📋 Browse Articles

[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 Rather than being superseded, [Ru(bpy) 3 ] 2+ now functions as both a robust technological workhorse and an indispensable reference for next-generation photocatalyst design.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

Glutathione (GSH), the most abundant intracellular thiol-containing antioxidant, plays a pivotal role in cellular metabolism and redox homeostasis. Its critical involvement in cancer and neurodegenerative diseases has made it an important target for thiol detection systems. In this work, we report the design and synthesis of two novel near-infrared (NIR) phosphorescent Ir(III) complexes as multifunctional probes for GSH detection and photodynamic therapy (PDT). These probes feature an α,β-unsaturated ketone moiety that selectively reacts with the thiol group in GSH, enabling the specific sensing of intracellular and extracellular GSH with applications in bioimaging. Beyond their sensing capabilities, both Ir(III) complexes exhibit strong reactive oxygen species (ROS) generation efficiency, aggregation-induced emission (AIE) characteristics, and mitochondria-targeting properties, making them highly effective for PDT. Notably, upon cellular uptake, these complexes deplete mitochondrial GSH, disrupting redox homeostasis and triggering a rapid accumulation of localized ROS. This dual mechanism─combining GSH depletion and enhanced ROS production─induces potent apoptotic cell death. This work provides a strategic approach for developing advanced NIR photosensitizers with AIE activity, mitochondria-specific targeting, and the ability to simultaneously engage type I and type II PDT pathways while modulating intracellular antioxidant defense systems. Such multifunctional theranostic probes offer considerable potential for enhancing the efficacy of photodynamic cancer therapy, particularly in the treatment of hypoxic tumors. Show less

Cisplatin and its analogs are extensively utilized as metal-based anticancer agents in clinical settings due to their mechanism of action, which involves targeting genomic double-stranded DNA to induce cytotoxicity in cancer cells. However, the associated severe side effects and DNA damage repair-inducing drug resistance present significant challenges. In recent years, G-quadruplex nucleic acids, formed through the self-assembly of guanine-rich nucleic acid sequences, have emerged as a compelling target for the design of novel anticancer therapeutics. The strategic design of platinum complexes that selectively interact with, stabilize, or cleave G-quadruplex structures represents a promising approach for developing effective anticancer agents to overcome cisplatin resistance. This review will emphasize the advancements made over the past decade in interacting G-quadruplexes with platinum complexes as potential anticancer therapeutics. The ongoing development of platinum complexes spans from targeting nuclear DNA G-quadruplexes to mitochondrial DNA and cytoplasmic RNA G-quadruplexes, evolving from monotherapy approaches, such as chemotherapy and photodynamic therapy, to a combination of radiotherapy, immunotherapy, and more, highlighting the dynamic progress of platinum complexes. At the end, we have summarized 4 points of pending issues in this fast-growing field, which we hope can provide some help to the development of this field. Show less

Photodynamic therapy (PDT) is a promising strategy for head and neck squamous cell carcinoma (HNSCC), but the immune consequences of tumor cell death remain incompletely understood. We compared two ruthenium(II) polypyridine photosensitizers (PSs) in HNSCC models and found that both were potently phototoxic (nanomolar IC₅₀s), triggered diverse cell death pathways (including autophagy and ferroptosis), and promoted hallmark danger signals of immunogenic cell death (ICD). Strikingly, only one PS induced apoptosis and strong endoplasmic reticulum (ER) stress, yet paradoxically led to immune tolerance in vivo. Conversely, the PS that did not induce apoptotic cell death with milder stress responses resulted in a better antitumor immunity in vivo. These unexpected findings challenge the prevailing view that PDT-triggered apoptosis and ER stress are essential for ICD. Our study underscores the complexity of PDT-induced cell death balance and immunogenic signals and highlights the need to redefine ICD-inducing criteria for the rational design of next-generation PSs. Show less

