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AbstractHydrolytically stable PdII and PtII complexes supported by acyclic diaminocarbene ligands represent a novel class of structural organometallic anticancer agents exhibiting nanomolar antiproliferative activity in a panel of cancer cell lines (IC50 0.07–0.81 μM) and up to 300‐fold selectivity for cancer cells over normal primary fibroblasts. The lead drug candidate was 300 times more potent than cisplatin in vitro and showed higher efficacy in reducing the growth of aggressive MDA‐MB‐231 xenograft tumors in mice. Show less

This investigation sought to understand how physical activity, sleep quality, and depression interrelate among university students in a particular region of China. It involved a diverse group of 2363 students from three institutions, using a cross-sectional approach with well-established measurement tools. These tools demonstrated strong reliability and validity, with Cronbach's alpha values indicating robust internal consistency. The data revealed that higher levels of physical activity were inversely related to depression and directly related to better sleep quality, highlighting the potential of exercise and sleep improvement to reduce depressive symptoms among this demographic. Show less

DNA structure has many potential places where endogenous compounds and xenobiotics can bind. Therefore, xenobiotics bind along the sites of the nucleic acid with the aim of changing its structure, its genetic message, and, implicitly, its functions. Currently, there are several mechanisms known to be involved in DNA binding. These mechanisms are covalent and non-covalent interactions. The covalent interaction or metal base coordination is an irreversible binding and it is represented by an intra-/interstrand cross-link. The non-covalent interaction is generally a reversible binding and it is represented by intercalation between DNA base pairs, insertion, major and/or minor groove binding, and electrostatic interactions with the sugar phosphate DNA backbone. In the present review, we focus on the types of DNA–metal complex interactions (including some representative examples) and on presenting the methods currently used to study them. Show less

AbstractG-quadruplex DNA secondary structures are formed in guanine-rich sequences and have been found to play an important role in regulating different biological processes. Indeed, guanine-rich sequences with the potential to form G-quadruplexes are present in different regions in the human genome, such as telomeres and the promoter region of different genes, including oncogene promoters. Thus, the rational design of small molecules capable of interacting, stabilising or damaging with high specificity these secondary structures represents an important strategy for the development of potent anticancer drugs. In this review, we highlight the interaction between G-quadruplex structures and their ligands, specifically emphasising the role of metal complexes. We provide detailed structural insight into the binding modes of metal complex-G-quadruplex interaction by analysing 18 sets of coordinates from X-ray and NMR currently available in the Protein Data Bank (PDB), with a primary focus on X-ray structural data. Show less

As the most frequent and deadly type of cancer in women, breast cancer has a high propensity to spread to the brain, bones, lymph nodes, and lungs. The discovery of cisplatin marked the beginning of the development of anticancer metal-based medications, although the drug's severe side effects have limited its usage in clinical settings. The remarkable antimetastatic and anticancer activity of different ruthenium complexes such as NAMI-A, KP1019, KP1339, etc. reported in the 1980s has bolstered the discovery of ruthenium complexes with various types of ligands for anticancer applications. The review meticulously elucidates the cytotoxic and antimetastatic potential of reported ruthenium complexes against breast cancer cells. Notably, arene-based and cyclometalated ruthenium complexes emerge as standout candidates, showcasing remarkable potency with notably low IC50 values. These findings underscore the promising therapeutic avenues offered by ruthenium-based compounds, particularly in addressing the challenges posed by conventional treatments in refractory or aggressive breast cancer subtypes. Moreover, the review comprehensively integrates a spectrum of ruthenium complexes, spanning traditional metal complexes to nano-based formulations and light-activated variants, underscoring the versatility and adaptability of ruthenium chemistry in breast cancer therapy. Show less

