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.

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).

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.

Nanometric-Mapping and In Situ Quantification of Site-specific Photoredox Activities on 2D Nanoplates.

Defective layered bismuth oxychloride (BiOCl) exhibits excellent photocatalytic activities in water purification and environmental remediation. Herein, in situ single-molecule fluorescence microscopy is used to spatially resolve the photocatalytic heterogeneity and quantify the photoredox activities on individual structural features of BiOCl. The BiOCl nanoplates with respective dominant {001} and {010} facets (BOC-001 and BOC-010) are fabricated through tuning the pH of the solution. The corner position of BOC-001 exhibits the highest photo-oxidation turnover rate of 262.7 ± 30.8 s-1 µm-2, which is 2.1 and 65.7 times of those of edges and basal planes, respectively. A similar trend is also observed on BOC-010, which can be explained by the heterogeneous distribution of defects at each structure. Besides, BOC-001 shows a higher photoredox activity than BOC-010 at corners and edges. This can be attributed to the superior charge separation ability, active high-index facets of BOC-001, and its co-exposure of anisotropic facets steering the charge flow. Therefore, this work provides an effective strategy to understand the facet-dependent properties of single-crystalline materials at nanometer resolution. The quantification of site-specific photoredox activities on BiOCl nanoplates sheds more light on the design and optimization of 2D materials at the single-molecule level.

Functionalized Polyamine Synthesis with Photoredox Catalysis.

Polyamines, such as putrescine and spermidine, are pivotal in various biological processes across living organisms. Despite their significance, structurally modified polyamines offer a less-explored avenue for discovering bioactive compounds. The limitation is attributed to the synthetic difficulty of accessing functionalized polyamines. In this study, we accomplished photoredox-catalyzed functionalization of polyamines to diversify their structure. The rapid functionalization allows attaching fluorophores to the target polyamine, facilitating the development of molecular probes for advancing chemical biology studies.

Towards a General Access to 1-Azaspirocyclic Systems via Photoinduced, Reductive Decarboxylative Radical Cyclizations.

A convenient and versatile approach to important 1-azaspirocyclic systems relevant to medicinal chemistry and natural products is reported herein. The main strategy relies on a reductive decarboxylative cyclization of redox-active esters which can be rapidly assembled from abundant cyclic azaacids and tailored acceptor sidechains, with a focus on alkyne acceptors enabling the generation of useful exo-alkene moieties. Diastereoconvergent variants were studied and could be achieved either through remote stereocontrol or conformational restriction in bicyclic carbamate substrates. Two sets of metal-free photocatalytic conditions employing inexpensive eosin Y were disclosed and studied experimentally to highlight key mechanistic divergences.

Photomediated Hexafluoroisopropoxylation of Unactivated Aryl Halides.

The use of fluoroalkoxy groups, such as trifluoromethoxy and 2,2,2-trifluoroethoxy groups, in pharmaceutical and agrochemical development has increased dramatically in recent years. However, hexafluoroisopropoxy groups have remained significantly underrepresented, presumably due to limited synthetic methods for accessing this substituent in good yields. Herein, we report a mild, photochemical nucleophilic aromatic substitution (SNAr) approach for the synthesis of hexafluoroisopropyl aryl ethers from unactivated and abundant aryl halides. Notably, aryl chloride and bromide functionality are efficiently engaged by this methodology in addition to the traditional aryl fluoride nucleofuge. This method provided access to a diverse array of hexafluoroisopropyl aryl ethers, including multiple examples of late-stage functionalization of active pharmaceutical ingredients. A simple flow system was adapted for 10x scale-up, maintaining good yield for the reaction. Initial mechanistic studies indicate single electron oxidation of the arene as a key step in product formation.

Preparation of Carbazoles Involving 6π-Electrocyclization, Photoredox-, Electrochemical-, and Thermal Cyclization Reactions: Mechanistic Insights.

Carbazole is a heterocyclic motif that can be found in a diverse array of natural and unnatural products displaying a wide range of biological and physiological properties. Furthermore, this heterocycle is part of electronic materials like photoconducting polymers and organic optoelectronic materials owing to its excellent photophysical characteristics. Consequently, the development of synthetic strategies for carbazole scaffolds holds potential significance in biological and material fields. In this regard, a variety of preparation methods has been developed to exploit their efficient and distinct formation of new C-C and C-heteroatom bonds under mild conditions and enabling broad substrate diversity and functional group tolerance. Therefore, this review focuses on the synthesis of a set of carbazole derivatives describing a variety of methodologies that involve direct irradiation, photosensitization, photoredox, electrochemical and thermal cyclization reactions.

Indole Nucleophile Triggers Mechanistic Divergence in Ni-Photoredox N-Arylation.

This study presents a Ni-photoredox method for indole N-arylation, broadening the range of substrates to include indoles with unprotected C3-positions and base-sensitive groups. Through detailed mechanistic inquiries, a Ni(I/III) mechanism was uncovered, distinct from those commonly proposed for Ni-catalyzed amine, thiol, and alcohol arylation, as well as from the Ni(0/II/III) cycle identified for amide arylation under almost identical conditions. The key finding is the formation of a Ni(I) intermediate bearing the indole nucleophile as a ligand prior to oxidative addition, which is rare for Ni-photoredox carbon-heteroatom coupling and has a profound impact on the reaction kinetics and scope. The pre-coordination of indole renders a more electron-rich Ni(I) intermediate, which broadens the scope by enabling fast reactivity even with challenging electron-rich aryl bromide substrates. Thus, this work highlights the often-overlooked influence of X-type ligands on Ni oxidative addition rates and illustrates yet another mechanistic divergence in Ni-photoredox C-heteroatom couplings.

