Design, Synthesis of (±)‐Millpuline A, and Biological Evaluation for the Lung Cell Protective Effects through SRC

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Design, Synthesis of (±)-Millpuline A, and Biological Evaluation for the Lung Cell Protective Effects through SRC

We report a visible-light-induced intermolecular [2+2] photocycloaddition reaction based on flavonoids to synthesize (±)-millpuline A and 20 derivatives (B1–B20), which could be constructed to address the problems of low yield, poor physicochemical properties, and lack of target definition in total synthesis of complex natural products.


Abstract

In this study, a visible-light-induced intermolecular [2+2] photocycloaddition reaction based on flavonoids was constructed to address the problems of low yield, poor physicochemical properties, and lack of target definition in total synthesis of (±)-millpuline A whose bioactivity remains unknown. As a result, 20 derivatives were synthesized for bioactivity evaluation. Consequently, lung cell protective effects of (±)-millpuline A and compound B13 a were revealed for the first time and the crucial role of stereoconfiguration of the cyclobutane moiety in their protective effects against NNK in normal lung cells was demonstrated. Moreover, through target prediction and experimental verification in MLE-12 cells, SRC was determined to be the target of (±)-millpuline A regarding its protective effect in NNK-induced lung cell injury. Results from RT-Q-PCR and HTRF experiments verified that (±)-millpuline A could repress SRC activity through a transcriptional mechanism but not acting as an inhibitor to directly bind to and thereby inhibit SRC protein. The results in this paper are informative for the further development of visible light-catalyzed cycloaddition of flavonoids and lay a scientific foundation for understanding the bioactivity and underlying mechanism of (±)-millpuline A and other structurally similar natural skeletons.

A Detailed Insight into the Effects of Morphologies of Cerium Oxide on Fenton‐like Reactions for Different Applications

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A Detailed Insight into the Effects of Morphologies of Cerium Oxide on Fenton-like Reactions for Different Applications

In the context of the Fenton-like reaction involving cerium oxide, cubic CeO2 primarily facilitate the decomposition of H2O2 into reactive oxygen species, resulting in significant damage to lung adenocarcinoma cells. In contrast, rod-like CeO2 predominantly engage in the complexation of H2O2, leading to the formation of peroxides, thereby demonstrating a pronounced capability of organic dye degradation.


Abstract

As an exceptional Fenton-like reagent, cerium oxide (CeO2) finds applications in biomedical science and organic pollutants treatment. The Fenton-like reaction catalyzed by CeO2 typically encompasses two distinct processes: one resembling the classical Fenton reaction, wherein cerium (Ce3+) triggers the decomposition of hydrogen peroxide (H2O2) to yield reactive oxygen species (ROS), and the other involves the complexation of H2O2 on the Ce3+ surface, leading to the formation of peroxides. However, the influence of diverse CeO2 morphologies on these two reaction pathways has not been comprehensively explored. In this study, CeO2 exhibiting three typical morphologies, rods, cubes, and spheres, were prepared. The generation of ROS and peroxides was evaluated using the 3,3,5,5-tetramethylbenzidine (TMB) oxidation reaction and the reduction current of H2O2, respectively. Moreover, the impacts of pH variations and CeO2/H2O2 concentrations on the production and conversion of these two reaction products were investigated. To corroborate the distinctions between the resultant products and their applicability, apoptosis assays and acid orange 7 (AO7) degradation analyses were performed. Notably, CeO2 rods exhibited the highest proportion of Ce3+, predominantly engaging in complexation with H2O2 to foster peroxide formation, thereby facilitating the robust degradation of AO7. However, the generated peroxides appeared to occupy Ce3+ sites, thereby impeding the H2O2 decomposition process. Conversely, Ce3+ species on the surface of CeO2 cubes were primarily involved in H2O2 decomposition, leading to heightened ROS production, and thus showcasing substantial potential for damaging A549 tumor cells. It is worth noting that the ability of these Ce3+ species to form peroxides through complexation with H2O2 was comparatively reduced. In summation, this study sheds light on the intricate interplay between distinct CeO2 morphologies and their divergent impacts on Fenton-like reactions. These findings expand our comprehension of the influences on its reactivity of CeO2 morphologies and open new insights for applications in diverse domains, from organic dye degradation to tumor therapy.

