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Hepatocellular carcinoma (HCC) is a highly refractory malignancy, for which treatment relies on molecule targeted therapy and/or conventional chemotherapy in clinic. However, these approaches generally suffer from limited efficacy or severe toxicity, restricting their applications. Guided by the targeted drug conjugate (TDC) strategy, the pharmacophore of lenvatinib was modified by incorporating DN604 (C₆H₁₀N₂O₅Pt), a carboplatin analogue, to generate a Pt(II) complex Len-604 (C₃₀H₃₃ClN₈O₉Pt). This compound was found to possess the specific capability to bind to fibroblast growth factor receptor 4 (FGFR4) protein both in vitro and in vivo, facilitating targeted delivery of DN604 to tumor sites and consequently triggering serious DNA damage in cancer cells. It exhibited potent cytotoxicity against human hepatocellular carcinoma cell lines HUH-7 and SMMC-7721, with IC₅₀ values of 5.62 and 5.64 μM, respectively. Significantly, in HUH-7 xenograft models, Len-604 exhibited stronger antitumor activity than lenvatinib, while showing lower toxicity than cisplatin and its physical mixture with lenvatinib. Show less

Understanding ligand properties is essential for computational high-throughput screening of transition metal complexes. However, ligand properties such as net charge and other information such as their application area are often absent or inconsistently recorded in crystallographic datasets. Here, we construct a ligand dataset from 126,985 mononuclear transition metal complexes curated from the Cambridge Structural Database. Using an iterative charge-balancing workflow that combines complex charges, metal oxidation states, and consensus across crystallographic observations, we confidently assign net charges to 66,810 ligands among 94,581 identified unique ligand structures to curate the Boston Open-Shell Ligand (BOS-Lig) dataset. The workflow assigns ligand charges in homoleptic complexes first and then iteratively propagates these assignments across heteroleptic environments, allowing charges to be inferred even when direct charge information is unavailable. We analyze cases where simple heuristics such as the octet rule would have failed and introduce a purity metric to identify when our charge assignments may be incorrect. Each ligand is also classified in terms of its metal coordinating atoms and whether there are multiple variants (i.e., hemilability). We then link complexes to their associated journal abstracts and apply a topic-modeling workflow to link 25,146 ligands with functional application areas spanning reactivity, redox chemistry, biological chemistry, and photophysical chemistry. Together, we provide an experimentally grounded dataset of ligand chemical space that connects charge and functional application as a foundation for computational screening and data-driven ligand design. Show less

A molecular Co^III complex (1), supported by a 14-membered macrocyclic ligand, was developed. The oxygen reduction reaction (ORR) catalyzed by 1 was investigated under electrochemical and spectrochemical conditions in acetonitrile, using trifluoroacetic acid (TFAH) as the proton source, and revealed selective catalytic 4e^-/4H⁺ reduction in both cases. Kinetic analyses revealed a first-order dependence on the concentrations of both catalyst and O₂, but no dependence on TFAH or decamethylferrocene (under chemical conditions). The catalytic rate constant was determined to be 3.6 × 10³ M^-1 s^-1 under electrochemical and 90 M^-1 s^-1 under spectrochemical conditions. A reported Co(III) complex (2), featuring a bis-pyridine-dioxime ligand architecture, also catalyzed the 4e^-/4H⁺ reduction of O₂ but displayed first-order dependence on catalyst, TFAH, and O₂. These results suggest that variations in the coordination environment around the Co center lead to distinct ORR mechanisms, despite identical product selectivity. Complex 1 exhibited an effective overpotential of 0.78 V, which is 240 mV lower than that of 2 (η_eff = 1.02 V), underscoring the role of ligand architecture in tuning the catalytic overpotential. Overall, this study underscores the pivotal role of ligand design in shaping ORR kinetics, mechanism, and efficiency, offering valuable insights for the development of ORR catalysts. Show less

Defense-associated reverse transcriptases (DRTs) are widespread bacterial anti-phage systems that use unconventional mechanisms of polynucleotide synthesis. We show that DRT3, which comprises two distinct RTs (Drt3a and Drt3b) and a noncoding RNA (ncRNA), synthesizes alternating poly(GT/AC) double-stranded DNA. Cryo-electron microscopy structures at 2.6 Å resolution reveal a D3-symmetric 6:6:6 complex of Drt3a, Drt3b, and ncRNA. Drt3a produces the poly(GT) strand using a conserved ACACAC template within the ncRNA. Notably, Drt3b synthesizes a complementary, protein-primed poly(AC) strand in the complete absence of a nucleic acid template, using conserved active site residues specific to Drt3b to enforce precise base alternation. These findings expand the functional landscape of nucleic acid polymerases, revealing a protein-templated mechanism for sequence-specific DNA synthesis. Show less