AbstractThe mitochondrial calcium uniporter (MCU) is a transmembrane protein that is responsible for mediating mitochondrial calcium (mCa2+) uptake. Given this critical function, the MCU has been implicated as an important target for addressing various human diseases. As such, there has a been growing interest in developing small molecules that can inhibit this protein. To date, metal coordination complexes, particularly multinuclear ruthenium complexes, are the most widely investigated MCU inhibitors due to both their potent inhibitory activities as well as their longstanding use for this application. Recent efforts have expanded the metal‐based toolkit for MCU inhibition. This concept paper summarizes the development of new metal‐based inhibitors of the MCU and their structure‐activity relationships in the context of improving their potential for therapeutic use in managing human diseases related to mCa2+ dysregulation. Show less

Herein, we present a comparative study on the chemistry and biological activity of N-heterocyclic carbene (NHC)Pt(II)/Au(I) complexes. Accordingly, representative compounds of the cis/trans- [PtL2X2] (X = Cl (5, 6) or I (7, 8)), [PtL3Cl]+ (9), [AuLX] (X = Cl (10) or I (11)), and [AuL2]+ (12) type, where L is 1,3-diethylbenzimidazol-2-ylidene, were synthesized and characterized in detail to elucidate the role of the metal center on their physicochemical and biological properties. The stability of the complexes in the presence of cell culture medium and their reactivity toward relevant biomolecules were investigated by RP-HPLC. In addition, their effects on plasmid DNA and in vitro cytotoxicity in ovarian cancer cells and non-malignant fibroblasts were evaluated. Cationic [AuL2]+ and [PtL3X]+ species displayed the highest cytotoxicity and stability in cell culture medium in the series. They exhibited IC50 values lower than the established metallodrugs cisplatin and auranofin in both wild-type and cisplatin-resistant ovarian cancer cells, being able to circumvent cisplatin resistance. Finally, Pt(II)–NHC complexes form 5′-guanosine monophosphate adducts under physiologically relevant conditions and interact with plasmid DNA in contrast to their Au(I) analogs, corroborating their distinct modes of action. Show less

The great clinical success of cisplatin and its derivatives has convinced people that metal complexes could play a more significant role in human cancer therapy. However, targeting and drug resistance are still two dominant problems that need to be urgently solved for metallodrugs’ efficacy and clinical translation. As an important component of metal complexes, organometallics have been experiencing rapid development in recent years. Compared with platinum drugs, emerging anti-tumor organometallics targeting dynamic bioprocesses provide an effective strategy to overcome conventional problems. This review focuses on burgeoning anti-tumor strategies and provides up-to-date advances in anti-tumor organometallics development based on their action mechanisms. Specifically, important tumor-overexpressed proteins and nucleic acids as organometallics’ anti-tumor targets are systematically presented, followed by organometallics that exert their anti-tumor activity by perturbing tumor intracellular energy/redox/metal/immune homeostasis. Finally, nine cell death pathways including apoptosis, paraptosis, autophagy, oncosis, necrosis, necroptosis, ferroptosis, pyroptosis, and immunogenic cell death (ICD) that can be induced by organometallics are reviewed, and their morphological and biochemical features are summarised. This review at the interface of chemistry, biology, and medicine aims to enlighten the rational development of organometallic anti-tumor agents. Show less

Treatment of triple-negative breast cancer (TNBC) has long been a medical challenge because of the lack of effective therapeutic targets. Targeting lipid, carbohydrate, and nucleotide metabolism pathways has recently been proven as a promising option in view of three heterogeneous metabolic-pathway-based TNBC subtypes. Here, we present a multimodal anticancer platinum(II) complex, named Pt(II)caffeine, with a novel mode of action involving simultaneous mitochondrial damage, inhibition of lipid, carbohydrate, and nucleotide metabolic pathways, and promotion of autophagy. All these biological processes eventually result in a strong suppression of TNBC MDA-MB-231 cell proliferation both in vitro and in vivo. The results indicate that Pt(II)caffeine, influencing cellular metabolism at multiple levels, is a metallodrug with increased potential to overcome the metabolic heterogeneity of TNBC. Show less

