Search

Two 3-(p-substituted phenyl)-3a,8a-dihydro-4H-cyclohepta[d]isoxazoles were synthesized by 1,3-dipolar cycloaddition of the corresponding nitrile oxides with cycloheptatriene. Two endoperoxides were synthesized as facially selective and single products in high yields (93%--95%) from the reactions of isoxazole derivatives with singlet oxygen. The exact configurations of the endoperoxide with a methyl group in the phenyl ring and the diol synthesized from it were confirmed by X-ray analysis. To elucidate the mechanism, the formation energy of the endoperoxide was investigated by simulations using the software package Gaussian 09 and density functional theory calculations via the M06-2X/6-311+G(d,p) level method in dichloromethane. The results were consistent with experimental findings showing the formation of isoxazole products. [ABSTRACT FROM AUTHOR]

Aromatic architectures able to capture, store and release singlet oxygen have sparked the interest of the scientific community as an attractive strategy to generate singlet oxygen. Among these structures, anthracenes are efficient singlet oxygen batteries with applications in various fields such as chemistry, materials science or medicine. Until now, studies have mainly focused on symmetrical 9,10‐disubstituted anthracenes bearing (hetero)aryl groups or substituted alkyne motifs. In this work, we investigated unsymmetrical anthracene molecules to explore their propensity to trap and to release singlet oxygen. Kinetic studies confirmed the impact of electron‐rich and electron‐deficient substituents on the photooxygenation step and on the release of singlet oxygen triggered by thermolysis of the endoperoxides. [ABSTRACT FROM AUTHOR]

This article discusses the synthesis of a heavy-atom-free BODIPY dye called carbonyl-BDP and its application in the photooxygenation of 1-naphthol to 1,4-naphthoquinone. BODIPY dyes are known for their strong visible-light absorption and good photochemical and thermal stabilities, making them suitable for organic transformations. The introduction of carbonyl groups into the BODIPY system enhances its ability to generate singlet oxygen, which is important for photocatalytic reactions. The researchers successfully demonstrated the photooxygenation of 1-naphthol using carbonyl-BDP as a photosensitizer under white-light irradiation. [Extracted from the article]

Histidine photooxygenation has been the subject of extensive investigation for many years. The intricate nature of histidine distinguishes it from other amino acids, as its side chain readily undergoes changes in charge state and tautomerization in response to pH, and the polarity of the imidazole ring inverts upon oxidation. This complexity gives rise to a diverse range of oxidation products and mechanisms, posing challenges in their interpretation. This review aims to provide a thorough overview of the chemistry involved in histidine photooxygenation, encompassing a comprehensive analysis of resulting products, mechanisms engaged in their formation, and analytical techniques that have contributed to their identification. Additionally, it explores a wide range of applications stemming from this transformation, offering valuable insights into its practical implications in fields such as materials science, biomedical research, and drug development. By bridging the existing gap in literature, this review serves as a resource for understanding the intricacies of histidine photooxygenation and its diverse ramifications. [ABSTRACT FROM AUTHOR]

Polycyclic aromatic endoperoxides are important sources of singlet oxygen (1O2) and their formation from polyacenes is well established. Anthracene carboxyimides are of particular interest as they exhibit excellent antitumor activity and possess unique photochemical properties. However, the photooxygenation of the synthetically versatile anthracene carboxyimide moiety has not been reported due to its competing [4+4] photodimerization reaction. Herein, we describe the reversible photo‐oxidation of an anthracene carboxyimide. X‐ray crystallographic analysis surprisingly revealed the formation of a racemic mixture of chiral hydroperoxides, rather than the expected endoperoxide. The photoproduct undergoes both photo‐ and thermolysis to form 1O2. Activation parameters were derived for the thermolysis and the mechanisms of photooxygenation and thermolysis are discussed. The anthracene carboxyimide also showed high selectivity and sensitivity for nitrite anions in acidic aqueous media and possessed stimuli‐responsive behaviour. [ABSTRACT FROM AUTHOR]