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

A fundamental biological mechanism, programmed cell death (PCD), is essential for tissue homeostasis, immunological control, and development. Its dysregulation is a characteristic of many diseases in multicellular organisms, including cancer, where unchecked proliferation is made possible by evading cell death. Therefore, one of the main tenets of contemporary anticancer therapies is the restoration or induction of PCD in cancer cells. One potential, least invasive method among these is photodynamic treatment (PDT). PDT uses light-activatable photosensitisers, which cause cancer cells to explode with reactive oxygen species (ROS) when exposed to light. These ROS harm important biomolecules, throw off the cellular redox equilibrium, and cause cells to die. PDT-induced cell death was previously believed to be mostly caused by autophagy, necrosis, or apoptosis. Recent research, however, has shown that it can trigger a wider range of unconventional cell death pathways. ROS can cause ferroptosis by oxidising membrane lipids, fragmenting DNA, and lowering intracellular glutathione (GSH) levels. Similarly, necroptosis or pyroptosis can result from severe oxidative stress activating death receptor signalling. Sometimes, in response, cells use survival strategies like autophagy, which can also lead to cell death. This review explores these new, unconventional methods of cell death and how PDT can be used to take advantage of them. Next-generation photosensitisers based on iridium (Ir), ruthenium (Ru), and rhenium (Re) complexes are given special attention because they provide deep tissue penetration, improved photostability, and adjustable ROS production. Their incorporation into PDT has revolutionary potential for improving cancer treatment precision and conquering therapeutic resistance. Show less

Immunogenic cell death (ICD), as a specific type of regulated cell death, enhances the infiltration of effector T cells into tumors and boosts the anti-tumor immune response. Studies have shown that photodynamic therapy (PDT) can effectively activate the immune system at tumor sites, inducing immunogenic cell death. However, PDT requires a supply of oxygen and a deeper light penetration depth. To improve PDT efficiency, therapies targeting organelles have been developed. Different organelles mediate critical signaling pathways during the ICD process. By precisely targeting these organelles, oxidative stress and damage can be induced, thereby amplifying the PDT effects and triggering ICD in tumor cells. This review summarizes the strategies for PDT-induced ICD via targeting various organelles and explores the potential of biomaterials utilized in PDT-induced ICD for tumor immunotherapy. 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

Metabolic theories for the origin of life posit that inorganic catalysts enabled self-organized chemical precursors to the pathways of metabolism, including those that make genetic molecules. Recently, experiments showing nonenzymatic versions of a number of core metabolic pathways have started to support this idea. However, experimental demonstrations of nonenzymatic reaction sequences along the de novo ribonucleotide biosynthesis pathways are limited. Here we show that all three reactions of pyrimidine nucleobase biosynthesis that convert aspartate to orotate proceed at 60 °C without photochemistry under aqueous conditions in the presence of metals such as Cu2+ and Mn4+ . Combining reactions into one-pot variants is also possible. Life may not have invented pyrimidine nucleobase biosynthesis from scratch, but simply refined existing nonenzymatic reaction channels. This work is a first step towards uniting metabolic theories of life's origin with those centered around genetic molecules. Show less

AbstractFew other elements play a more central role in biology than hydrogen. The interactions, bonding and movement of hydrogen atoms are central to biological catalysis, structure and function. Yet owing to the elusive nature of a single hydrogen atom few experimental and computational techniques can precisely determine its location. This is exemplified in short hydrogen bonds (SHBs) where the location of the hydrogen atom is indicative of the underlying strength of the bonds, which can vary from 1–5 kcal/mol in canonical hydrogen bonds, to an almost covalent nature in single‐well hydrogen bonds. Owing to the often‐times inferred position of hydrogen, the role of SHBs in biology has remained highly contested and debated. This has also led to discrepancies in computational, biochemical and structural studies of proteins thought to use SHBs in performing chemistry and stabilizing interactions. Herein, we discuss in detail two distinct examples, namely the conserved catalytic triad and the photoreceptor, photoactive yellow protein, where studies of these SHB‐containing systems have permitted contextualization of the role these unique hydrogen bonds play in biology. Show less

