Gilles Gasser

The diiron(I) complexes [Fe2Cp2(CNR)3{CN(Me) (R)}][CF3SO3] ([2a-b][CF3SO3], R = Xyl, Cy; Xyl = 2,6-C6H3Me2, Cy = cyclohexyl) and [Fe2Cp2(CNR)2{CN(Me) (R)}2][CF3SO3]2 ([3a-c][CF3SO3]2, R = Xyl, Cy, Me) were synthesized in moderate-to-high yields from [Fe2Cp2(CO)4]. They were characterized by IR and NMR spectroscopy and single-crystal X-ray diffraction in five representative cases. The electrochemical behavior of [2a][CF3SO3] and [3a][CF3SO3]2 was investigated by cyclic voltammetry and IR-spectroelectrochemistry, assisted by DFT calculations. UV–vis and 1H NMR studies showed ≥84% of each complex remaining intact after 72 h of incubation at 37 °C in aqueous media. Complexes [3a-c][CF3SO3]2 displayed significant aqueous solubility, and [2b][CF3SO3] and [3a-b][CF3SO3]2 exhibited amphiphilic character (−1 < Log Pow < +1). The monocationic species [2a-b][CF3SO3] exerted strong cytotoxicity in A2780, A549, and U87 cancer cell lines, with [2a][CF3SO3] showing IC50 values in the nanomolar range. Among dicationic complexes, [3a][CF3SO3]2 exhibited significant activity despite limited cellular uptake, whereas [3b-c][CF3SO3]2 were inactive. Compounds [2a][CF3SO3], [2b][CF3SO3] and [3a][CF3SO3]2 impaired mitochondrial bioenergetics without detectable elevation of intracellular ROS levels in both A549 and U87 cells. No significant interaction with double-stranded DNA was detected by ethidium bromide displacement assays. Conversely, fluorescence titrations with bovine serum albumin indicated the formation of 1:1 adducts for [2a]+ and [3a]2+.

Small dyes are indispensable tools for probing biological processes. Among them, Nile Red (NR) is widely used for imaging lipid‐rich environments. However, the structural diversification of its phenoxazine core remains limited. Herein, we exploit B─N/C─C isosterism to connect the western and eastern fragments of NR through a B─N linkage, enabling the design of NR‐inspired boronic acid‐derived salicylidenehydrazone (NR‐BASHY) dyes with enhanced structural and functional versatility. This strategy allows the modular one‐pot synthesis of NR‐BASHY dyes, which exhibit promising photophysical properties. These include intense absorption ( ε up to 50,800 M ^–1 cm ^–1 ) and high brightness ( ε × Φ _f up to 17,000 M ^–1 cm ^–1 ) and a pronounced solvatofluorochromism with emission spanning the red to near‐infrared spectral region. In strong contrast to NR, NR‐BASHY can act as photosensitizers, featuring efficient singlet‐oxygen generation ( Φ _Δ up to 0.8) and photoinduced cytotoxicity against the U87 glioblastoma cell line in the submicromolar range (IC ₅₀ ca. 0.5 μM), while maintaining low dark toxicity (>100 μM). Moreover, the modular architecture of NR‐BASHY dyes enables click‐reaction mediated bioconjugation with the GV1001 peptide, highlighting the potential of this platform for targeted bioimaging applications.

CRET-activated cyclometalated iridium photosensitizers generate intracellular ROS without external light, overcoming light penetration limits in tumour environments.

About 50 years after their development, the benzimidazole anthelmintic drugs still occupy a key role in the treatment of parasitic diseases. Like other anti‐infective drugs, their extensive use has led to resistance development and now requires new solutions to treat these diseases. Organometallic derivatization of existing drugs has become a common strategy to design new drug candidates, which could benefit from enhanced activity against resistant or sensitive strains through the incorporation of an organometallic fragment. In this study, we describe the development of a new series of organometallic derivatives of benzimidazole anthelmintics. Ten derivatives, six of which were organometallic, were synthesized and characterized. In silico and in vitro studies were performed to determine their biological activity. Therefore, they were screened against a range of nematodes and other parasites. Biological activities were found for some of the derivatives against Strongyloides ratti , Ancylostoma ceylanicum , Trichuris muris , Schistosoma mansoni , Echinococcus multilocularis, or Leishmania infantum in similar ranges as the parent anthelmintics. Even if the activity of the benzimidazole scaffold was not systematically enhanced, this strategy is a good starting point for the development of new antiparasitic compounds and for further study of the mode of action of these drugs.

