Michael Addition Research Articles

Determining a point of departure for skin sensitization potency and quantitative risk assessment of fragrance ingredients using the GARDskin dose-response assay.

Potency and quantitative risk assessment are essential for determining safe concentrations for the formulation of potential skin sensitizers into consumer products. Several new approach methodologies (NAMs) for skin sensitization hazard assessment have been developed, validated, and adopted in OECD test guidelines. However, work is ongoing to develop NAMs for predicting skin sensitization potency on a quantitative scale for use as a point of departure (POD) in next-generation risk assessment (NGRA). GARDskin Dose-Response (DR) is an adaptation of the validated GARDskin assay (OECD TG 442E), and the readout of the assay is a quantitative potency prediction similar to the No Expected Sensitization Induction Level (NESIL) value (µg/cm2). The goal of this study was to evaluate the performance of the GARDskin DR assay for potency prediction of fragrance ingredients. One hundred (100) fragrance ingredients from a reference database covering varied structural reactivity domains and potency were tested in GARDskin DR. Materials tested had varied protein-binding reactivity alerts, including Schiff base, Michael addition, SN2, and acylation. Potency categories were predicted with a total accuracy of 37% and an approximate accuracy (exact match or off by 1 category) of 81%. Combining predicted weak and very weak categories increased total accuracy to 53% and approximate accuracy to 98%. The mean prediction error for the NESIL and local lymph node assay (LLNA) EC3 was 3.15- and 3.36-fold, respectively. Based on the results of this study, GARDskin DR is a promising predictor of skin sensitization potency with an applicability domain covering a wide range of fragrance ingredient reaction mechanisms, increasing the confidence in using the assay to conduct NGRA, ultimately reducing the need for animal testing.

Efficient Assembly of Cyclohexane‐Tethered Bispirooxindoles via Carboanion Relay Enabled [1 + 2 + 2 + 1] Annulation

Comprehensive SummaryA novel carboanion relay enabled [1 + 2 + 2 + 1] cascade cyclization reaction utilizing rarely used isatin‐derived β‐silylcarbinols and aryl methyl ketones as readily available starting materials has been developed, endowing a powerful platform for the streamline synthesis of cyclohexane‐tethered bispirooxindoles in decent yields with high diastereoselectivities. This protocol was realized by merging triple Michael additions and C—C bond cleavage using Cs2CO3 as a robust promotor under transition metal‐free conditions. The practicability of this method is demonstrated by its simple operation, broad substrate scope as well as easy scale‐up.

Chiral Thiourea Catalyzed Enantioselective Cascade Synthesis of 2,3‐Dihydrobenzofurans

We established an efficient asymmetric cascade pathway for the construction of trans‐2,3‐dihydrobenzofurans. This reaction proceeds via a Michael addition followed by an oxa‐substitution, employing in‐situ generated pyridinium ylide and ortho‐hydroxy chalcone derivatives in the presence of a chiral thiourea catalyst at ambient temperature. This method accomplishes good to excellent yields and adequate stereoselectivity, with up to 84% ee and >20:1 diastereomeric ratio. A key advantage of this cascade [4+1] annulation approach is its ability to construct chiral DHBs under mild conditions with notable yields and selectivity.

Facile fabrication of PEG-PPG block copolymer via Michael addition reaction and its successful application as all-solid-state electrolyte for rechargeable lithium metal batteries

Facile fabrication of PEG-PPG block copolymer via Michael addition reaction and its successful application as all-solid-state electrolyte for rechargeable lithium metal batteries

Polydopamine nanoparticles loaded with sodium ferulate for targeted therapy of myocardial infarction in endothelial cells.

Myocardial infarction (MI) is a leading cause of heart failure and death in cardiovascular diseases. Most drug trials currently fail due to inadequate local drug activity and side effects. In this study, we developed a novel polydopamine (PDA) nano delivery system that carries sodium ferulate (SF) and is modified with RGD peptides (SF/RGD-PDA NPs) for precise targeted delivery. SF is a clinical adjuvant for cardiovascular and cerebrovascular diseases but lacks targeting and has a short half-life. PDA, known for its excellent biocompatibility and surface modifiability, serves as an effective carrier. SF was loaded onto PDA through π-π stacking, while RGD was attached via a Michael addition reaction, resulting in stable SF/RGD-PDA NPs with an average particle size of 206.13 nm. In vitro and in vivo studies indicate that this targeted formulation has good safety. Targeting studies showed a 2.19-fold increase in nanoparticle accumulation in the heart and a 5.94-fold increase in cellular uptake efficiency. Pharmacodynamic studies revealed a 1.45-fold increase in endothelial cell proliferation, a 1.46-fold increase in angiogenesis rate, and a significant reduction in MI area. These findings suggest that SF/RGD-PDA NPs can improve endothelial cell function and reduce MI area through targeted delivery.