Unveiling the Noncovalent Interaction of Thiazol‐2‐ylidene and Its Derivatives as N‐heterocyclic Carbene with Different Proton Donor Molecules

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Unveiling the Noncovalent Interaction of Thiazol-2-ylidene and Its Derivatives as N-heterocyclic Carbene with Different Proton Donor Molecules

A systematic noncovalent interaction study of thiazole-2-ylidene derivatives with five different proton donor molecules. This computational investigation will contribute towards designing of an efficient catalyst for synthetic chemists and drug designing for medicinal chemistry.


Abstract

The importance of noncovalent interaction has gained attention in various domains covering drug and novel catalyst design. The present study mainly characterizes the role of hydrogen bond (H-bond) and other intermolecular interactions in different (1 : 1) complex analogues formed between the N-aryl-thiazol-2-ylidene (YR) and five proton donor (HX) molecules. The analysis of the singlet-triplet energy gap ( ) confirmed the stability of the singlet state for this class of N-aryl-thiazol-2-ylidenes than the triplet state. The interaction energy values of the YR-HX complexes follow the order: YR-NH3<YR-HCN<YR-H2O<YR-MeOH<YR-HF. In addition, substituting the H-atom of the N−H bond with bulky groups (−R) leads to an increase in the interaction energy of the YR-HX complexes. Hence, it was found that the replacement of N-atom in N-heterocyclic carbene (NHC) by S-atom forming N-aryl-thiazol-2-ylidene results in comparable intermolecular interactions with proton donor molecules similar to imidazole-2-ylidene (NHC). The current study enlightened the role of noncovalent interactions in carbene complexes with proton donor molecules. We hope that our work on carbene chemistry will pave the way for its application in the designing and synthesis of efficient catalysts.

Dose Addition Models Accurately Predict the Subacute Effects of a Mixture of Perfluorooctane Sulfonate (PFOS) and Perfluorooctanoic Acid (PFOA) on Japanese Quail (Coturnix japonica) Chick Mortality.

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Abstract

Biomonitoring data have consistently demonstrated that fish, wildlife, and humans are exposed to multiple per- and polyfluoroalkyl substances (PFAS) in drinking water and foods. Despite ubiquitous exposure to mixtures of PFAS, there is a lack of in vivo PFAS mixture research that addresses if these chemicals act in a cumulative, dose-additive manner or if they behave independently. For this reason, there is a critical need for mixtures studies designed to evaluate the cumulative toxicity and potential chemical interactions to support the assessment of human and ecological risks as well as define appropriate regulatory actions. The primary objective of this communication was to evaluate the previously published Japanese quail chick mortality concentration-response data for PFOS and PFOA and the mixture of PFOS+PFOA and use statistical modeling to determine if the effects of the mixtures were accurately predicted by either dose- (DA) or response addition (RA) modeling. In addition, we wanted to compare different DA models to determine if one model produced more accurate predictions than the others. Results support the hypothesis of cumulative effects on shared endpoints from PFOA and PFOS co-exposure and dose additive approaches for predictive estimates of cumulative effects. Given the limited number of in vivo studies that have been executed with enough individual PFAS and PFAS mixture concentration-response data to test the hypothesis of DA for PFAS mixtures, this reanalysis of the data is an important contribution to our understanding of how PFAS mixtures act. The analysis will provide support for regulatory agencies as they begin to implement PFAS cumulative hazard assessments in higher vertebrates.

Metal‐Free Defluoroborylation of 3,3‐Difluoropropenes

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Metal-Free Defluoroborylation of 3,3-Difluoropropenes

A metal-free defluoroborylation of 3,3-difluoropropenes has been developed. The reaction involves the convenient borylation agent B2pin2 and a combination of both TBAF and HMDS as an activating system. The fluorinated allylboronates were used as a platform to prepare functionalized monofluoroalkenes.