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.

A Photoredox Thiol-yne Reaction for the Synthesis of Vinyl Sulfide-Based Coumarins and its Effect on Fluorescence Properties.

Coumarins still remain one of the most widely explored fluorescent dyes, with a broad spectrum of applications spanning various fields, such as molecular imaging, bioorganic chemistry, materials chemistry, or medical sciences. Their fluorescence is strongly based on a push-pull mechanism involving an electron-donating group (EDG), mainly located at the C7 or C8 positions of the dye core. Unfortunately, up to now, these positions have been very limited to hydroxyl or amino groups. In this study, we present in detail the synthesis of the first series of coumarins bearing a vinyl sulfide as the EDG at the C7 position. These derivatives were prepared by thiol-yne reaction, promoted by ruthenium- or porphyrin-based photoredox catalysis, enabling rapid late-stage diversification. We also functionalized coumarins with short peptides, and BSA protein as a proof-of-concept study, in a single-step process. This strategy, capable of proceeding under aqueous conditions, overcomes the protection/deprotection steps usually required by traditional methods, which also use strong bases and organic solvents. Moreover, the photophysical properties such as absorption and emission of obtained coumarins (for 3-CF3, 3-benzothiazole, 6-8-difluoro derivatives), predominantly exhibited large Stokes shifts (up to 204 nm) and maintained intramolecular charge transfer (ICT) characteristics.

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.

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.

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.

The Role of Base in Reaction Performance of Photochemical Synthesis of Thiazoles: An Integrated Theoretical and Experimental Study.

Artificial intelligence (AI)/machine learning (ML) is emerging as pivotal in synthetic chemistry, offering revolutionary potential in retrosynthetic analysis, reaction conditions and reaction prediction. We have combined chemical descriptors, primarily based on Density Functional Theory (DFT) calculations, with various AI/ML tools such as Multi-Layer Perceptron (MLP) and Random Forest (RF), to predict the synthesis of 2-arylbenzothiazole in photoredox reactions. Significantly, our models underscore the critical role of the molecular structure and physicochemical characteristics of the base, especially the total atomic polarizabilities, in the rate-determining steps involving cyclohexyl and phenethyl moieties of the substrate. Moreover, we validated our findings in articles through experimental studies. It showcases the power of AI/ML and quantum chemistry in shaping the future of organic chemistry.

Redox-Neutral Multicatalytic Cerium Photoredox-Enabled Cleavage of O-H Bearing Substrates.

The need for synthetic methodologies capable of rapidly altering molecular structure are in high demand. Most existing methods to modify scaffolds rely on net exothermicity to drive the desired transformation. We sought to develop a general strategy for the cleavage of C-C bonds ß to hydroxyl groups independent of inherent substrate strain. To this end we have applied a multicatalytic cerium photoredox-based system capable of activating O-H bonds in lactols to deliver formate esters. The same system is also capable of effecting hydrodecarboxylation and hydrodecarbonylation reactions. Initial mechanistic probes demonstrate atomic chlorine (Cl⋅) is generated under the reaction conditions, but substrate activation through cerium-alkoxides or -carboxylates cannot be ruled out.

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.

Photoredox Catalysis by 21-Thiaporphyrins: A Green and Efficient Approach for C-N Borylation and C-H Arylation.

Photoredox catalysis provides a green and sustainable alternative for C-H activation of organic molecules that eludes harsh conditions and use of transition metals. The photocatalytic C-N borylation and C-H arylation mostly depend on the ruthenium and iridium complexes or eosin Y and the use of porphyrin catalysts is still in infancy. A series of novel 21-thiaporphyrins (A2B2 and A3B type) were synthesized having carbazole/phenothiazine moieties at their meso-positions and screened as catalysts for C-N borylation and C-H arylation. This paper demonstrates the 21-thiaporphyrin catalyzed C-N borylation and het-arylation of anilines under visible light. The method utilizes only 0.1 mol % of 21-thiaporphyrin catalyst under blue light for the direct C-N borylation and het-arylation reactions. A variety of substituted anilines were used as source for expensive and unstable aryl diazonium salts in the reactions. The heterobiaryls and aryl boronic esters were obtained in decent yields (up to 88 %). Versatility of the 21-thiaporphyrin catalyst was tested by thiolation and selenylation of anilines under similar conditions. Mechanistic insight was obtained from DFT studies, suggesting that 21-thiaporphyrin undergo an oxidative quenching pathway. The photoredox process catalyzed by 21-thiaporphyrins offers a mild, efficient and metal-free alternative for the formation of C-C, C-S, and C-Se bonds in aryl compounds; it can also be extended to borylation reaction.

Earth-Abundant Recyclable Magnetic Iron Oxide Nanoparticles for Green-light Mediated C-H Arylation in Heterogeneous Phase.

A magnetically isolable iron oxide nanoparticles is introduced as an efficient heterogeneous photocatalyst for non-directed C-H arylation employing aryl diazonium salts as the aryl precursors. This first-row transition metal-based photocatalyst revealed versatile activities and is applicable to a wide range of substrates, demonstrating brilliant efficacy and superior recyclability. Detailed catalytic characterization describes the physical properties and redox behavior of the Fe-catalyst. Adequate control experiments helped to establish the radical-based mechanism for the C-H arylation.

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.