In the quest for new therapies targeting hypoxia, aromatic endoperoxides have intriguing potential as oxygen releasing agents (ORAs) able to free O2 in tissues upon suitable trigger. Four aromatic substrates were synthesized and the formation of their corresponding endoperoxides was optimized in organic solvent upon selective irradiation of Methylene Blue, a low-cost photocatalyst, producing the reactive singlet oxygen species. Complexation of the hydrophobic substrates within a hydrophilic cyclodextrin (CyD) polymer allowed their photooxygenation in homogeneous aqueous environment using the same optimized protocol upon dissolution in water of the three readily accessible reagents. Notably, reaction rates were comparable in buffered D2O and organic solvent and, for the first time, the photooxygenation of highly hydrophobic substrates was achieved for millimolar solutions in non-deuterated water. Quantitative conversion of the substrates, straightforward isolation of the endoperoxides and recovery of the polymeric matrix were achieved. Cycloreversion of one ORA to the original aromatic substrate was observed upon thermolysis. These results hold great potential for the launch of CyD polymers both as reaction vessels for green, homogeneous photocatalysis and as carrier for the delivery of ORAs in tissues. [ABSTRACT FROM AUTHOR]

Oxygen atom incorporation into organic molecules is one of the most powerful strategies to increase their pharmacological activity and to obtain valuable intermediates in organic synthesis. Traditional oxidizing agents perform very well, but their environmental impact and their low selectivity constitute significant limitations. On the contrary, visible-light-promoted oxygenations represent a sustainable method for oxidizing organic compounds, since only molecular oxygen and a photocatalyst are required. Therefore, photocatalytic oxygenation reactions exhibit very high atom-economy and eco-compatibility. This mini-review collects and analyzes the most recent literature on organo-photocatalysis applications to promote the selective oxygenation of organic substrates. In particular, acridinium salts, Eosin Y, Rose Bengal, cyano-arenes, flavinium salts, and quinone-based dyes are widely used as photocatalysts in several organic transformations as the oxygenations of alkanes, alkenes, alkynes, aromatic compounds, amines, phosphines, silanes, and thioethers. In this context, organo-photocatalysts proved to be highly efficient in catalytic terms, showing similar or even superior performances with respect to their metal-based counterparts, while maintaining a low environmental impact. In addition, given the mild reaction conditions, visible-light-promoted photo-oxygenation processes often display remarkable selectivity, which is a striking feature for the late-stage functionalization of complex organic molecules. [ABSTRACT FROM AUTHOR]

Non-invasive phototherapy has been emerging as an ambitious tactic for suppression of amyloid-β (Aβ) self-assembly against Alzheimer's disease (AD). However, it remains a daunting challenge to develop efficient photosensitizers for Aβ oxygenation that are activatable in a deep brain tissue through the scalp and skull, while reducing side effects on normal tissues. Here, we report an Aβ targeted, low-dose X-ray-excitable long-afterglow scintillator (ScNPs@RB/Ab) for efficient deep-brain phototherapy. We demonstrate that the as-synthesized ScNPs@RB/Ab is capable of converting X-rays into visible light to activate the photosensitizers of rose bengal (RB) for Aβ oxygenation through the scalp and skull. We show that the ScNPs@RB/Ab persistently emitting visible luminescence can substantially minimize the risk of excessive X-ray exposure dosage. Importantly, peptide KLVFFAED-functionalized ScNPs@RB/Ab shows a blood–brain barrier permeability. In vivo experimental results validated that ScNPs@RB/Ab alleviated Aβ burden and slowed cognitive decline in triple-transgenic AD model mice at extremely low X-ray doses without side effects. Our study paves a new pathway to develop high-efficiency transcranial AD phototherapy. Non-invasive phototherapy has been emerging as an ambitious tactic for suppression of amyloid-β (Aβ) self-assembly against Alzheimer's disease (AD). However, it remains a daunting challenge to develop efficient photosensitizers for Aβ oxygenation that are activatable in a deep brain tissue through the scalp and skull, while reducing side effects on normal tissues. Herein, we report an Aβ targeted, low-dose X-ray-excitable long-afterglow scintillators (ScNPs@RB/Ab) for efficient deep-brain phototherapy. In vivo experimental results validated that ScNPs@RB/Ab alleviated Aβ burden and slowed cognitive decline in triple-transgenic AD model mice at extremely low X-ray doses without side effects. [Display omitted] [ABSTRACT FROM AUTHOR]