Two new 'hybrid' metallodrugs of Au(III) (AuTAML) and Cu(II) (CuTAML) were designed featuring a tamoxifen-derived pharmacophore to ideally synergize the anticancer activity of both the metal center and the organic ligand. The compounds have antiproliferative effects against human MCF-7 and MDA-MB 231 breast cancer cells. Molecular dynamics studies suggest that the compounds retain the binding activity to estrogen receptor (ERα). In vitro and in silico studies showed that the Au(III) derivative is an inhibitor of the seleno-enzyme thioredoxin reductase, while the Cu(II) complex may act as an oxidant of different intracellular thiols. In breast cancer cells treated with the compounds, a redox imbalance characterized by a decrease in total thiols and increased reactive oxygen species production was detected. Despite their different reactivities and cytotoxic potencies, a great capacity of the metal complexes to induce mitochondrial damage was observed as shown by their effects on mitochondrial respiration, membrane potential, and morphology. Show less

Transition-metal acyclic carbene complexes have received increasing attention in recent years. As acyclic carbene ligands show strong σ-donating properties comparable to N-heterocyclic carbene (NHC) ligands, transition-metal complexes with acyclic carbene ligands also demonstrate outstanding performance and functional properties similar to their NHC counterparts. Therefore, transition-metal acyclic carbene complexes are considered viable alternatives to NHC complexes in the development of metal-based functional materials. As transition-metal acyclic carbene complexes can be prepared from metal isocyanide synthetic precursors, substituents of different electronic and steric natures as well as functional moieties can be readily introduced into acyclic carbene ligands by changing the isocyanide ligand. Moreover, the open structure of acyclic carbene ligands has made their structure and the electronic properties strongly dependent on the substituents as well as the micro-environment. As a result, the functional properties of acyclic complexes can be drastically varied by rational molecular design of the ligands. The environmental sensitivity of the properties of these complexes also made them ideal for the development of stimuli-responsive materials and chemical sensors. In this article, the preparation, electronic properties and design of metal acyclic carbene complexes with different functional properties for the development of advanced materials are described. Show less

Metalation, the acquisition of metals by proteins, must avoid mis-metalation with tighter binding metals. This is illustrated by four selected proteins that require different metals: all show similar ranked orders of affinity for bioavailable metals, as described in a universal affinity series (the Irving-Williams series). Crucially, cellular protein metalation occurs in competition with other metal binding sites. The strength of this competition defines the intracellular availability of each metal: its magnitude has been estimated by calibrating a cells' set of DNA-binding, metal-sensing, transcriptional regulators. This has established that metal availabilities (as free energies for forming metal complexes) are maintained to the inverse of the universal series. The tightest binding metals are least available. With these availabilities, correct metalation is achieved. Show less

Abstract A novel mononuclear manganese(II) complex with 5-methyltetrazole and 4,7-dimethyl-1,10-phenanthroline is synthesized and characterized by physico-chemical methods (elemental and powder XRD analyses, IR spectroscopy). It is shown by the single-crystal XRD analysis that the coordination environment of the manganese(II) atom is a distorted octahedron. The stability of the complex in an aqueous solution and in phosphate-buffered saline is studied by optical spectroscopy. The cytotoxic activity of the obtained compound is studied on human laryngeal carcinoma cells (Hep-2) and non-cancerous human fibroblasts (MRC-5). The complex exhibits pronounced cytotoxic properties in the studied concentration range: IC50 is 11.1±0.4 µM on the Hep-2 cancer cell line and 0.63±0.05 µM on the MRC-5 line. Show less

