lower stability of the metal complexes compared to their corresponding non-substituted TSC analogues. Complexation with Cu(II) enhanced the activity against human colon adenocarcinoma (Colo205) and lung adenocarcinoma (A549) cell lines, although only moderate cytotoxicity was observed. Association with the protein-stabilized gold nanoclusters induced partial dissociation of the selected Cu(II) complex. Overall, while the methylenetrimethylammonium group in position 6 of the pyridine ring improves aqueous solubility, it adversely affects both metal ion binding capacity and in vitro cytotoxicity against cancer cell lines.