Abstract

The defluorinative functionalization of allylic fluorides represents an attractive approach for the preparation of molecules containing a monofluoroalkene core. In that sense, introducing a “boryl nucleophile” is a powerful strategy to obtain polyvalent borylated intermediates as versatile synthetic precursors. To perform this reaction without the use of transition metals, the nucleophilic character of a diborane/fluoride system was exploited in a SN2′ type-substitution reaction of gem-difluoropropenes to install a pinacolborane group. The use of HMDS as a silylated additive is necessary to improve the reactivity. A direct oxidation of the intermediate boronates allowed the isolation of the corresponding β-fluoroallyl alcohols in low to good yields (9–81 %). Other synthetic transformations of a (2-fluoroallyl)boronate are also illustrated.

Ecotoxicity of Lead to a Phytoplankton Community: Effects of pH and Phosphorus Addition and Implications for Risk Assessment

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Abstract

Ecological risk assessment and water quality criteria for lead (Pb) are increasingly making use of bioavailability-based approaches to account for the impact of toxicity-modifying factors, such as pH and dissolved organic carbon. For phytoplankton, which are among the most Pb-sensitive freshwater species, a Pb bioavailability model has previously been developed based on standard single-species exposures at a high phosphorus (P) concentration and pH range of 6.0 to 8.0. It is well known that P can affect metal toxicity to phytoplankton and that the pH of many surface waters can be above 8.0. We aimed to test whether the single-species bioavailability model for Pb could predict the influence of pH on Pb toxicity to a phytoplankton community at both low and high P supply. A 10-species phytoplankton community was exposed to Pb for 28 days at two different pH levels (7.2 and 8.4) and two different P supply levels (low and high, i.e., total P input 10 and 100 µg/L, respectively) in a full factorial 2 × 2 test design. We found that the effects of total Pb on three community-level endpoints (biodiversity, community functioning, and community structure) were highly dependent on both pH and P supply. Consistent lowest-observed-effect concentrations (LOECs) ranged between 21 and >196 µg total Pb/L and between 10 and >69 µg filtered Pb/L. Long-term LOECs were generally higher, that is, 69 µg total Pb/L (42 µg filtered Pb/L) or greater, across all endpoints and conditions, indicating recovery near the end of the exposure period, and suggesting the occurrence of acclimation to Pb and/or functional redundancy. The highest toxicity of Pb for all endpoints was observed in the pH 7.2 × low P treatment, whereas the pH 8.4 × low P and pH 8.4 × high P treatment were the least sensitive treatments. At the pH 7.2 × high P treatment, the algal community showed an intermediate Pb sensitivity. The effect of pH on the toxicity of filtered Pb could not be precisely quantified because for many endpoints no effect was observed at the highest Pb concentration tested. However, the long-term LOECs (filtered Pb) at low P supply suggest a decrease in Pb toxicity of at least 1.6-fold from pH 7.2 to 8.4, whereas the single-species algal bioavailability model predicted a 2.5-fold increase. This finding suggests that bioavailability effects of pH on Pb toxicity cannot be extrapolated as such from the single species to the community level. Overall, our data indicate that, although the single-species algal Pb bioavailability model may not capture pH effects on Pb ecotoxicity in multispecies systems, the bioavailability-based hazardous concentration for 5% of the species was protective of long-term Pb effects on the structure, function, and diversity of a phytoplankton community in a relevant range of pH and P conditions. Environ Toxicol Chem 2023;00:1–17. © 2023 SETAC

Catalytic Enantioselective Synthesis of Inherently Chiral Molecules: Recent Advances

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Catalytic Enantioselective Synthesis of Inherently Chiral Molecules: Recent Advances

Inherent chirality represents a distinct form of molecular chirality that does not fit into the four traditional types of molecular chiral elements, which has been observed in a diverse range of molecular structures. This review summarizes the recent advances in the catalytic enantioselective synthesis of inherently chiral molecules, including chiral calixarenes, saddle-shaped chiral cycles, mechanically planar chiral rotaxanes and others.