Based on bis-hetarylhydrazone H2L, a condensation product of 2,6-diacetylpyridine with 2-hydrazinobenzoxazole, a series of mononuclear copper(II) coordination compounds have been synthesized: [Cu(HL)NO3], [Cu(HL)(H2O)]ClO4, [Cu(HL)X] (X = Br−, X = Cl−). The structure of the compounds has been studied by means of NMR, IR, ESR, X-ray absorption spectroscopy and X-ray single crystal diffraction methods. In the compounds the copper center is in the square pyramidal environment. All compounds have been screened in vitro for their cytotoxic activity against HepG2 and MRC-5 cell lines. The ligand H2L shows no cytotoxicity at tested concentrations (1–100 μM), while all the Cu(II) complexes exhibit significant dose-dependent cytotoxic effects with IC50 values in the range of 1.4–3.0 μM (HepG2 cells). Show less

Abstract The complex [Zn(Phen)(H2O)L2] (I), where HL is 5-benzyltetrazole, Phen is 1,10-phenanthroline, was synthesized. The compound was characterized by standard physicochemical methods (elemental analysis, powder X-ray diffraction, IR spectroscopy). According to X-ray diffraction data (CCDC no. 2220597), zinc coordination environment in the crystal structure of I corresponds to a distorted trigonal bipyramid. The ligand HL is monodentate and is coordinated via tetrazolate ring nitrogen. The stability of complex I was studied by NMR spectroscopy in DMSO. The cytotoxic properties of the compound were assessed against HepG-2 (hepatocellular carcinoma) and MRC-5 (noncancerous human fibroblasts) cells. Complex I exhibits weak cytotoxic properties in the studied concentration range (1–100 µM). Show less

Abstract Five coordination compounds [Cu2(Bipy)2L4]·C2H5OH (Iа, Ib), [Cu2(Dmbipy)2L4] (II), [Cu2(Phen)2L4]·H2O (IIIa), [Cu2(Dmphen)2L4] (IVa), and [Cu2(Phendione’)2L4]·2C2H5OH·2H2O (V) are synthesized from 5-(4-chlorophenyl)-1H-tetrazole (HL), where Bipy is 2,2'-bipyridine, Dmbipy is 4,4'-dimethyl-2,2'-bipyridine, Phen is 1,10-phenanthroline, Dmphen is 4,7-dimethyl-1,10-phenanthroline, and Phendione’ is 6-ethoxy-6-hydroxy-1,10-phenanthrolin-5-one. The crystal structures of the complexes are determined by X-ray diffraction (XRD) of single crystals (CIF files CCDC nos. 2225368 (Ia), 2225369 (Ib), 2225370 (II), 2225372 (IIIa), 2225373 (IVa), and 2225371 (V)). The compounds are binuclear due to the bridging function of the tetrazolate anion, and the coordination number of copper is five in all synthesized complexes. The cytotoxic activity of the complexes against the Hep2 and HepG2 cancer cell lines and non-cancerous human fibroblasts MRC-5 is studied. The complexes exhibit pronounced cytotoxic properties, and compound V has the maximum selectivity index with respect to the cancer cells. Show less

Despite the proven potential of metal complexes as therapeutics, the lack of computational tools available for the high-throughput screening of their interactions with proteins is a limiting factor toward clinical developments. To address this challenge, we introduce MetalDock, an easy-to-use, open access docking software for docking metal complexes to proteins. Our tool integrates the AutoDock docking engine with three well-known quantum software packages to automate the docking of metal-organic complexes to proteins. We used a Monte Carlo sampling scheme to obtain the missing Lennard-Jones parameters for 12 metal atom types and demonstrated that these parameters generalize exceptionally well. Our results show that the poses obtained by MetalDock are highly accurate, as they predict the binding geometries experimentally determined by crystal structures with high spatial reproducibility. Three different case studies are presented that demonstrate the versatility of MetalDock for the docking of diverse metal-organic compounds to different biomacromolecules, including nucleic acids. Show less