We report the facile synthesis of new gold(I) carbene complexes based on a mesoionic cobaltocenylidene metallocarbene via a fluorinative desilylation reaction. The carbene has been characterized by a variety of spectroscopic methods, revealing that it has the highest HEP value reported for a MIC so far, suggesting that the carbene is highly electron donating. The properties of the new class of metallo-mesoionic carbenes is further investigated, revealing also exceptionally low TEP values. Electrochemical studies also suggest the cobaltocenium moiety to be further reducible. In addition, the cell growth inhibitory effects of the new metallocarbene complexes were explored in cancer cells and bacteria. The combination of electrochemical activity, exceptional electron donating properties and their putative application in medicinal chemistry makes these new metallo-MICs a highly interesting new class of ligands. Show less

Glucose transporter 1 (GLUT1), the most extensively distributed member of the glucose transporter protein family, plays a pivotal role in regulating glucose metabolism and is indispensable for cellular growth, proliferation, and differentiation. Various metabolic disorders arise from the dysregulation of GLUT1 expression, which disrupts glucose homeostasis. The upregulation of GLUT1 has been identified in multiple cancer cells, facilitating tumor progression, metastasis, and resistance to treatment. Recent years have seen a surge in the discovery of GLUT1 inhibitors exhibiting improved selectivity and efficacy. Herein, we introduce the structure and biological function of GLUT1, GLUT1 related oncogenesis, and primarily focuses on recent advancements in the study of GLUT1 inhibitors over the last decade. Notably, this review is restricted to inhibitors that act through direct interaction with the GLUT1 protein, excluding agents that exert indirect effects via upstream signaling or metabolic regulation. Show less

Mononuclear nonheme iron(III)-peroxo complexes bearing N-tetramethylated cyclam (n-TMC) ligands, [Fe^III(O₂)(n-TMC)]⁺ (n = 12, 13, and 14), have recently shown highly intriguing reactivities in various oxidation reactions, such as the cis-dihydroxylation and C-H functionalization reactions, which were previously associated only with high-valent iron-oxo intermediates in heme and nonheme iron enzymes. Herein, we extend our study to report [Fe^III(O₂)(n-TMC)]⁺ mediated N-demethylation of N,N-dimethylanilines (DMAs), another reaction that was previously associated only with high-valent iron-oxo cores. Most importantly, we provide definitive evidence of the occurrence of electron transfer from DMAs to [Fe^III(O₂)(n-TMC)]⁺, thereby establishing an electron-transfer (ET) pathway for the N-demethylation reaction. Investigation of the ET reactivity of [Fe^III(O₂)(n-TMC)]⁺ in light of the Marcus theory of ET, and a comparison of the N-demethylation and the ET rate constants corroborate a mechanism, whereby N-demethylation of DMAs by [Fe^III(O₂)(n-TMC)]⁺ proceeds via the peroxide O-O bond cleavage of [Fe^III(O₂)(n-TMC)]⁺ to form a transient [Fe^IV(O^2-)(O^• -)(n-TMC)]⁺ species, which undergoes a proton-coupled electron-transfer (PCET) or an uncoupled electron transfer-proton transfer (ET/PT) in the presence of DMAs. Saturation kinetics support the rate-determining formation of [Fe^IV(O^2-)(O^• -)(n-TMC)]⁺ in a pre-equilibrium step with the same values of the O-O bond cleavage rate constants irrespective of the substrates, such as DMAs and one-electron oxidants. The present study corroborates that mononuclear nonheme iron(III)-peroxo cores are not mere pass-through points en route to high-valent metal-oxo intermediates, but they can play an important role in the diverse oxidation reactions of Rieske oxygenases, such as in the N-demethylation reaction. Show less