Photodynamic therapy (PDT) is a clinically approved therapeutic modality that has shown great potential for the treatment of cancers owing to its excellent spatiotemporal selectivity and inherently noninvasive nature. However, PDT has not reached its full potential, partly due to the lack of ideal photosensitizers. A common molecular design strategy for effective photosensitizers is to incorporate heavy atoms into photosensitizer structures, causing concerns about elevated dark toxicity, short triplet-state lifetimes, poor photostability, and the potentially high cost of heavy metals. To address these drawbacks, a significant advance has been devoted to developing advanced smart photosensitizers without the use of heavy atoms to better fit the clinical requirements of PDT. Over the past few years, heavy-atom-free nonporphyrinoid photosensitizers have emerged as an innovative alternative class of PSs due to their superior photophysical and photochemical properties and lower expense. Heavy-atom-free nonporphyrinoid photosensitizers have been widely explored for PDT purposes and have shown great potential for clinical oncologic applications. Although many review articles about heavy-atom-free photosensitizers based on porphyrinoid structure have been published, no specific review articles have yet focused on the heavy-atom-free nonporphyrinoid photosensitizers.In this account, the specific concept related to heavy-atom-free photosensitizers and the advantageous properties of heavy-atom-free photosensitizers for cancer theranostics will be briefly introduced. In addition, recent progress in the development of heavy-atom-free photosensitizers, ranging from molecular design approaches to recent innovative types of heavy-atom-free nonporphyrinoid photosensitizers, emphasizing our own research, will be presented. The main molecular design approaches to efficient heavy-atom-free PSs can be divided into six groups: (1) the approach based on traditional tetrapyrrole structures, (2) spin-orbit charge-transfer intersystem crossing (SOCT-ISC), (3) reducing the singlet-triplet energy gap (ΔE_ST), (4) the thionation of carbonyl groups of conventional fluorophores, (5) twisted π-conjugation system-induced intersystem crossing, and (6) radical-enhanced intersystem crossing. The innovative types of heavy-atom-free nonporphyrinoid photosensitizers and their applications in cancer diagnostics and therapeutics will be discussed in detail in the third section. Finally, the challenges that need to be addressed to develop optimal heavy-atom-free photosensitizers for oncologic photodynamic therapy and a perspective in this research field will be provided. We believe that this review will provide general guidance for the future design of innovative photosensitizers and spur preclinical and clinical studies for PDT-mediated cancer treatments. Show less

Platinum-based anticancer drugs represented by cisplatin play important roles in the treatment of various solid tumors. However, their applications are largely compromised by drug resistance and side effects. Much effort has been made to circumvent the drug resistance and general toxicity of these drugs. Among multifarious designs, monofunctional platinum(II) complexes with a general formula of [Pt(3A)Cl] + (A: Ammonia or amine) stand out as a class of “non-traditional” anticancer agents hopeful to overcome the defects of current platinum drugs. This review aims to summarize the development of monofunctional platinum(II) complexes in recent years. They are classified into four categories: fluorescent complexes, photoactive complexes, targeted complexes, and miscellaneous complexes. The intention behind the designs is either to visualize the cellular distribution, or to reduce the side effects, or to improve the tumor selectivity, or inhibit the cancer cells through non-DNA targets. The information provided by this review may inspire researchers to conceive more innovative complexes with potent efficacy to shake off the drawbacks of platinum anticancer drugs. Show less

Ten manganese(I) tricarbonyl diimine complexes bound to variably functionalised 5‐aryl‐tetrazolato ligands were prepared, and their photochemical properties were investigated. Upon exposure to light at 365 nm, each complex decomposed to its free diimine and tetrazolato ligands, simultaneously dissociating three CO ligands, as evidenced by changes in the IR spectra of the irradiated complexes over time. The anti‐bacterial properties of one of these complexes were tested against Escherichia coli. While the complex displayed no effect on the bacterial growth in the dark, pre‐irradiated solutions inhibited bacterial growth. Comparative studies revealed that the antibacterial properties originate from the presence of free 1,10‐phenanthroline. Show less

Novel biotinylated diazido-Pt(IV) complexes exhibit high visible light photocytotoxicity while being stable in the dark. Photocytotoxicity and cellular accumulation of all-trans-[Pt(py)2(N3)2(biotin)(OH)] (2a) were enhanced significantly when bound to avidin; irradiation induced dramatic cellular morphological changes in human ovarian cancer cells treated with 2a. Show less

