Lutetium texaphyrin: A photocatalyst that triggers pyroptosis via biomolecular photoredox catalysis.

Photon-controlled pyroptosis activation (PhotoPyro) is a promising technique for cancer immunotherapy due to its noninvasive nature, precise control, and ease of operation. Here, we report that biomolecular photoredox catalysis in cells might be an important mechanism underlying PhotoPyro. Our findings reveal that the photocatalyst lutetium texaphyrin (MLu) facilitates rapid and direct photoredox oxidation of nicotinamide adenine dinucleotide, nicotinamide adenine dinucleotide phosphate, and various amino acids, thereby triggering pyroptosis through the caspase 3/GSDME pathway. This mechanism is distinct from the well-established role of MLu as a photodynamic therapy sensitizer in cells. Two analogs of MLu, bearing different coordinated central metal cations, were also explored as controls. The first control, gadolinium texaphyrin (MGd), is a weak photocatalyst but generates reactive oxygen species (ROS) efficiently. The second control, manganese texaphyrin (MMn), is ineffective as both a photocatalyst and a ROS generator. Neither MGd nor MMn was found to trigger pyroptosis under the conditions where MLu was active. Even in the presence of a ROS scavenger, treating MDA-MB-231 cells with MLu at concentrations as low as 50 nM still allows for pyroptosis photo-activation. The present findings highlight how biomolecular photoredox catalysis could contribute to pyroptosis activation by mechanisms largely independent of ROS.

Photoredox catalysis may be a general mechanism in photodynamic therapy.

Elucidating the underlying photochemical mechanisms of action (MoA) of photodynamic therapy (PDT) may allow its efficacy to be improved and could set the stage for the development of new classes of PDT photosensitizers. Here, we provide evidence that "photoredox catalysis in cells," wherein key electron transport pathways are disrupted, could constitute a general MoA associated with PDT. Taking the cellular electron donor nicotinamide adenine dinucleotide as an example, we have found that well-known photosensitizers, such as Rose Bengal, BODIPY, phenoselenazinium, phthalocyanine, and porphyrin derivatives, are able to catalyze its conversion to NAD+. This MoA stands in contrast to conventional type I and type II photoactivation mechanisms involving electron and energy transfer, respectively. A newly designed molecular targeting photocatalyst (termed CatER) was designed to test the utility of this mechanism-based approach to photosensitizer development. Photoexcitation of CatER induces cell pyroptosis via the caspase 3/GSDME pathway. Specific epidermal growth factor receptor positive cancer cell recognition, high signal-to-background ratio tumor imaging (SBRTI = 12.2), and good tumor growth inhibition (TGI = 77.1%) are all hallmarks of CatER. CatER thus constitutes an effective near-infrared pyroptotic cell death photo-inducer. We believe the present results will provide the foundation for the synthesis of yet-improved phototherapeutic agents that incorporate photocatalytic chemistry into their molecular design.

Radius measurement via super-resolution microscopy enables the development of a variable radii proximity labeling platform.

The elucidation of protein interaction networks is critical to understanding fundamental biology as well as developing new therapeutics. Proximity labeling platforms (PLPs) are state-of-the-art technologies that enable the discovery and delineation of biomolecular networks through the identification of protein-protein interactions. These platforms work via catalytic generation of reactive probes at a biological region of interest; these probes then diffuse through solution and covalently "tag" proximal biomolecules. The physical distance that the probes diffuse determines the effective labeling radius of the PLP and is a critical parameter that influences the scale and resolution of interactome mapping. As such, by expanding the degrees of labeling resolution offered by PLPs, it is possible to better capture the various size scales of interactomes. At present, however, there is little quantitative understanding of the labeling radii of different PLPs. Here, we report the development of a superresolution microscopy-based assay for the direct quantification of PLP labeling radii. Using this assay, we provide direct extracellular measurements of the labeling radii of state-of-the-art antibody-targeted PLPs, including the peroxidase-based phenoxy radical platform (269 ± 41 nm) and the high-resolution iridium-catalyzed µMap technology (54 ± 12 nm). Last, we apply these insights to the development of a molecular diffusion-based approach to tuning PLP resolution and introduce a new aryl-azide-based µMap platform with an intermediate labeling radius (80 ± 28 nm).

Visible Light Promoted Site-Specific Functionalization of α-Acyloxy Carboxamides: Unlocking a Forbidden Chemical Space in the Passerini Reaction.

The facile generation of the α-acyloxy carboxamide radical is hereby reported for the first time, utilizing a photoredox catalyzed reaction of Passerini adducts synthesized using a 4-formyl-1,4-dihydropyridine as the carbonyl component. This radical effectively engages in a Giese reaction with a range of olefins, ultimately leading to the synthesis of novel Passerini-derived products not previously amenable to direct aldehyde-based transformations. Consequently, the resulting strategy, developed both in batch and in flow, offers a promising opportunity to expand the chemical space accessible through the Passerini reaction, virtually incorporating "impossible" aldehydes.