We elucidate the mechanism of the manganese-catalyzed N-alkylation of aniline with benzyl alcohol mediated by a bis(1,2,3-triazolylidene) Mn(I) complex through a combination of experimental studies and density functional theory (DFT) calculations. Activation of the precatalyst by a base leads to the formation of an anionic alkoxo complex featuring a deprotonated methylene bridge, which is identified as the catalytically active species. Notably, the methylene linker exhibits previously unrecognized noninnocent behavior, undergoing reversible deprotonation and participating directly in proton-transfer steps of the catalytic cycle. Kinetic isotope effects and deuterium-labeling experiments support the involvement of both hydride transfer and alcohol-assisted proton processes in the rate-determining steps. These findings uncover a new mode of metal-ligand cooperation in triazolylidene-based manganese catalysts and provide mechanistic guidelines for the design of cooperative ligands in base-metal-borrowing hydrogen catalysis. Show less

ABSTRACT Understanding how metals coordinate to organic ligands is a precondition for the rational design of metal complexes and catalysts. Whereas certain types of ligands are capable of just one easy‐to‐predict coordination modality, others may present tens and sometimes even hundreds of coordination options (mono‐, bi‐, or polydentate), and predicting the correct one may be a challenge even to seasoned chemists. The current paper describes a “hybrid” computational approach in which a Machine Learning, ML, algorithm learns to predict complex coordination patterns using knowledge‐based “rules” derived from the Cambridge Structural Database, CSD. This model is applicable to a broad scope of ligands (including hemilabile and haptic ones as well as those with denticity > 6) and different metals at different oxidation states. The algorithm's code is disclosed and can be readily deployed in RDKit via our RDMetallics python‐wrapper. It is also deployed as a publicly accessible web portal for demonstration and use. Show less

[Ru(bpy) 3 ] 2+ has long served as the archetypal coordination complex for probing inorganic photophysics and photochemistry. Its intense visible MLCT absorption, quantitative intersystem crossing, and microsecond 3 MLCT lifetime established it as a benchmark photosensitizer across energy conversion, sensing, and catalysis. This review complements a recent historical perspective on [Ru(bpy) 3 ] 2+ by providing a contemporary view of its use as a versatile platform for advanced photochemical design. We first discuss updated views of its excited-state landscape, including refined descriptions of metal-centered states, minimum-energy crossing points, and photodissociation pathways, as well as the profound influence of counterions and microenvironments on excited-state energetics, stability, and reactivity. We then survey emerging applications, multiphoton solvated electron generation, mechanochemical ball-mill photoredox catalysis, and spin-forbidden red-light excitation. Next, we examine polynuclear complexes and dyads derived from the [Ru(bpy) 3 ] 2+ scaffold, emphasizing delocalized and antidissipative 3 MLCT states, long-lived charge separation, and integration into biohybrid or supramolecular architectures. Finally, we outline "real-life" applications in industrial photoredox chemistry, electrochemiluminescence immunoassays, oxygen sensing, and photodynamic therapy, and we position [Ru(bpy) 3 ] 2+ alongside emerging photosensitizers based on earth-abundant metals. Rather than being superseded, [Ru(bpy) 3 ] 2+ now functions as both a robust technological workhorse and an indispensable reference for next-generation photocatalyst design. Show less

A new generation of backbone-functionalized NHC–gold( i ) complexes reveals ferroptosis through comprehensive mechanistic and biological investigation. Show less

Ferroptosis is a form of iron-mediated regulated cell death driven by lipid peroxidation (LPO). It has not only further improved our understanding of the cell death mechanism but also shown enormous potential in therapeutic applications. While the precise subcellular itinerary of ferroptotic cell death remains a subject of ongoing debate, radical-trapping antioxidants (RTAs) are widely recognized as efficient antiferroptotic agents due to their ability to interrupt LPO chain propagation. Here, we highlight recent pioneering works in the field, showing how probes derived from RTAs serve as powerful chemical tools for resolving the mechanism of ferroptosis across multiple cellular compartments. Show less

The most significant factor in the design of high-performance nonlinear optical (NLO) materials is electronic symmetry, which directly influences hyperpolarizability and second harmonic generation (SHG) response. This work presents two isostructural one-dimensional coordination complexes, {[Co₂(CMP)₂(BIPY)₂(H₂O)₆]·11H₂O}_n (I) and {[Ni₂(CMP)₂(BIPY)₂(H₂O)₆]·11H₂O}_n (II), (CMP = Cytidine Monophosphate, BIPY = 4,4'-bipyridine), crystallized in the noncentrosymmetric (NCS) P2₁ space group. The cobalt-based complex (I) establishes an NCS environment due to its pronounced octahedral distortion and lower electronic symmetry, coupled with intrachain hydrogen bonding and π-π stacking, resulting in enhanced hyperpolarizability and a robust second-harmonic generation response. Conversely, the nickel-based complex (II) demonstrates comparatively weaker NLO characteristics attributable to its higher symmetry. Experimental and theoretical findings have established that the superior NLO performance of complex (I) is intrinsically linked to its low symmetry, narrow band gap, and significant intermolecular interactions. This research demonstrates that disrupting electronic symmetry can significantly amplify the nonlinear optical response through supramolecular architecture in coordination polymers. Show less