Mechanistic Understanding of Differences in Cytotoxicity Induced by Food Additives Methyleugenol and Methylisoeugenol.

Methyleugenol (ME) has been classified as a "group 2B carcinogen" by IARC. Its positional isomer methylisoeugenol (MIE) has been considered to be of "generally recognized as safe'' status by FDA. ME was more cytotoxic than MIE in cultured mouse primary hepatocytes. The underlying mechanism of this difference is unclear. Our metabolism study revealed ME and MIE were oxidized to epoxides ME-E/MIE-E as well as to phase I metabolites ME-1'-OH (MEOH)/MIE-3'-OH (MIEOH). MEOH was further dehydrogenated to α,β-unsaturated ketone (Michael acceptor, ME-M) by P450 enzymes and was biotransformed to sulfate (ME-S) by sulfotransferases. However, MIEOH was mainly oxidized to α,β-unsaturated aldehyde (Michael acceptor, MIE-M) by P450s subsequently, while MIE-M was rapidly oxidized to cinnamic acid (MIE-C) catalyzed by aldehyde dehydrogenases. Furthermore, cinnamic acid (MIE-C) was found to be a very weak electrophilic metabolite. In vitro and in vivo studies showed that ME possesses higher metabolic activation efficiencies than MIE across three pathways, while MIE shows a higher efficiency in generating MIE-C compared to ME. Taken together, the observed difference in cytotoxicity between ME and MIE may stem from their difference in metabolic pathways due to the difference in the position of their double bonds.

Scandium(III)-Enlarged Salen Complex-Catalyzed Asymmetric Michael Addition of Indoles to Enones

Salens are a class of important ligands and have been widely applied in asymmetric catalytic organic reactions. Enlarged salen-like ligands containing flexible chains were synthesized from L-phenylalanine, ethane/propanediamines, and salicylaldehydes, and successfully utilized in the scandium-catalyzed enantioselective Michael addition of indoles and enones (2-cinnamoylpyridine 1-oxides). The catalytic system demonstrates excellent reactivity and stereoselective control over electron-rich indole substrates with up to 99% yield and 99% enantiomeric excess. The enlarged Salen ligands with flexible and rigid combined linkers fit their coordination with large rare earth elements. Their coordination abilities were tuned by the electronic effect of substituents on their salicylaldehyde moiety, facilitating the construction of excellent chiral environments in the scandium(III)-catalyzed asymmetric Michael addition of indoles to 2-cinnamoylpyridine 1-oxides.

CBr4-Catalyzed Substituent-Dependent Michael Addition/Paal-Knorr Cyclization of Indole with α,β-Unsaturated Ketones.

We report CBr4 catalyzed Michael addition of indole to α,β-unsaturated ketones for the synthesis of β-indolylketones through halogen bonding catalysis. This reaction is compatible with a diverse range of chalcones, including drug-derived chalcones containing sensitive functional groups such as amides, yielding the addition products in good yields. Additionally, 3-indolyl furanoid motifs have been synthesized through the Michael addition followed by Paal-Knorr cyclization by utilizing various unsymmetrical 1,4-enediones in a one-pot process with good yields.

Data Checking of Asymmetric Catalysis Literature Using a Graph Neural Network Approach.

The range of chemical databases available has dramatically increased in recent years, but the reliability and quality of their data are often negatively affected by human-error fidelity. The size of chemical databases can make manual data curation/checking of such sets time consuming; thus, automated tools to help this process are highly desirable. Herein, we propose the use of Graph Neural Networks (GNNs) to identifying potential stereochemical misassignments in the primary asymmetric catalysis literature. Our method relies on the use of an ensemble of GNN models to predict the expected stereoselectivity of exemplars for a particular asymmetric reaction. When the majority of these models do not correlate to the reported outcome, the point is labeled as a possible stereochemical misassignment. Such identified cases are few in number and more easily investigated for their cause. We demonstrate the use of this approach to spot potential literature stereochemical misassignments in the ketone products resulting from catalytic asymmetric 1,4-addition of organoboron nucleophiles to Michael acceptors in two different databases, each one using a different family of chiral ligands (bisphosphine and diene ligands). Our results demonstrate that this methodology is useful for curation of medium-sized databases, speeding this process significantly compared to complete manual curation/checking. In the datasets investigated, human expert checking was reduced to 2.2% and 3.5% of the total data exemplars.