ZUSAMMENFASSUNG: Die Effektivität der photodynamischen Therapie (PDT) wird wesentlich durch einen intrinsischen photophysikalischen Konflikt zwischen den beiden ROS‐generierenden Mechanismen eingeschränkt. Typ‐I‐Prozesse erfordern einen stark reduzierenden angeregten Zustand, um Elektronentransferreaktionen zu ermöglichen, während Typ‐II‐Prozesse einen langlebigen Triplettzustand benötigen, um eine effiziente Energietransferreaktion auf molekularen Sauerstoff zu gewährleisten. Da beide Mechanismen aus demselben Triplettzustand hervorgehen, führt die Optimierung der einen Eigenschaft zwangsläufig zu Einbußen bei der anderen. Dies begrenzt die oxidative Potenz und die breite Anwendbarkeit konventioneller Photosensibilisatoren innerhalb der heterogenen Tumormikroumgebung. Um diese Einschränkung zu überwinden, wird hier das Design, die Synthese und biologische Evaluierung eines cyclometallierten, photoschaltbaren Iridium(III)‐Komplexes beschrieben, der gezielt so konstruiert wurde, dass er nach Lichtanregung eine intramolekulare homolytische Bindungsspaltung durchläuft und dabei ein kurzlebiges Biradikal‐Zwischenprodukt bildet. Die daraus resultierende Spezies vereint gleichzeitig ein stark reduzierendes Radikalintermediat mit einem durch eine chinoide Struktur stabilisierten, langlebigen Triplettzustand. Dadurch werden sowohl Typ‐I‐Elektronentransfer‐ als auch Typ‐II‐Energietransferprozesse parallel aktiviert, sodass in einem synergetischen Zusammenspiel Superoxid, Hydroxylradikale und Singulett‐Sauerstoff erzeugt werden. Dieser kombinierte oxidative Stress löst die PANoptose aus—ein koordinierter Zelltodmechanismus, der gleichzeitig apoptotische, nekroptotische und pyroptotische Signalwege aktiviert—und induziert darüber hinaus eine ausgeprägte systemische antitumorale Immunantwort. Damit etabliert die intramolekulare Erzeugung von Biradikalen ein vielversprechendes molekulares Designprinzip für die nächste Generation von Photosensibilisatoren für die photodynamischen Krebsimmuntherapie.

Development of novel metallotherapeutics poses both significant potential and numerous challenges due to their complex reactivity in physiological systems and the ambiguity of molecular targets. Advances in target-agnostic and phenotypic-based drug profiling approaches have yielded success in anticancer therapeutic development, but their application to the development and discovery of metal-based drug candidates has been limited. This study demonstrates the use of morphological profiling on a diverse library of metal-containing compounds to elucidate mechanisms of action, providing new insights into the activities of established chemotherapeutics and guiding downstream studies of select novel compounds in the absence of predefined molecular targets. The validity of this strategy was established using a subset of clinically approved anticancer therapeutics, where morphological profiling discerned the mechanistic differences among oxaliplatin, cisplatin, carboplatin, and the clinical-stage ruthenium-based compound BOLD-100. Subsequently, a combination of cytotoxicity and selectivity assessments in conjunction with an analysis of morphological profiles of the compound library identified a novel ruthenium 2-(2-pyridyl)benzimidazole-based compound series, which induced changes in the mitochondrial morphology of cancer cells. This association was investigated further, revealing an accompanying increase in levels of mitochondrial reactive oxygen species and a corresponding depolarization of the mitochondrial membrane. This application of morphological profiling will enable the rapid identification of promising metal-containing therapeutics, aiding in rational development strategies and mitigating persistent challenges in metallotherapeutic development.