Combining single-cell parallel profiling of genome conformation, histone modifications, chromatin accessibility and gene expression reveals dynamics and intranuclear spatial clustering of epigenome profiles, enabling sophisticated analysis of the regulatory landscape across cell types and tissues. Show less

Coacervates are dense aqueous phases that form by liquid-liquid phase separation. Seven Pt(II) complexes with different charges and nucleotide reactivities were examined for their ability to induce coacervate formation in a 21-mer single-stranded DNA (ssDNA). Only AMPZ ([cis-{Pt(NH₃)₂}₂(μ-pyrazolato)(μ-OH)](NO₃)₂), a cationic dinuclear Pt(II) complex, efficiently induced coacervate formation in ssDNA containing only thymine (T21-DNA). AMPZ has very low reactivity with thymine but relatively high reactivity with guanine, and when three of the thymines in T21-DNA were substituted with a guanine to produce T18-G3-DNA, the resulting coacervate was observed to undergo gelation via the formation of an extensive Pt-DNA coordination-bonded network. We then examined the construction of coacervates that comprise multiple phases by adding AMPZ to a mixture of two types of ssDNAs, a highly reactive T10-G11-DNA and a minimally reactive T21-DNA, and found that two distinct assembly states─a cell mimetic assembly and a DNA-encapsulating gel─could be formed. Show less

Described are multiple approaches using density functional theory to probe the acid catalyzed aquation of the hexaammineruthenium(II) cation (Ru(NH₃)₆²⁺ + H₃O⁺ → Ru(NH₃)₅(H₂O)²⁺ + NH₄⁺) reported initially by Taube and co-workers. These computations support the proposal that the initial step is protonation of the Ru(II) center and/or the metal-NH₃ bond, thereby activating the latter toward dissociation. DFT analysis was also carried out for the hypothetical acid-mediated aquation of the isoelectronic hexaamminerhodium(III) complex, Rh(NH₃)₆³⁺. The computations suggest a key mechanistic difference for the latter pathway, namely that protonation of the NH₃ occurs late in a reaction coordinate involving dissociation of the Rh-NH₃ with no direct interaction of H⁺ with the metal center. Furthermore, while the calculated activation energy is considerably higher in the latter case, the calculations suggest that protonation could play an important role in such ligand substitution reactions. Show less

Biomedical research benefits from the rapid growth and diversity of experimentally detected protein-protein interactions (PPIs) by gaining important biological insights. However, increasingly dense PPI networks can be challenging to interpret and apply. The 2025 update of the Integrated Interactions Database (IID) enhances accessibility and utility through several new features. We identify and incorporate network structural components from co-purified protein sets, as well as curated and predicted complexes, enabling users to explore network organization beyond binary interactions. Functional, pathway, and disease associations of these components can be analyzed, enabling interactions to be grouped into higher-order structures with known or provisional biological roles. Users can now filter interactions by five detection types: pairwise, co-purification, colocalization, proximity, and other evidence. To extend the value and information of predicted interactions, we include interaction interface predictions for 53 647 PPIs, generated using the MEGADOCK docking algorithm, adding molecular detail for structural biology and variant impact studies. Finally, we map PPIs to 15 immune cell types and 12 additional normal tissues, offering tissue-specific views of interaction networks increasingly relevant in disease and immunology research. IID 2025 now includes over 1 million experimentally detected human PPIs, representing an 83% increase from the previous release, alongside expanded non-human networks. The portal remains publicly available at https://ophid.utoronto.ca/iid. Show less

Ligands containing a dearomatized ligand motif are often employed to stabilize transition metal complexes and may be employed in catalytic transformations. While complexes containing one dearomatized structural feature are common, dual dearomatized systems are seldom encountered. In this article, we describe the synthesis of various iron complexes based upon a macrocyclic PNPN ligand. Synthetic entry to the dual dearomatized ligand (PNPN*) can be achieved upon deprotonation of the Fe dibromide complex with base in the presence of π-acidic ligands. The electronic structure of these complexes was examined by NMR- and ⁵⁷Fe Mössbauer spectroscopy and computationally modeled. Reactivity studies regarding ligand substitution of the π-acidic ligands and protonation of the PNPN* scaffold are described. Show less