Deuteration Degree Controllable Synthesis of Aryl Deuteromethyl Ethers Through Dual photoredox and Thiol Catalysis.

Herein, we report a facile and efficient deuteration degree controllable method for the preparation of aryl deuteromethyl ethers through dual photoredox and thiol catalysis using phenols as the starting materials and inexpensive D2O and CDCl3 as the deuterium sources. All aryl d1, d2, and d3 deuteromethyl ethers can be precisely prepared with good to excellent yields and deuteration ratios. The reaction operates under mild conditions without the need for high temperatures or high loading of transition metal catalysts, and a wide range of functional groups are well tolerated.

Selective Mono-Defluorinative Cross-Coupling of Trifluoromethyl arenes via Multiphoton Photoredox Catalysis.

A new cross-coupling of trifluoromethyl arenes has been realized via multiphoton photoredox catalysis. Trifluoromethyl arenes were demonstrated to undergo selective mono-defluorinative alkylation under mild reaction conditions providing access to a series of valuable α,α-difluorobenzylic compounds. The reaction shows broad substrate scope and general functional group tolerance. In addition to the electron-deficient trifluoromethyl arenes that are easily reduced to the corresponding radical anion, more challenging electron-rich substrates were also successfully applied. Steady-State Stern-Volmer quenching studies indicated that the trifluoromethyl arenes were reduced by the multiphoton excited Ir-based photocatalyst.

Photoredox/Bismuth Relay Catalysis Enabling Reductive Alkylation of Nitroarenes with Aldehydes.

The effective transition metal-free photoredox/bismuth dual catalytic reductive dialkylation of nitroarenes with benzaldehydes has been reported. The nitroarene reduction through visible light-driven photoredox catalysis was integrated with subsequent reductive dialkylation of anilines under bismuth catalysis to enable the cascade reductive alkylation of nitroarenes with carbonyls. Salient features of this relay catalysis system include mild reaction conditions, no requirement for transition metal catalysts, easy handling, step-economy, and high selectivity.

Photoredox-Catalyzed Preparation of Sulfones Using Bis-Piperidine Sulfur Dioxide - An Underutilized Reagent for SO2 Transfer.

Sulfonyl groups are widely observed in biologically relevant molecules and consequently, SO2 capture is an increasingly attractive method to prepare these sulfonyl-containing compounds given the range of SO2 -surrogates now available as alternatives to using the neat gas. This, along with the advent of photoredox catalysis, has enabled mild radical capture of SO2 to emerge as an effective route to sulfonyl compounds. Here we report a photoredox-catalyzed cross-electrophile sulfonylation of aryl and alkyl bromides making use of a previously under-used amine-SO2 surrogate; bis(piperidine) sulfur dioxide (PIPSO). A broad selection of alkyl and aryl bromides were photocatalytically converted to their corresponding sulfinates and then trapped with various electrophiles in a one-pot multistep procedure to prepare sulfones and sulfonamides.

Benzothiadiazole-Based Ordered Mesoporous Polymer as a Versatile, Metal-Free Heterogeneous Photocatalyst.

Visible-light active heterogeneous organophotocatalysts have recently gained considerable interest in organic synthetic community. Ordered mesoporous polymers (OMPs) are highly promising as heterogeneous alternative to traditional precious metal/organic dyes-based photocatalysts. Herein, we report the preparation of a benzothiadiazole functionalized OMPs (BT-MPs) through a "bottom-up" strategy. High ordered periodic porosity, large surface area, excellent stability and rational energy-band structures guarantee the high catalytic activity of BT-MPs. As a result, at least six conversions, e. g., the [3+2] cycloaddition of phenols with olefins, the selective oxidation of sulfides, the C-3 thiocyanation of indole and the aminothiocyanation of ß-keto ester, could be promoted smoothly by BT-MPs. In addition, BT-MPs was readily recovered with well maintaining its photocatalytic activity and could be reused for at least eight times. This study highlights the potential of exploiting photoactive OMPs as recyclable, robust and metal-free heterogeneous photocatalysts.

Facile Access to Terminal Nitroalkanes via Anti-Markovnikov Hydronitration and Hydronitroalkylation of Alkenes Using Photoredox Catalysis.