Toxic amyloid- β (A β) aggregates are closely related to neurodegenerative diseases. Photo-oxygenation of A β aggregates exhibits high efficiency in inhibiting A β fibrillation and degrading A β aggregates. However, indiscriminative photo-oxygenation will damage functional proteins, leading to a failure in anti-A β therapies. Herein, we develop a new quinolinium-based photo-oxygenation catalyst and introduce a non-radiative de-excitation pathway based on twisted intramolecular charge transfer (TICT) for the selective photo-oxygenation of A β 1–40 aggregates. The catalyst exhibits strong A β 1–40 fibrils binding affinity and activatable photo-oxygenation activity by limiting intramolecular rotation. Spectroscopic and microscopic characterizations demonstrate that the catalyst can efficiently inhibit A β 1–40 fibrillation and degrade preformed A β 1–40 fibrils even in a very low inhibitor:protein ratio (I:P = 0.05). Significantly attenuated neurotoxicity is also confirmed. These results provide new insight into the design of activatable photo-oxygenation catalysts for the selective inhibition of A β aggregation. [Display omitted] • A novel quinolinium-based photo-oxygenation catalyst is developed for the selective photo-oxygenation of Aβ 1–40 aggregates. • Photo-oxygenation of Aβ 1–40 aggregates by the catalyst under laser irradiation can efficiently suppress the aggregation of Aβ 1–40 peptides and degrade Aβ 1–40 aggregates even in a very low inhibitor: peptide ratio (e.g., 0.05). • The catalyst exhibits a significant neuroprotective effect against Aβ-mediated cytotoxicity. [ABSTRACT FROM AUTHOR]

The abnormal accumulation of β-amyloid protein (Aβ) is considered as the main pathological hallmark of Alzheimer's disease (AD). The design of potent multifunctional theranostic agents targeting Aβ is one of the effective strategies for AD prevention and treatment. Nanomotors as intelligent, advanced, and multifunctional nanoplatforms can perform many complex tasks, but their application in AD theranostics is rare. Herein, sub-10nm multifunctional dual-carbon dots composites (ERCD) with photo-propelled nanomotor behavior are fabricated by conjugating near-infrared (NIR) carbon dots (RCD) of thermogenic and photodynamic capability with the previously reported epigallocatechin gallate-derived carbonized polymer dots (ECD). ERCD-1 (ECD:RCD = 1:2.5) showed potent inhibitory capability similar to ECD in the absence of NIR light, and exhibited photooxygenation activity and nanomotor behavior powered by "self-thermophoretic force" under NIR irradiation, significantly enhancing the inhibition, disaggregation, and photooxygenation capabilities. The nanomotor suppressed Aβ fibrillization and rapidly disaggregated mature Aβ fibrils at very low concentrations (0.5 µg mL -1 ). Moreover, the NIR-activated ERCD-1 imaged Aβ plaques in vivo and prolonged nematode lifespan by 6 d at 2 µg mL -1 . As a proof-of-concept, this work opened a new avenue to the design of multifunctional sub-10nm nanomotors targeting Aβ for AD theranostics., (© 2024 Wiley‐VCH GmbH.)

[Display omitted] • Single-step diimide reduction of saturated 6-(4′-aryloxy phenyl) vinyl 1,2,4-trioxanes has been reported. • Antimalarial activities of the synthesized compounds were evaluated by oral route against multi-drug resistant Plasmodium yoelii nigeriensis. • Cyclopentane-based trioxanes provided best protection to infected mice amongst all. • Trioxane 12b1 is four-fold active than β-arteether via oral route. Novel saturated 6-(4′-aryloxy phenyl) vinyl 1,2,4-trioxanes 12a(1 – 3)–12d(1 – 3) and 13a(1 – 3)–13d(1 – 3) have been designed and synthesized, in one single step from diimide reduction of 11a(1 – 3)–11d(1 – 3). All the newly synthesized trioxanes were evaluated for their antimalarial activity against multi-drug resistant Plasmodium yoelii nigeriensis via oral route. Cyclopentane-based trioxanes 12b1, 12c1 and 12d1 , provided 100 % protection to the infected mice at 24 mg/kg × 4 days. The most active compound of the series, trioxane 12b1 , provided 100 % protection even at 12 mg/kg × 4 days and 60 % protection at 6 mg/kg × 4 days. The currently used drug, β-arteether provides only 20 % protection at 24 mg/kg × 4 days. [ABSTRACT FROM AUTHOR]

Amyloids, proteinous aggregates with β-sheet-rich fibrils, are involved in several neurodegenerative diseases such as Alzheimer's disease; thus, their detection is critically important. The most common fluorescent dye for amyloid detection is thioflavin-T (ThT), which shows on/off fluorescence upon amyloid binding. We previously reported that an engineered globular protein with a flat β-sheet, peptide self-assembly mimic (PSAM), can be used as an amyloid binding model. In this study, we further explored the residue-specific properties of ThT-binding to the flat β-sheet by introducing systematic mutations. We found that site-specific mutations at the ThT-binding channel enhanced affinity. We also evaluated the binding of a ThT-based photocatalyst, which showed the photooxygenation activity on the amyloid fibril upon light radiation. Upon binding of the photocatalyst to the PSAM variant, singlet oxygen-generating activity was observed. The results of this study expand our understanding of the detailed binding mechanism of amyloid-specific molecules. [ABSTRACT FROM AUTHOR]