Synergistic Cu(II)/Amine-Catalyzed Cyclization of Enynone: Assembly of Tetralone and Tetrahydronaphthylimine.

An unprecedented synergistic copper- and amine-catalyzed cyclization of enynone is reported. This reaction features an efficient and straightforward construction of multisubstituted tetralone through an amine-assisted regioselective oxygen atom transfer process and stereoselective intramolecular Michael addition cyclization. Under dehydrative reaction conditions, the synthesis of tetrahydronaphthylimine derivatives with ketone group tolerance is achieved, which could be challenging via traditional methods. The utility of this reaction is demonstrated by further transformations of obtained molecules toward a variety of valuable multisubstituted naphthyl skeletons.

Total Synthesis of Antiausterity Agent Callistrilone O Reveals Promising Antitumor Activity in a Melanoma Homograft Mouse Model.

The antiausterity strategy in anticancer drug discovery has attracted much attention as a way to exterminate cancer cells under nutrient deprived conditions which are commonly found in solid tumors. These tumors under low nutrient stress are known to be malignant and often resist conventional drug therapy. As a potential drug candidate, we focused on the meroterpenoid natural product callistrilone O which has demonstrated extremely potent antiausterity properties toward PANC-1 pancreatic carcinoma in vitro. Here, we report for the first time the total synthesis of callistrilone O in seven steps from phloroglucinol. A Friedel-Crafts-type Michael addition and an oxidative [3 + 2] cycloaddition with Fetizon's reagent were used to construct the molecular skeleton. The preferential cytotoxicity of callistrilone O was also evaluated with multiple starvation-resistant cancer cell lines under low nutrient conditions. Furthermore, callistrilone O was found to strongly suppress B16 melanoma tumor growth without critical toxicity in vivo. Overall, this study presents a novel anticancer agent candidate from natural products with a concise synthetic route which can be readily applied to the synthesis of derivatives.

Michael and Schiff-Base Reactions-Assisted Fluorescence Sensor Based on the MOF Nanosheet Microspheres for the Effective Discrimination and Detection of Hydroquinone and Catechol.

A novel sensing platform was constructed for the recognition and identification of dihydroxybenzene isomers based on the MOF-0.02TEA fluorescence sensor with the morphology of nanosheet microspheres through coordination modulation. Based on the sensing principle that the amino group on the MOF-0.02TEA can make the Michael reaction with o-benzoquinone and p-benzoquinone, which were individually the oxidation intermediate of catechol and hydroquinone, the fluorescence intensity of MOF-0.02TEA could be quenched through the inner filter effect (IFE) without the interference from resorcinol. Besides, catechol and hydroquinone could be further distinguished with the assistance of the Schiff-base reaction by introducing o-phenylenediamine (OPD) to the detection system. The MOF-0.02TEA sensor exhibited good selectivity, and the detection limits for catechol and hydroquinone were 90.5 nmol/L and 0.52 μmol/L (S/N = 3), respectively. Moreover, the sensor could be used for the determination of dihydroxybenzene isomers in tap water and lake water.

Development and Characterization of Hyaluronic Acid Graft-Modified Polydopamine Nanoparticles for Antibacterial Studies.

The problem of antibiotic abuse and drug resistance is becoming increasingly serious. In recent years, polydopamine (PDA) nanoparticles have been recognized as a potential antimicrobial material for photothermal therapy (PTT) due to their excellent photothermal conversion efficiency and unique antimicrobial ability. PDA is capable of rapidly converting light energy into heat energy under near-infrared (NIR) light irradiation to kill bacteria efficiently. In order to solve the problem of PDA's tendency to aggregate and precipitate, this study improved its stability by grafting hyaluronic acid (HA) onto the surface of PDA. Using dopamine and hyaluronic acid as raw materials, hyaluronic acid (HA) was grafted onto polydopamine (PDA) nanoparticles via self-polymerization and Michael addition reactions under alkaline conditions to obtain PDA-HA-modified nanoparticles. We confirmed the successful grafting of hyaluronic acid via scanning electron microscopy (SEM), Fourier infrared spectroscopy (FTIR), nuclear magnetic hydrogen spectroscopy (¹H NMR), ultraviolet-visible spectroscopy (UV-vis), Raman spectroscopy (Raman), and dynamic light scattering (DLS) methods. Scanning electron microscopy (SEM) was used to observe the surface morphology and nanostructure of the grafted materials, providing information on the morphology and size distribution of the materials. Near-infrared performance experiments showed that the temperature of the PDA-HA solution increased rapidly under near-infrared light irradiation, demonstrating an excellent photothermal conversion performance. Antimicrobial properties were assessed via the colony counting method, and typical Gram-positive bacteria S. aureus and Gram-negative bacteria E. coli were selected as model strains. The experimental groups were tested under dark conditions and near-infrared (NIR) light irradiation. PDA/HA showed significant photothermal properties under NIR light irradiation, resulting in a rapid increase in the surrounding temperature to a level sufficient to kill bacteria. Under NIR light irradiation, PDA/HA exhibited 100% antimicrobial efficacy against both S. aureus and E. coli, while antimicrobial efficacy was limited under dark conditions. This indicates that the antibacterial activity of PDA/HA is highly dependent on NIR light activation.