The evolution of catalysis and functional group transfer reagents play a significant role in the development of anti-Markovnikov alkene hydrofunctionalization reactions, facilitating the access to value-added molecules. We herein report the first rational design of a modular intermolecular anti-Markovnikov hydronitration of alkenes, enabling the direct synthesis of terminal nitroalkanes under visible light-mediated photoredox catalysis. By employing the redox-active organic nitrating reagent N-nitrosuccinimide, the produced nitryl radicals, in the presence of an olefin and a hydrogen atom transfer (HAT) mediator, lead to an anti-Markovnikov addition with complete regioselectivity. Furthermore, we present results demonstrating the use of this catalytic system for chain expansion via anti-Markovnikov addition, utilizing substituted bromonitroalkanes as commercially available reagents. These transformations effectively address a gap in synthetic chemistry, enabling the direct synthesis of nitroalkanes from a variety of unactivated olefins in both complex molecules and unfunctionalized commodity chemicals.

Visible-Light-Driven Method for the Selective Synthesis of Amides and N-Acylureas from Carboxylic Acids and Thioureas.

In this work, we developed a visible-light-driven method for the selective synthesis of amides and N-acylureas from carboxylic acids and thioureas. This protocol was featured as avoidance of additional oxidants and transition metal catalysts, simple manipulations, low cost, broad substrate scope, and good functional group tolerance. As only oxygen serves as the oxidation reagent, this method provides a promising synthesis candidate for the formation of N-aryl amides and N-acylureas, including late-stage functionalization of complex pharmaceutical molecules and biologically active molecules.

Isonitrile Photochemistry: A Functional Group Class Coming in from the Cold.

Starting from a historical background that acknowledges isonitriles as a neglected class of compounds due to their unpleasant smell and hardly controlled reaction conditions with open shell species, the present concept article aims at highlighting the seeds of the modern isonitrile photochemistry. Representative essential transformations achieved via either UV light irradiation or radical initiators at high temperatures are brought into play to draw a parallel with the current literature relying on the exploitation of visible light photochemical methods. Such a comparison points out the potential of this enabling technology to further expand the scope of isonitrile chemistry and the unmet challenges which makes it a very stimulating field.

100†µs Luminescence Lifetime Boosts the Excited State Reactivity of a Ruthenium(II)-Anthracene Complex in Photon Upconversion and Photocatalytic Polymerizations with Red Light.

The triplet excited state lifetime of a photosensitizer is an essential parameter for diffusion-controlled energy- and electron-transfer, which occurs usually in a competitive manner to the intrinsic decay of a triplet excited state. Here we show the decisive role of luminescence lifetime in the triplet excited state reactivity toward energy- and electron transfer. Anchoring two phenyl anthracene chromophores to a ruthenium(II) polypyridyl complex (RuII ref) leads to a RuII triad with a luminescence lifetime above 100 µs, which is more than 40 times longer than that of the prototypical complex. The obtained RuII triad sensitizes energy transfer to anthracene-based annihilators more efficiently than RuII ref and enables red-to-blue photon upconversion with a pseudo anti-Stokes shift of 0.94 eV and a moderate upconversion efficiency near 1 % in aerated solution. Particularly, RuII triad allows rapid photoredox catalytic polymerizations of acrylate and acrylamide monomers under aerobic condition with red light, which are kinetically hindered for RuII ref. Our work shows that excited state lifetime of a photosensitizer governs the dynamics of the excited state reactions, which seems an overlooked but important aspect for photochemistry.

Reactive Reductive Species Participating Photodynamic Therapy for Cancer Treatment.

Although the development of oxidative photodynamic therapy (O-PDT) based on reactive oxygen species (ROS) has led to great progress in cancer treatment, tumor hypoxia, cellular adaptation and intrinsic antioxidant defenses are still obstacles at this stage. Fortunately, with the discovery and development of reactive reductive species (RRS) in the PDT process, reductive PDT (R-PDT) is receiving increasing research interest. R-PDT with oxygen-independence is an effective reduction therapy that promises excellent therapeutic efficacy in extremely hypoxic or even anaerobic environments. In the concept, we introduce representative strategies to boost the type-I photosensitizing pathway, and then focus on the most recent R-PDT involving hydrogen radical (H⋅) and the single electron transfer (SET) process.

Picking Two out of Three: Defluorinative Annulation of Trifluoromethyl Alkenes for the Synthesis of Monofluorinated Carbo- and Heterocycles.

The increasing demand of organofluorine compounds in medicine, agriculture, and materials sciences makes sophisticated methods for their synthesis ever more necessary. Nowadays, not only the C-F bond formation but also the selective C-F bond cleavage of readily available poly- or perfluorine-containing compounds have become powerful tools for the effective synthesis of organofluorine compounds. The defluorinative cross-coupling of trifluoromethyl alkenes with various nucleophiles or radical precursors in an SN 2' manner is a convergent route to access gem-difluoroalkenes, which in turn react with nucleophiles or radical precursors via an SN V-type reaction. If the SN V reactions occur intramolecularly, the dual C-F bond cleavage of trifluoromethyl alkenes allows facile assembly of monofluorinated cyclic skeletons with structural complexity and diversity. In this personal account, we summarized the advances in this field on the basis of coupling and cyclization partners, including binucleophiles, alkynes, diradical precursors and radical precursors bearing a nucleophilic site. Accordingly, the annulation reactions can be achieved by base-mediated sequential SN 2'/SN V reactions, transition metal catalyzed or mediated reactions, photoredox catalysis, and the combination of photocatalytic reactions with SN V reaction. In the context of seminal works of others in this field, a concise summary of the contributions of the authors is also offered.