Oxygen atom incorporation into organic molecules is one of the most powerful strategies to increase their pharmacological activity and to obtain valuable intermediates in organic synthesis. Traditional oxidizing agents perform very well, but their environmental impact and their low selectivity constitute significant limitations. On the contrary, visible-light-promoted oxygenations represent a sustainable method for oxidizing organic compounds, since only molecular oxygen and a photocatalyst are required. Therefore, photocatalytic oxygenation reactions exhibit very high atom-economy and eco-compatibility. This mini-review collects and analyzes the most recent literature on organo-photocatalysis applications to promote the selective oxygenation of organic substrates. In particular, acridinium salts, Eosin Y, Rose Bengal, cyano-arenes, flavinium salts, and quinone-based dyes are widely used as photocatalysts in several organic transformations as the oxygenations of alkanes, alkenes, alkynes, aromatic compounds, amines, phosphines, silanes, and thioethers. In this context, organo-photocatalysts proved to be highly efficient in catalytic terms, showing similar or even superior performances with respect to their metal-based counterparts, while maintaining a low environmental impact. In addition, given the mild reaction conditions, visible-light-promoted photo-oxygenation processes often display remarkable selectivity, which is a striking feature for the late-stage functionalization of complex organic molecules.

The photooxygenation of naphthalene to the corresponding endoperoxide (EPO) under various conditions is described. Substantial conversion is only observed at −10 °C and after more than two days, indicating that the [4+2] cycloaddition of singlet oxygen to this acene proceeds much more slowly than corresponding reactions of substituted naphthalenes, a rate constant of k=5.4±0.3 M−1s−1 was determined by competition kinetics. Another problem is the thermal lability and photochemical cleavage of the naphthalene EPO. We investigated the mechanism of this radical process depending on the light source and sensitizer in comparison to known cyclohexadiene EPO. Thus, bisepoxides and keto epoxides are formed after homolysis of the O−O bond by irradiation with sodium lamps or blue LEDs and subsequent cyclization. This process is accelerated by the sensitizers methylene blue and 9,10‐dicyanoanthracene, indicating an electron transfer mechanism. Finally, the cleavage of the peroxidic bond is inhibited with red LEDs, and photooxygenation under such conditions affords 20 % EPO. Thus, we could demonstrate that contrary to literature statements singlet oxygen does indeed react with naphthalene. [ABSTRACT FROM AUTHOR]

[Display omitted] • Malaria persists as a challenge to world health in low-income countries. • Resistance of malaria parasites added plight to affordable antimalarial drugs. • Antimalarial activities of the synthesized compounds were evaluated by oral and intramuscular routes against multi-drug resistant Plasmodium yoelii nigeriensis. • 17a1 and 17a2 are two-fold more active than artemisinin via oral route. Following the economic and social state of humanity, Malaria is categorized as one of the life-threatening illness epidemics in under developed countries. For the eradication of the same, 1,2,4-trioxanes 17a1-a2 , 17b1-b2 , 17c1-c2 15a-c , 18 and 19 have been synthesized continuing the creation of a novel series. Additionally, these novel compounds were tested for their effectiveness against the multidrug-resistant Plasmodium yoelii nigeriensis in mice model using both oral and intramuscular (im) administration routes. The two most potent compounds of the series, 17a1 and 17a2, demonstrated 100 % protection at 48 mg/kg x 4 days via oral route, which is twice as potent as artemisinin. In this model artemisinin provided 100 % protection at a dose of 48 mg/kg × 4 days and 80 % protection at 24 mg/kg × 4 days via im route. [ABSTRACT FROM AUTHOR]