Abstract As a kind of multifunctional materials with high porosity, tunable pore structure and easy functionalization, coordination complexes have been widely used in various fields. Here, three complexes were prepared by self‐assembly with Co(II) ions using tetrazolylacetic acids as ligands, 2,2′,2′′‐(benzene‐1,3,5‐triyltris(2 H ‐tetrazole‐5,2‐diyl)) triacetic acid (H 3 tzpha), 2‐(5‐(pyrazin‐2‐yl)‐2 H ‐tetrazol‐2‐yl) propanoic acid (Hpztzma) and 2‐(5‐(pyridin‐2‐yl)‐2 H ‐tetrazol‐2‐yl) acetic acid (Hpytza), and were characterized by X‐ray crystallography. These complexes can also self‐assemble into nanoparticles (NPs) in aqueous solution by nanocoprecipitation. In vitro CCK‐8 assay on three kind of human cancer cells (HeLa, HepG2 and Huh7) cells showed these Co(II) complexes have the best cytotoxicity against HeLa cells. And complex 1 had a half maximal inhibitory concentration (IC 50 value) of 14.8 μg mL −1 , which was superior to 16.5 μg mL −1 and 15.2 μg mL −1 of complex 2 and 3 . In addition, the effect of different ligands on cancer cell ablation was explored. The results showed the three NPs can effectively inhibit the proliferation of cancer cells in vitro and provided a strategy on designing highly efficient anticancer materials based on coordination complexes. Show less

Transition metal coordination complexes have provided cancer treatment with new insights to overcome the limitations of current chemotherapeutic agents. Utilization of bifunctional tetrazole–carboxylate ligands with Zn(II) obtained two self-assembled complexes [Zn(HL1)(bipy)3/2(H2O)]·CH3OH·4(H2O) (1) (H3L1 = 1,3,5-tri(2-carboxymethyltetrazol-5-yl) benzene) and [Zn(L2)2(H2O)2]2·2H2O (2) (HL2 = (5-pyridin-3-yl-tetrazol-2-yl)-acetic acid). The X-ray diffraction results showed that the two complexes displayed a two-dimensional (2D) layer structure and a one-dimensional (1D) layer structure. Nanocoprecipitation with DSPE-PEG-2000 resulted in the formation of complex nanoparticles (NPS) with excellent water dispersion. In vitro CCK-8 assay indicated the two NPs exert high cytotoxicity and sensitivity and a low half-maximum inhibitory concentration (IC50) towards HeLa than HepG2 cells. In addition, the cytotoxicity was also confirmed by live/dead co-stained experiments. The presented experimental results showed the 1 and 2 NPs were capable of inhibiting cell proliferation in vitro and may help design coordination complex-based anticancer candidates for cancer cells. Show less

AbstractThe long‐standing history of platinum coordination complexes in nucleic acid recognition attests to the unique suitability of such species for therapeutic applications. Here, we report the synthetic exploration and development of a family of di‐imine ligands, and their platinum(II) complexes, elaborated on a 3‐(2‐pyridyl)‐[1,2,4]triazolo[4,3‐a]pyridine platform which, in its unsubstituted form, has recently been shown to display exceptional capabilities for guanine quadruplex (G4) targeting. The identification of facile, high‐yielding synthetic methods for the derivatization of this platform for the incorporation of additional sites of interactions with guanine quadruplex loops and grooves, along with the optimization of platinum(II) complexation methods, are discussed. Gratifyingly, preliminary biophysical screening of this novel family of binders validates all but one family members as robust G4 binders and highlights enhanced selectivity for quadruplex versus duplex DNA compared to the parent compound. These results bear promise for practical developments based on this platform. Show less

Cancer is characterized by abnormal cell differentiation in or on the part of the body. The most commonly used chemotherapeutic drugs are developed to target rapidly dividing cells, such as cancer cells, but they also damage healthy epithelial cells. This has serious consequences for normal cells and become responsible for the development of various disorders. Several strategies for delivering the cytotoxic drugs to cancerous sites that limit systemic toxicity and other adverse effects have recently been evolved. Among them, biomolecule-conjugated metal complexes-based cancer targeting strategies have shown tremendous advantages in cancer therapy. This review focuses on several chemoselective biomolecules-bound metal complexes as prospective cancer therapy-targeted agents. In this review, we presented the details of the various extra- and intracellular targeting mechanisms in cancer therapy. We also addressed the current clinical issues and recent therapeutic strategies in targeted cancer therapy that may pave a way for the future direction of metal complexes-based targeted cancer therapy. Show less