Efficient Functionalization of Organosulfones via Photoredox Catalysis: Direct Incorporation of α-Carbonyl Alkyl Side Chains into α-Allyl-ß-Ketosulfones.

A novel and efficient method for functionalizing organosulfones has been established, utilizing a visible-light-driven intermolecular radical cascade cyclization of α-allyl-ß-ketosulfones. This process employs fac-Ir(ppy)3 as the photoredox catalyst and α-carbonyl alkyl bromide as the oxidizing agent. Via this approach, the substrates experience intermolecular addition of α-carbonyl alkyl radicals to the alkene bonds, initiating a sequence of C-C bond formations that culminate in the production of organosulfone derivatives. Notably, this technique features gentle reaction conditions and an exceptional compatibility with a wide array of functional groups, making it a versatile and valuable addition to the field of organic synthesis.

Substituent Effects in the Photophysical and Electrochemical Properties of Meso-Tetraphenylporphyrin Derivatives.

Porphyrins were identified some years ago as a promising, easily accessible, and tunable class of organic photoredox catalysts, but a systematic study on the effect of the electronic nature and of the position of the substituents on both the ground-state and the excited-state redox potentials of these compounds is still lacking. We prepared a set of known functionalized porphyrin derivatives containing different substituents either in one of the meso positions or at a ß-pyrrole carbon, and we determined their ground- and (singlet) excited-state redox potentials. We found that while the estimated singlet excited-state energies are essentially unaffected by the introduction of substituents, the redox potentials (both in the ground- and in the singlet excited-state) depend on the electron-withdrawing or electron-donating nature of the substituents. Thus, the presence of groups with electron-withdrawing resonance effects results in an enhancement of the reduction facility of the photocatalyst, both in the ground and in the excited state. We next prepared a second set of four previously unknown meso-substituted porphyrins, having a benzoyl group at different positions. The reduction facility of the porphyrin increases with the proximity of the substituent to the porphine core, reaching a maximum when the benzoyl substituent is introduced at a meso position.

Site-selective construction of N-linked glycopeptides through photoredox catalysis.

The glycosylation of peptides and proteins can significantly impact their intrinsic properties, such as conformation, stability, antigenicity, and immunogenicity. Current methods for preparing N-linked glycopeptides typically rely on amide bond formation, which can be limited by the presence of reactive functional groups like acids and amines. Late-stage functionalization of peptides offers a promising approach to obtaining N-linked glycopeptides. In this study, we demonstrate the preparation of N-linked glycopeptides through a photoredox-catalyzed site-selective Giese addition between N-glycosyl oxamic acid and peptides containing dehydroalanine (Dha) under visible light conditions. Unlike traditional methods that rely on the coupling of aspartic acid and glycosylamine, this approach utilizes the conjugation of N-glycosylated carbamoyl radicals with Dha, facilitating the straightforward modification of complex peptides.

Photoinduced Decarboxylative Radical Phosphinylation.

Reported herein is an unprecedented protocol for C(sp3 )-phosphinylation. With 1 mol % 4CzIPN (1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene) as the catalyst, the visible light induced reaction of redox-active esters of aliphatic carboxylic acids with dimethyl arylphosphonites or diethyl alkylphosphonites at room temperature provides the corresponding decarboxylative phosphinylation products in satisfactory yields. The protocol exhibits broad substrate scope and wide functional-group compatibility, enabling the late-stage modification of complex molecules and rapid synthesis of bioactive phosphinic acids such as glutamine synthetase phosphinothricin and a kynureninase inhibitor. A radical-polar crossover mechanism involving the formation and subsequent oxidation of phosphoranyl radicals followed by nucleophilic demethylation (or deethylation) is proposed.

Biomimetic Photoexcited Cobaloxime Catalysis in Organic Synthesis.

Drawing inspiration from nature has long been a cornerstone of chemical innovation, with natural systems offering a wealth of untapped potential for discovery. In this minireview, we delve into the burgeoning field of cobaloxime catalysis in organic synthesis, which mimics the catalytic activity of the natural organometallic alkylcobalamine enzymes. Our focus lies on elucidating the latest advancements in this area, as well as delineating the primary mechanistic pathways at play. By describing, and comparing these mechanisms, we provide a comprehensive overview of the current state-of-the-art, while also shedding light on the key unresolved challenges that await further exploration.