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

Many heavy transition metal compounds are active redox catalysts. Their redox potentials can be offset by differential spin-orbit coupling (SOC) effects in the case of strong perturbation of the ground-state energy of the oxidized or the reduced state. However, SOC effects are often considered negligible in the case of organometallic species, anticipating energetically well-separated, nondegenerate spin ground states for metal ions in strong ligand fields with low symmetry. We here report a rhenium(III) aminodiphosphine complex that undergoes proton-coupled electron transfer with a phenoxyl radical as a hydrogen abstractor. Experimental derivation of the PCET thermochemistry shows a deviation from coupled-cluster computations in the range of 6 kcal·mol^-1. The deviation can be attributed to a sizable SOC contribution by the amine precursor, which is largely quenched in the rhenium(IV) amido product. Our case study emphasizes potential pitfalls for coupled-cluster benchmarking of the reaction energetics of heavy d-block catalysts. Show less

While various metal complexes demonstrate immunogenic cell death (ICD)-inducing properties, there is a lack of studies comparing ICD properties in structurally similar complexes with different metal centers. In this study, we synthesized four structurally similar Rh(I) and Ir(I) complexes with redox-active 1,2-bis(arylimino)acenaphthene (Ar-bian) ligands and assessed their anticancer and ICD-inducing properties. Analysis of damage-associated molecular patterns (DAMPs), ROS localization and dying cell populations highlighted the distinct roles of the metal center and the ligands. Specifically, only Rh(I) complexes induced the release of the three essential DAMPs and high levels of late apoptotic cells, while the Ir(I) complexes failed to trigger crucial “eat-me” signals. This work offers valuable insights into structure–activity relationships in metal complexes in the context of ICD. Show less

Abstract Most clinically used chemotherapeutic agents act by inducing apoptosis. However, their clinical effectiveness is often limited by poor therapeutic efficacy and the rapid development of drug resistance. In contrast, oncosis, as an inflammatory form of cell death independent of adenosine triphosphate (ATP) and apoptotic pathways, exhibits unique advantages in overcoming tumor drug resistance and regulating anti‐tumor immune responses. Herein, we present the first iridium(III)‐based immunogenic oncosis inducers designed to concurrently induce oncosis and activate the cGAS–STING pathway, thereby bridging chemotherapy with immunotherapy. Through a bioisosteric design strategy, we identified benzoselenazole and benzothiazole derivatives as key pharmacophores for triggering oncosis. These iridium(III)‐based oncosis‐inducers rapidly disrupt mitochondrial architecture, induce oxidative stress, and promote Ca(II) release, which subsequently activate calpain and porimin to initiate oncosis in multidrug‐resistant cancer cells. Transcriptomic profiling further revealed their ability to regulate actin cytoskeleton organization, modulate ABC transporter activity, and affect glycolysis/gluconeogenesis. Notably, the metal complexes induce mitochondrial swelling and mt‐DNA damage, leading to robust activation of the cGAS–STING innate immune pathway and eliciting a strong anticancer immune response. Based on these multimodal mechanisms, the Ir(III)‐based immunogenic oncosis inducers were able to effectively kill drug‐resistant cancer cells and enhance the anticancer immune response in tumor mouse models. Show less

Artificial intelligence (AI) is being used in oncological drug development to address the high costs, low success rates, and long timelines that characterize traditional drug development pipelines. The use of machine learning (ML) and deep learning (DL) models in computer-aided drug design is constantly growing owing to their capacity to analyze large, heterogeneous datasets, their ability to capture nonlinear biological trends, and their integration of various molecular and clinical characteristics. AI applications accelerate target discovery by predicting protein structures, ranking disease-relevant genes, and assessing target drugability. AI can be used to conduct rapid searches of multiplexed chemical libraries, predict drug-target interactions, and optimize the pharmacological and physicochemical properties of drugs in virtual screening. Advanced neural network designs also aid in de novo drug design, which involves developing new molecular structures with therapeutic properties of interest. This review outlines how AI has been used for target identification, virtual screening, de novo molecular design, and, specifically, in cancer applications. It further discusses the major issues in AI-based drug development, such as data quality, model interpretation, computational constraints, and ethical and regulatory considerations, which remain essential obstacles to broader clinical translation. Show less