Cytochrome c (cyt c) is known for its role in the electron transport chain but transitions to a peroxidase-active state upon exposure to oxidative species. The peroxidase activity ultimately results in the release of cyt c into the cytosol for the engagement of apoptosis. The accumulation of oxidative modifications that accompany the onset of the peroxidase function are well-characterized. However, the concurrent structural and conformational transitions of cyt c remain undercharacterized. Fast photochemical oxidation of proteins (FPOP) coupled with mass spectrometry is a protein footprinting technique used to structurally characterize proteins. FPOP coupled with native ion mobility separation shows that exposure to H2O2 results in the accumulation of a compact state of cyt c. Subsequent top-down fragmentation to localize FPOP modifications reveals changes in heme coordination between conformers. A time-resolved functional assay suggests that this compact conformer is peroxidase active. Altogether, combining FPOP, ion mobility separation, and top-down and bottom-up mass spectrometry allows us to discern individual conformations in solution and obtain a better understanding of the conformational ensemble and structural transitions of cyt c as it transitions from a respiratory role to a proapoptotic role. Show less

Transition metal complexes are of increasing interest as photosensitizers in photodynamic therapy (PDT) and, more recently, for photochemotherapy (PCT). In recent years, Ru(II) polypyridyl complexes have emerged as promising systems for both PDT and PCT. Their rich photochemical and photophysical properties derive from a variety of excited-state electronic configurations accessible with visible and near-infrared light, and these properties can be exploited for both energy- and electron-transfer processes that can yield highly potent oxygen-dependent and/or oxygen-independent photobiological activity. Selected examples highlight the use of rational design in coordination chemistry to control the lowest-energy triplet excited-state configurations for eliciting a particular type of photoreactivity for PDT and/or PCT effects. These principles are also discussed in the context of the development of TLD1433, the first Ru(II)-based photosensitizer for PDT to enter a human clinical trial. The design of TLD1433 arose from a tumor-centered approach, as part of a complete PDT package that includes the light component and the protocol for treating non-muscle invasive bladder cancer. Briefly, this review summarizes the challenges to bringing PDT into mainstream cancer therapy. It considers the chemical and photophysical solutions that transition metal complexes offer, and it puts into context the multidisciplinary effort needed to bring a new drug to clinical trial. Show less

RuII compounds have been universally investigated due to their unique physical and chemical properties. In this paper, a new RuII compound based on 2,2′‐bipy and Hpmtz [2,2′‐bipy = 2,2′‐bipyridine, Hpmtz = 5‐(2‐pyrimidyl)‐1H‐tetrazole], namely [Ru(2,2′‐bipy)2(pmtz)][PF6]·0.5H2O was prepared and characterized by elemental analysis, IR and single‐crystal X‐ray diffraction. [Ru(2,2′‐bipy)2(pmtz)][PF6]·0.5H2O shows a mononuclear structure and forms a three‐dimensional network by non‐classic hydrogen bonds. The ability of generation of ROS (reactive oxygen species) makes it has a low phototoxicity IC50 (half‐maximal inhibitory concentration) after Xenon lamp irradiation on Hela cells in vitro. The results demonstrate that [Ru(2,2′‐bipy)2(pmtz)][PF6]·0.5H2O with high light toxicity and low dark toxicity may be a potential candidate for photodynamic therapy. Show less

The nucleotide excision repair system removes a wide variety of DNA lesions from the human genome, including photoproducts induced by ultraviolet (UV) wavelengths of sunlight. A defining feature of nucleotide excision repair is its dual incision mechanism, in which two nucleolytic incision events on the damaged strand of DNA at sites bracketing the lesion generate a damage-containing DNA oligonucleotide and a single-stranded DNA gap approximately 30 nucleotides in length. Although the early events of nucleotide excision repair, which include lesion recognition and the dual incisions, have been explored in detail and are reasonably well understood, the fate of the single-stranded DNA gaps and excised oligonucleotide products of repair have not been as extensively examined. In this review, recent findings that address these less-explored aspects of nucleotide excision repair are discussed and support the concept that postincision gap and excised oligonucleotide processing are critical steps in the cellular response to DNA damage induced by UV light and other environmental carcinogens. Defects in these latter stages of repair lead to cell death and other DNA damage signaling responses and may therefore contribute to a number of human disease states associated with exposure to UV wavelengths of sunlight, including skin cancer, aging and autoimmunity. Show less