Cancer is the deadliest disease in the world behind heart disease. Sadly, this remains true even as we suffer the ravages of the Covid-19 pandemic. Whilst current chemo- and radiotherapeutic treatment strategies have significantly improved the patient survival rate, disease reoccurrence continues to pose a deadly risk for all too many patients. Incomplete removal of tumour cells from the body increases the chances of metastasis and developing resistance against current treatments. Immunotherapy represents a therapeutic modality that has helped to overcome these limitations in recent decades. However, further progress is needed. So-called immunogenic cell death (ICD) is a recently discovered and unique mode of cell death that could trigger this necessary further progress. ICD involves stimulation of a tumour-specific immune response as a downstream effect. Facilitated by certain treatment modalities, cells undergoing ICD can trigger the IFN-γ mediated immune response involving cytotoxic T cells (CTLs) and γδ T cells that eradicate residual tumour cells. In recent years, there has been a significant increase in the number of small-molecules being tested as potential ICD inducers. A large number of these ICD inducers are metal-based complexes. In fact, anticancer metal drugs based on Pt, Ru, Ir, Cu, and Au are now known to give rise to an immune response against tumour cells as the result of ICD. Advances have also been made in terms of exploiting combinatorial and delivery strategies. In favourable cases, these approaches have been shown to increase the efficacy of otherwise ICD "silent" metal complexes. Taken in concert, rationally designed novel anticancer metal complexes that can act as ICD inducers show promise as potential new immunotherapies for neoplastic disease. This Tutorial Review will allow the readers to assess the progress in this fast-evolving field thus setting the stage for future advances. Show less

Medicinal inorganic chemistry is a burgeoning subfield of medicinal chemistry that focuses on the development of metal-based diagnostic and therapeutic agents. This tutorial review aims to provide an introductory primer, present a timely overview of recent discoveries and identify current challenges and opportunities of the field. Three specific areas of discovery are highlighted herein. The first part focuses on metal-based radiopharmaceuticals for diagnostic and therapeutic purposes and specific design criteria for the development of radiopharmaceuticals that combine fundamental aqueous coordination chemistry with elucidation of pharmacokinetics. The second part describes approaches to photodynamic therapy with metal complexes. Here, photophysical characterization, combined with the challenge of careful control of the chemical behavior and selective biological deposition of transition metals with significant off-target toxicity, is discussed. In the third part, we summarize emerging strategies to modulate enzyme inhibition with coordination chemistry, while also highlighting the utility of the unique properties of metal ions for the characterization of mechanisms of action of these emerging diagnostic and therapeutic agents. Show less

Metal complexes have demonstrated significant antitumor activities and platinum complexes are well established in the clinical application of cancer chemotherapy. However, the platinum-based treatment of different types of cancers is massively hampered by severe side effects and resistance development. Consequently, the development of novel metal-based drugs with different mechanism of action and pharmaceutical profile attracts modern medicinal chemists to design and synthesize novel metal-based agents. Among non-platinum anticancer drugs, gold complexes have gained considerable attention due to their significant antiproliferative potency and efficacy. In most situations, the gold complexes exhibit anticancer activities by targeting thioredoxin reductase (TrxR) or other thiol-rich proteins and enzymes and trigger cell death via reactive oxygen species (ROS). Interestingly, gold complexes were recently reported to elicit biochemical hallmarks of immunogenic cell death (ICD) as an ICD inducer. In this review, the recent progress of gold(I) and gold(III) complexes is comprehensively summarized, and their activities and mechanism of action are documented. Show less