Antifouling Hydrogel Based on Zwitterionic Poly(carboxybetaine diacrylate) Cross-Linkers.

Antifouling zwitterionic materials have extensive applications in the biomedical field. This study designed and successfully synthesized a novel poly(carboxybetaine) diacrylate (PCBDA) via cationic ring-opening polymerization of 2-methyl-2-oxazine, chain modification by the Michael reaction, and chain end transformation to acrylate. The cross-linker was obtained with a tunable molecular weight. Through photopolymerization, poly(carboxybetaine) (PCB) hydrogels with varying solid contents were obtained, and the effects of the solid content on the hydration properties, mechanical properties, and microstructure of the PCB hydrogels were investigated. Furthermore, the non-fouling properties of the PCB hydrogels were compared to those of commercial polyethylene glycol (PEG) hydrogels. Protein adsorption on PCB hydrogels was reduced by more than 60% compared to low-fouling PEG hydrogels. PCB hydrogels exhibit antibacterial adhesion properties similar to those of PEG hydrogels. In cell adhesion experiments, no cell adhesion was observed on the PCB hydrogels, indicating their superior anti-cell adhesion function. This advancement offers a more promising alternative to polyethylene glycol diacrylate (PEGDA) cross-linkers in the design of hydrogels.

Development of a pressure-sensitive adhesive utilizing a highly sensitive cross-linking system with photoanionic curing

AbstractPressure-sensitive adhesives (PSAs) can rapidly adhere to any substrate under low pressure. In general, acrylic PSAs are designed to undergo a thermal curing reaction. In recent years, UV-curable PSAs have attracted increasing attention because of their rapid curing and solvent-free production. However, radical curing cannot be performed in room air, and the development of an anionic curable type is desirable. Therefore, we synthesized a novel copolymer with anionic curability using an acetoacetate–Michael addition reaction cross-linking system and applied it to PSA tape. The developed PSA tape showed good performance 2 h after coating and UV irradiation. It comprises a specific polymer that reacts with high sensitivity even when a 1 wt% photobase generator is added. In addition, it has an ideal peel strength of 1.3 N cm–1 and it demonstrated high heat resistance up to 220 °C in a shear adhesion failure temperature test. The proposed polymer is expected to provide new benefits for PSA tape, such as temporarily fixing semiconductor devices.

The Adducts Lipid Peroxidation Products with 2′-DeoxyNucleosides: A Theoretical Approach of Ionisation Potential

The human body contains ~1014 cells—each of which is separated by a lipid bilayer, along with its organeller. Unsaturated fatty acids are located on the external layer and, as a result, are particularly exposed to harmful factors, including xenobiotics and ionising radiation. During this activity, lipid peroxidation products are generated, e.g., 4-hydroxy-2-nonenal (HNA), 4-oxo-2(E)-nonenal (ONE), and malondialdehyde (MDA). The mentioned aldehydes can react with cytosolic 2′-deoxynucleosides via Michael addition. In this paper, the following adducts have been taken into theoretical consideration: ε-dCyt, H-ε-dAde, ε-dCyt, H-ε-dAde, H-ε-dGua, R/S-OH-PdGua, N2,3-ε-dGua, M1-dGua, N1-ε-dGua, and HNE-dGua. The presence of the above molecules can alter a cell’s antioxidant pool. With this in mind, the adiabatic ionisation potential (AIP) and vertical ionisation potential (VIP), as well as the spin and charge distributions, are discussed. For this purpose, DFT studies were performed at the M06-2x/6-31++G** level of theory in the aqueous phase (both non-equilibrated (NE) and equilibrated (EQ) solvent–solute interaction modes), together with a Hirshfeld charge and spin distribution analysis. The obtained results indicate that the AIPs of all the investigated molecules fell within a range of 5.72 and 5.98 eV, which is consistent with the reference value of 7,8-dihydro-8-oxo-2′-deoxyguanosine (OXOdGua), 5.78 eV. N2,3-ε-dGua and M1-dGua were the only exceptions, whose VIP and AIP were noted as higher. The electronic properties analysis of 2′-deoxynucleoside adducts with lipid peroxidation products reveals their potential influence on the cells’ antioxidant pool, whereby they can affect the communication process between proteins, lipids, and nucleotides.