The efficacy of photodynamic therapy (PDT) is fundamentally constrained by an intrinsic photophysical trade‐off between its two ROS‐generating mechanisms. Type I pathways require a strongly reducing excited state to drive electron transfer, whereas type II pathways demand a long‐lived triplet state to enable efficient energy transfer to molecular oxygen. Since both originate from the same triplet manifold, optimizing one property inevitably compromises the other, limiting the oxidative potency and broad applicability of conventional photosensitizers within the heterogeneous tumor microenvironment. To overcome this limitation, in this study, the design, synthesis, and biological evaluation of a cyclometalated iridium(III) photoswitchable complex is reported, engineered to undergo photo‐induced intramolecular homolytic bond cleavage to generate a transient biradical intermediate. The resulting open‐shell species simultaneously consist of a strongly reducing radical intermediate and a quinoid‐stabilized long‐lived triplet excited state, concurrently activating type I electron‐transfer and type II energy‐transfer pathways to produce in tandem superoxide, hydroxyl radicals, and singlet oxygen. This synergistic dual‐pathway oxidative stress triggers PANoptosis, a coordinated cell‐death program concurrently engaging apoptotic, necroptotic, and pyroptotic machinery, and elicits a robust systemic antitumor immune response, establishing intramolecular biradical generation as a compelling molecular design principle for next‐generation photodynamic cancer immunotherapy.

Photodynamic therapy (PDT) is a promising, effective, and non‐invasive treatment for superficial cancers, utilizing reactive oxygen species (ROS) generated by induced light‐irradiated photosensitizers (PS) to provoke cancer cell death. Photothermal therapy (PTT) on the other hand, relies on heat generation by light‐irradiated PS for effective thermal cancer treatment. Both treatments have limitations when applied individually; however, a synergistic approach combining both PDT and PTT could overcome these shortcomings. Protoporphyrin (PpIX) is an effective and widely used PS for PDT but in its molecular form, its application is hindered by significant biopharmaceutical drawbacks, such as high hydrophobicity.

ConspectusSince the approval of cisplatin in the late 1960s, metal-based chemotherapies have garnered a continuous amount of attention. Driven by the intrinsic limitations of platinum-based therapy, neighboring elements have been investigated for clinical use, among others, in the context of photodynamic therapy (PDT) and photoactivated chemotherapy (PACT). Ruthenium- and iridium-based photosensitizers (PSs) have led the field owing to their exceptional photophysical properties and low systemic toxicity. In contrast, osmium-based drug candidates have been slower to emerge, partly due to concerns over the well-known OsO₄ toxicity. Yet, recent developments have highlighted osmium polypyridyl complexes as promising candidates for phototherapy, thanks to their high photostability, long-lived excited states, and red-to-NIR absorption stemming from strong spin-orbit coupling. Sadler's osmium-arene complexes and McFarland's Os-4T compound, a structural analogue of the Ru-based TLD-1433 currently in clinical trial, demonstrated effective photoactivation and cytotoxicity, even under hypoxic conditions.Furthermore, osmium complexes can be chemically tuned to target organelles such as mitochondria and lysosomes or to selectively bind tumor markers such as carbonic anhydrases. Recent reports have also added an immuno-oncology dimension to osmium chemistry: the ability to trigger immunogenic cell death (ICD). This specialized cell death mode, characterized by the release of specific signaling molecules, activates dendritic cells and primes T-cell responses, converting immunologically "cold" tumors into "hot" ones. Studies from our group and others have demonstrated that photoactivated Os(II) polypyridyl complexes can efficiently induce ICD under clinically relevant red-light conditions and even in hypoxia.These features allow spatial and biochemical precision, which can also synergize with immune checkpoint inhibitors. The result is that they can function as photochemical immunoadjuvants, small molecules that combine light-induced spatial control and active targeting with the systemic reach of immunotherapy.This Account provides a timely and forward-looking overview of osmium phototherapeutics, emphasizing the link between metal-based photochemistry and cancer immunology. We contrast osmium with ruthenium, iridium, and organic systems, summarize recent in vitro and in vivo results, and propose future directions. Our laboratories have contributed several leading studies in this space, including structure-activity studies, ICD assays, and mechanistic exploration. Given the absence of a focused review in this area and the clinical momentum around both PDT/PACT and immunotherapy, the time is ideal for a concise and authoritative Account.