The abnormal aggregation of β-amyloid protein (Aβ) is one of the main pathological hallmarks of Alzheimer's disease (AD), and thus development of potent scavengers targeting Aβ is considered an effective strategy for AD treatment. Herein, photosensitizer-doped carbonized polymer dots (PS-CPDs) were synthesized by a one-step hydrothermal method using photosensitizer (PS) and o -phenylenediamine ( o PD) as precursors, and furtherly applied to inhibit Aβ aggregation via photooxygenation. The inhibition efficiency of such PS-CPDs can be adjusted by varying the type of photosensitizer, and among them, methylene blue-doped carbonized polymer dots (MB-CPDs) showed the strongest photooxygenation inhibition capability. The results demonstrated that under 650 nm NIR light irradiation, MB-CPDs (2 μg/mL) produced reactive oxygen species (ROS) to efficiently inhibit Aβ fibrillization and disaggregate mature Aβ fibrils and increased the cultured cell viability from 50% to 83%. In vivo studies confirmed that MB-CPDs extended the lifespan of AD nematodes by 4 days. Notably, the inhibitory capability of MB-CPDs is much stronger than that of MB and previously reported carbonized polymer dots. This work indicated that potent photooxygenation carbon dots can be obtained by using a photosensitizer as one of the precursors, and the results have provided new insights into the design of potent photooxygenation carbon nanomaterials targeting Aβ in AD treatment.

Design of mesoporous silicon nanoplatform loaded with photosensitizer and CPPO Schematic diagram of the process of synthesis and photooxygenation of extracellular protein Aβ. [Display omitted] • In situ- triggered and chemiexcited photooxygenation of Aβ was reported. • A photo-oxidation agent for Aβ aggregates, BD-6 - 3 , was designed and synthesized. • BD-6 - 3 and CPPO were loaded by MSNs, and decorated with Lf, to obtain Lf@6 - 3. • Our study will shed light on chemiexcited photooxygenation of misfolding proteins. Photooxygenation of Aβ protein has emerged as an effective and promising strategy against Alzheimer's disease (AD). However, the penetration depth of excitation light into the skull and brain is limited, which restricts its further development. In this work, for the first time, we report an in situ -triggered and chemi-excited photooxygenation system capable of photooxygenating aggregated Aβ without the need for an external excitation source. A photosensitizer (BD-6 - 3) has been designed and synthesized that could mediate photooxidative degradation of Aβ aggregates under white light. BD-6 - 3 and bis[2,4,5-trichloro-6-(pentoxycarbonyl) phenyl] ester were loaded in mesoporous silica nanoparticles, which were in turn decorated with lactoferrin to afford the in situ -triggered and chemi-excited photooxygenation system Lf@6 - 3. It could be activated by the high concentration of H 2 O 2 in the pathological microenvironment of AD to produce chemiluminescence. Singlet oxygen (1O 2) produced can photooxygenate Aβ aggregates, thereby inactivating them and suppressing their neurotoxic effect. [ABSTRACT FROM AUTHOR]

We are investigating catalytic approaches to participating in the chemical networks of living organisms. Catalysts that enable us to do so activate stable molecules with high selectivity under physiological conditions and will form the basis of a new area of medicine, catalysis medicine. Additionally, our research will contribute to progress in both physical and life sciences based on catalysis. In this Perspective, we provide a general overview of the concept of catalysis medicine, with examples of our recent achievements in chemical catalyst-promoted synthetic epigenetics in living cells and amyloid degradation in Alzheimer's disease model mice. This Perspective postulates the potential for catalysis research to act as a foundation from which to tackle important interdisciplinary problems. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] A new series of 1,2,4-trioxanes 9a1-a4 , 9b1-b4, 10 – 13 and 9c1-c4 were synthesized and evaluated against multidrug-resistant Plasmodium yoelii nigeriensis in Swiss mice via oral and intramuscular (i.m.) routes. Adamantane-based trioxane 9b4 , the most active compound of the series, provided 100% protection to the infected mice at the dose 48 mg/kg × 4 days and 100% clearance of parasitemia at the dose 24 mg/kg × 4 days via oral route. Adamantane-based trioxane 9b4 , is twice active than artemisinin. We have also studied the photooxygenation behaviour of allylic alcohols 6a - b (3-(4-alkoxynaphthyl)-but-2-ene-1-ols) and 6c (3-[4-(tert -butyl-dimethyl-silanyloxy)-naphthalen-1-yl]-but-2-en-1-ol). Being behaving as dienes, they furnished corresponding endoperoxides, while behaving as allylic alcohols, they yielded β-hydroxyhydroperoxides. All the endoperoxides (7a-c) and β-hydroxyhydroperoxides (8a-c) have been separately elaborated to the corresponding 1,2,4-trioxanes, except from endoperoxide 7c. It is worthy to note that TBDMS protected naphthoyl endoperoxide 7c unable to deliver 1,2,4-trioxane, which demonstrated the strength of the O-Si bond is not easy to cleave under acidic condition. [ABSTRACT FROM AUTHOR]