Rational engineering of a recognition group to construct a two-photon reaction-based fluorescent probe for rapid and selective sensing of cysteine.

It is highly required to rationally design fluorescent probes via a molecular engineering strategy with desired analytical performance for applications in sensing and imaging. Reaction-based fluorescent probes for highly selective sensing of cysteine (Cys) are mainly based on the participation of Cys in reactions such as, addition-cyclization with acrylates, cyclization with aldehydes, coordination displacement, Michael addition reactions, and cleavage reactions. Cys-triggered reactions with the O atoms of ether bonds has also been used to construct reaction-based fluorescent probes based on the substitution of the ether with the nucleophilic thiolate of Cys. However, many of the developed probes still suffer from long response times, interference from homocysteine (Hcy) and glutathione (GSH), high background fluorescence, and a lack of two-photon absorption (TPA) properties. Herein, we successfully design a Cys-sensitive two-photon fluorescent probe (F-BTD) using a donor-acceptor-donor (D-A-D) type π-extended benzothiadiazole framework as the fluorophore, with nitrobenzofuran (NBD) as the recognition unit. The proposed F-BTD probe displays some advantages over other probes including a rapid response time, high selectivity, low background fluorescence, and two-photon imaging capability. The F-BTD probe is applied to the two-photon fluorescence imaging of endogenous and exogenous Cys in HeLa cells with satisfactory results. For comparison, commonly used biothiol recognition groups including 2,4-dinitrobezensulfonyl and 2,4-dinitrophenyl are also used to construct S-BTD and N-BTD probes, respectively. The response mechanism of F-BTD to Cys is studied in detail through kinetic studies and transition-state analysis. This study may provide an example of how to design fluorescent probes with desired analytical performance by considering the recognition group as an important index of the design.

Mussel-inspired novel coating with cariogenic biofilm inhibition and in situ remineralization properties for caries treatment

A facile and dual-functional PDA@PC hybrid coating, prepared via the Michael addition and Schiff base reactions, exhibits remarkable performance in terms of antibiofilm activity and remineralization capabilities for dental caries management.

Stereodivergent assembly of δ-valerolactones with an azaarene-containing quaternary stereocenter enabled by Cu/Ru relay catalysis.

Developing methodologies for the expedient construction of biologically important δ-valerolactones bearing a privileged azaarene moiety and a sterically congested all-carbon quaternary stereocenter is important and full of challenges. We present herein a novel multicatalytic strategy for the stereodivergent synthesis of highly functionalized chiral δ-valerolactones bearing 1,4-nonadjacent quaternary/tertiary stereocenters by orthogonally merging borrowing hydrogen and Michael addition between α-azaaryl acetates and allylic alcohols followed by lactonization in a one-pot manner. Enabled by Cu/Ru relay catalysis, this cascade protocol offers the advantages of atom/step economy, redox-neutrality, mild reaction conditions, and broad substrate tolerance. Scale-up experiments and synthetic transformations further demonstrated the potential for synthetic applications. Mechanistic experiments support the envisioned bimetallic relay catalytic mechanism, and the key role of Cs2CO3 in promoting lactonization was also revealed.

Hydrogel formed in situ through Schiff base reaction between gallic acid-grafted soybean protein isolate and oxidized dextran: Interactions, physicochemical properties, and digestive characteristics.

Herein, we developed multifunctional hydrogels formed between soybean protein (SPI)-gallic acid conjugate and oxidized dextran (ODex) via a Schiff base reaction. The effects of ODex on the morphology, structure, and functional properties of the hydrogels were elucidated. The results showed that the crosslinking modes in the hydrogels include hydrogen bonding, Schiff bases, Michael addition, and π-π stacking. The synergistic crosslinking of gallic acid and ODex conferred the hydrogels with an appropriate equilibrium swelling ratio, dense morphology, excellent mechanical properties, high thermal stability, and water-holding properties. When the addition of ODex was 0.8 (w/w), the hydrogel had a higher crosslinking degree (76.31%), smaller average pore diameter (0.322μm), and higher zero shear viscosity (748.5mPa. s). In addition, in vitro digestion tests showed that hydrogel degradation was delayed upon increasing the degree of crosslinking, which improved the hydrogel's capacity to adsorb bile salts and control the release of curcumin. This study provides a theoretical basis for the design of high-quality protein hydrogels and other multifunctional materials suitable for various applications.