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Including energy dynamics in research could improve our understanding of diseases and of the healing processes that sustain health. Including energy dynamics in research could improve our understanding of diseases and of the healing processes that sustain health. 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

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

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. TLDR: The first iridium(III)-based immunogenic oncosis inducers designed to concurrently induce oncosis and activate the cGAS-STING pathway are presented, thereby bridging chemotherapy with immunotherapy. Show less

A series of ESIPT-capable Ir^III-(acyclic diaminocarbene species) (ESIPT = Excited-state intramolecular proton transfer) exhibiting strong photoluminescence properties is described. The emission profile is strongly influenced by the nature of the azaheterocyclic fragment in the diaminocarbene ligand: pyrazine-derived species display phosphorescence bands red-shifted by approximately 100 nm compared to their pyridine analogues. This redshift is attributed to the luminescence of tautomerized species formed via an ESIPT process, wherein the iridium center enhances the basicity of the pyrazine ring, facilitating proton transfer from the C_carbene-NH groups. This interpretation is supported by the solvatochromic emission behavior of complexes prepared and corroborated by density functional theory calculations. Prepared Ir^III-(acyclic diaminocarbene species) complexes represent the first example of metal-organic luminophores in which the ESIPT mechanism involves direct participation of the metal center, resulting in orange emission. Show less

Nanocarriers are fundamentally transforming targeted drug delivery (TDD) by addressing the major limitations of conventional therapies, such as systemic toxicity and poor drug localization. These nanoscopic vehicles, including liposomes and polymeric nanoparticles, typically sized between 1 and 100 nanometers, are engineered to encapsulate, protect, and escort therapeutic agents until they reach the precise site of action. The key to their success lies in targeted delivery mechanisms. Passive targeting utilizes the enhanced permeability and retention (EPR) effect, where nanocarriers accumulate preferentially in leaky tumor vasculature. Active targeting involves surface modification with specific ligands (e.g., functional chemical/group, antibodies, or peptides) that bind to overexpressed receptors on diseased cells, ensuring high local drug concentration. This precision significantly boosts therapeutic efficacy while minimally affecting healthy tissues, leading to fewer side effects. This review provides an in-depth examination of TDD, highlighting how nanocarriers are essential in achieving precision and improving therapeutic outcomes. It explores the diverse strategies and suitable materials utilized to guide therapeutic agents specifically to disease sites while minimizing systemic toxicity. Show less

An integrated multimodal imaging workflow of cryogenic super-resolution fluorescence microscopy and soft X-ray tomography, Orbitrap secondary ion mass spectrometry, and inductively coupled plasma-mass spectrometry has revealed the unexpected targeting of a half-sandwich cyclopentadienyl Rh(III) phenylazopyridine anticancer complex to cellular lipid membranes and lipid droplets. The complex accumulates in plasma membranes with a surprisingly intense switch-on luminescence in living cancer cells, drives remodeling of lipid droplet architecture, and penetrates deeply into lipid-rich tissue environments. DFT modeling shows strong supramolecular interactions between the complex and glycerophosphorylcholine lipids. Show less

Encouraged by the promising anticancer activity of a iodidogold(I)-N-heterocyclic carbene (NHC) complex with a 1,3-diethyl-4-anisyl-5-(4-chlorophenyl)imidazol-2-ylidene ligand system, a series of new gold(I), gold(III) and platinum(II) complexes coordinated to this ligand system were designed, prepared, and characterized using NMR spectroscopy and mass spectrometry methods. A preliminary anticancer screening of the complexes using four esophageal adenocarcinoma (EAC) cell lines showed promising activities for the cationic triphenylphosphino-NHC-gold(I) and bis-NHC-gold(I) complexes, accompanied by strong antiproliferative, colony-, and spheroid-forming inhibitory effects. The compounds were relatively less toxic to the normal esophageal cell line Het-1A and the monocyte cell line THP-1. Moreover, these compounds induced caspase 3/7 activity and downregulated anti-apoptotic proteins (Bcl-XL, Bcl-2, and Mcl-1) in EAC cells. Further, the cell cycle promoter cyclin D1 was suppressed by these NHC-gold(I) complexes. Finally, we observed strong reactive oxygen species (ROS) induction in EAC cells with NHC-gold(I) complexes 8 and 11. TLDR: A preliminary anticancer screening of the complexes using four esophageal adenocarcinoma (EAC) cell lines showed promising activities for the cationic triphenylphosphino-NHC-gold(I) and bis-NHC-gold(I) complexes, accompanied by strong antiproliferative, colony-, and spheroid-forming inhibitory effects. 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