Abstract

Inherent chirality represents a distinct category of molecular chirality that does not fall within the traditional classification of four chiral elements: central, axial, planar, and helical chirality. While extensive research has been conducted on the catalytic enantioselective construction of these conventional chiralities, the corresponding synthesis of inherently chiral molecules has remained largely unexplored. This minireview provides a comprehensive summary of recent advancements in this field, focusing on the catalytic asymmetric synthesis of inherently chiral calixarenes, saddle-shaped tetraphenylenes and their heterocycle derivatives, mechanically planar chiral rotaxanes and chiral multilayer 3D frameworks, as well as our perspective in this field.

CO2‐Based Carbamate Synthesis Utilizing Reusable Polymer‐Supported DBU

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CO2-Based Carbamate Synthesis Utilizing Reusable Polymer-Supported DBU

A novel and advantageous protocol for accessing carbamates through the known three-component coupling reaction involving carbon dioxide, amines, and alkyl halides is described. Employing mild conditions, simple experimental set-up, and immobilized DBU, this protocol addresses several drawbacks from the previous described methods. No classical purification procedures are necessary and the immobilized DBU can be recycled and reused several times.


Abstract

The present study highlights a novel and advantageous protocol for accessing carbamates through the well-established three-component coupling reaction involving CO2, amines, and alkyl halides. By employing an immobilized organic base, operating under mild reaction conditions, an array of alkyl carbamates in yields of up to 95 % could be isolated. This approach offers a broad and versatile product scope, allowing for the facile modification of both the amine and alkyl halide reactants. Notably, the pioneering use of an immobilized organic base, specifically the polymer-supported 1,8-diazabicyclo[5.4.0]undec-7-ene (PS-DBU), in this three-component reaction eliminates the need for classical purification steps, streamlining the process. To ensure practicality and sustainability, extensive studies were conducted to verify the recovery and reusability of the polymer-supported DBU catalyst, which consistently maintained the high chemical yield of the carbamates across multiple cycles. Overall, this innovative protocol represents a significant advancement in carbamate synthesis, combining efficiency, generality, and the potential for DBU recycling.

Three‐Component Reactions of Quinoxalin‐2(1H)‐ones: Recent Advances

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Three-Component Reactions of Quinoxalin-2(1H)-ones: Recent Advances

This Review focuses on the very recent advances (from 2021 to the beginning of 2023) in the field of three-component reactions of quinoxalin-2(1H)-ones at the C3 position. According to the kind of radical types involved, some representative examples and detailed reaction mechanism have been categorized and discussed.


Abstract

The multicomponent reactions of quinoxalin-2(1H)-ones has attracted considerable interest due to their significant biological and chemical activities. The very recent advances (from 2021 to the beginning of 2023) on the radical three-component cascade reaction of quinoxalin-2(1H)-one derivatives at the C3 position were summarized in this mini-review. According to the kind of radical types involved, some representative examples and detailed reaction mechanism have been categorized and discussed.

The red front was covered by Figure 1.

Strategies for the Controlled Hydrostannylation of Alkynes

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Strategies for the Controlled Hydrostannylation of Alkynes

This Concept article summarises recent advances in approaches to the synthesis of important vinyl stannane building blocks in a stereocontrolled and regiocontrolled manner. Particular emphasis is put on those routes in which judicious choice of ligand affords a switchable reaction, providing routes to stereodefined olefins from a single starting material.


Abstract

Organostannanes have represented one of the most widely applied reagents in modern cross-coupling chemistry and represent a key reagent in the synthesis of a range of pharmaceutically relevant scaffolds. This Concept article reviews recent advances in approaches to the synthesis of these building blocks in a stereocontrolled and regiocontrolled manner. Particular focus is paid to methods which allow for divergent synthesis of alkenylstannanes and developments in methods which present opportunities for sustainable synthesis.