The human nucleotide excision repair system targets a wide variety of DNA adducts for removal from DNA, including photoproducts induced by UV wavelengths of sunlight. A key feature of nucleotide excision repair is its dual incision mechanism, which results in generation of a small, damage-containing oligonucleotide approximately 24 to 32 nt in length. Detection of these excised oligonucleotides using cell-free extracts and purified proteins with defined DNA substrates has provided a robust biochemical assay for excision repair activity in vitro. However, the relevance of a number of in vitro findings to excision repair in living cells in vivo has remained unresolved. Over the past few years, novel methods for detecting and isolating the excised oligonucleotide products of repair in vivo have therefore been developed. Here we provide a basic outline of a sensitive and versatile in vivo excision assay and discuss how the assay both confirms previous in vitro findings and offers a number of advantages over existing cell-based DNA repair assays. Thus, the in vivo excision assay offers a powerful tool for readily monitoring the repair of DNA lesions induced by a large number of environmental carcinogens and anticancer compounds. Show less

The redox properties of both metals and ligands in transition metal complexes offer unusual routes for new mechanisms of anticancer therapy. Metal complexes can introduce artificial reductive and oxidative stress into cancer cells, including behavior as photoactivatable agents and catalysts. Relatively inert metal complexes (“prodrugs”) can be activated by redox processes within cancer cells. Examples of pharmaceuticals activated by bioreduction include three PtIV and two RuIII compounds that have already entered clinical trials. More recently, novel CoIII, FeIII, PtIV, Ru(III/II), OsII, and IrIII complexes have been reported to exhibit redox‐mediated anticancer activity. Redox activation strategies can introduce new methods to increase cancer cell selectivity and combat drug resistance. Using combination therapy together with redox modulators to increase potency is also possible. This essay focuses on metal complexes that are activated in the reducing environment of cancer cells. Show less

Cell death triggered by photodynamic therapy can occur through different mechanisms: apoptosis, necrosis or autophagy. However, recent studies have demonstrated the existence of other mechanisms with characteristics of both necrosis and apoptosis. These new cell death pathways, collectively termed regulated necrosis, include a variety of processes triggered by different stimuli. In this study, we evaluated the cell death mechanism induced by photodynamic treatments with two photosensitizers, meso-tetrakis (4-carboxyphenyl) porphyrin sodium salt (Na-H2TCPP) and its zinc derivative Na-ZnTCPP, in two human breast epithelial cell lines, a non-tumoral (MCF-10A) and a tumoral one (SKBR-3). Viability assays showed that photodynamic treatments with both photosensitizers induced a reduction in cell viability in a concentration-dependent manner and no dark toxicity was observed. The cell death mechanisms triggered were evaluated by several assays and cell line-dependent results were found. Most SKBR-3 cells died by either necrosis or apoptosis. By contrast, in MCF-10A cells, necrotic cells and another cell population with characteristics of both necrosis and apoptosis were predominant. In this latter population, cell death was PARP-dependent and translocation of AIF to the nucleus was observed in some cells. These characteristics are related with parthanatos, being the first evidence of this type of regulated necrosis in the field of photodynamic therapy. Show less

Photochemical reactions of azo and triazo derivatives of mesoionic 1,3-diphenyltetrazolium heterocycles and related compounds were studied. The reaction paths were found to depend markedly on the types of substrate, substituent and reaction solvent giving diverse products. Upon irradiation of the 1,1′3,3′-tetraphenylazoditetrazolium salt 1, the addition of hydrogen and acetone to the NN bond was observed in methanol and acetone, respectively, whereas the bond was cleaved in diethyl ketone to give the 5-aminotetrazolium salt 10. The corresponding radical cation 11 also gave the reduction product in methanol. On the other hand, the 1,3-diphenyl-5-(phenylazo)tetrazolium salt 12 underwent nitrogen evolution giving the 1,3-diphenyltetrazolium salt 13via the corresponding tetrazolium radical. Triazene derivatives 14 and 17 underwent an N–N bond cleavage to give tetrazolio-5-amide 4. The mesoionic triazene compounds bearing a tosyl 18 or cyano group 19 gave products 20 and 23. Triphenylphosphinotriazene 24 liberated nitrogen to give phosphinoimide 25 and its hydrolysis product 10. Tetrazolylamide 26 lost a phenyldiazonium group from the 1,3-diphenyltetrazolium ring to give the guanidine derivative 27. Show less