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

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

Immunotherapy represents a paradigm shift in oncology, rooted in a century of evolving scientific understanding and clinical application. From the pioneering use of Coley’s toxins in the late nineteenth century to the introduction of cytokine-based interventions, the trajectory of immunotherapeutic approaches has paralleled advancements in immunology and molecular biology. This review comprehensively examines the historical development and progressive refinement of immunotherapy for cancer, charting the transition from non-specific immune stimulation to targeted immune modulation. Central to this discussion are the sophisticated mechanisms by which tumour cells evade immune detection and destruction. These include downregulation of antigen presentation machinery, secretion of immunosuppressive cytokines, recruitment of regulatory T cells and myeloid-derived suppressor cells, and exploitation of immune checkpoint pathways, particularly CTLA-4 and PD-1/PD-L1 axes. The advent of immune checkpoint inhibitors has yielded durable clinical responses in diverse malignancies, substantiating their role as foundational agents in cancer therapy. Nonetheless, both primary and acquired resistance to immune checkpoint inhibition remain significant clinical obstacles. Resistance mechanisms are multifactorial, involving tumour-intrinsic genetic alterations, modulation of the tumour microenvironment, and adaptive changes in immune cell phenotypes. Contemporary research endeavors are directed at overcoming these barriers, including the optimization of combinatorial regimens, development of next-generation checkpoint modulators, tumour-specific vaccines, and the integration of adoptive cell therapies. Future directions in cancer immunotherapy are poised to leverage advances in systems biology, genomics, and single-cell technologies to individualize interventions and enhance therapeutic efficacy. Ultimately, a comprehensive delineation of tumour-immune interactions will underpin the next generation of rational, effective, and durable cancer immunotherapies. 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

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

TLDR: This work presents the first rationally designed cyclometalated Au(III) complex that functions as a necroptosis-dependent ICD inducer, offering a promising strategy for metal-based chemoimmunotherapy. Show less

Liquid-liquid phase separation (LLPS) is a fundamental biophysical process driving the formation of dynamic biomolecular condensates, which spatially organize cellular biochemistry without membrane delimitation. These condensates arise from multivalent, weak interactions among intrinsically disordered proteins, modular interaction motifs, and RNA scaffolds, enabling highly tunable and reversible compartmentalization of biomolecules. This phase behavior regulates critical cellular functions such as gene expression, signal transduction, and stress response, while its dysregulation contributes to pathological aggregation and disease. Recent advances leverage LLPS principles to design synthetic condensates with controllable composition, properties, and activities. Combining structural insights, quantitative phase behavior, and synthetic biology tools, engineered condensates have been developed for enhanced catalysis, metabolic control, targeted drug delivery, and biosensing. This review summarizes the molecular mechanisms, design strategies, and translational prospects of LLPS-mediated condensates, thereby paving the way for future exploration at the interface of cellular biophysics and bioengineering. Show less

By applying our pioneering "Targeted Drug Conjugate (TDC)" concept, a new PARP1-specific Pt(II)-based TDC for the treatment of ovarian cancer was reported. In vitro biological assays indicated that the representative compound Ola-604 could target PARP1, exhibit an inhibitory effect on SKOV3 cancer cells, and overcome cisplatin resistance via inducing cell apoptosis, causing cell cycle arrest, enhancing the cellular accumulation of platinum element, promoting the level of DNA platination within the genome, and suppressing DNA damage repair. Notably, compound Ola-604 demonstrated higher tumor growth inhibitory efficacy than cisplatin, olaparib, and their physical mixture in SKOV3 mice xenograft models, while exhibiting lower toxicity. Overall, the TDC entity sets a new benchmark for precision therapy in ovarian cancer. 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

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

[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