Michael Addition Research Articles

Dimeric ent-kauranoids isolated from Isodon japonica var. Glaucocalyx and their anti-inflammatory activities

The phytochemical investigation of the aerial parts of Isodon japonica var. glaucocalyx afforded four undescribed (glaucocalyxin O-R, 1–4) and six known ent-kauranoids (5–10). Their structures were established using NMR and MS measurements. Compounds 1 and 2 are dimeric ent-kaurane-type diterpenoids. Moreover, the plausible biogenetic pathways for compounds 1 and 2 were proposed as Michael addition between two monomers. Eight compounds were assayed for their anti-inflammatory activity by evaluating NO production in LPS-induced RAW 267.4 cells, and compounds 7, 8 and 9 exhibited relatively remarkable anti-inflammatory activities at 10 μM.

L-proline-Brønsted acid deep eutectic mixture (DEM) triggered consecutive Claisen–Schmidt and Michael addition reactions

L-proline-Brønsted acid deep eutectic mixture (DEM) triggered consecutive Claisen–Schmidt and Michael addition reactions

Michael Addition Inducing Self-Assembly to Construct Mechanochromic BP Film.

Liquid crystalline blue phase (BP) with 3D cubic nanostructure has attracted much interest in the fields of photonic crystals due to their unique optical properties and the ability to control the flow of light. However, there remains a challenge for simultaneously achieving self-assembly and mechanochromic response of soft 3D cubic nanostructures. Herein, a scalable strategy for the preparation of soft 3D cubic nanostructured films using oligomerization of the Michael addition reaction, which can induce the assembly of double-twisted cylinders for collective replication, remodeling, recombination, and growth, with a phase transition from BPII to BPI, and to chiral nematic phase, is presented. The prepared BP patterns can be obtained by Michael addition oligomerization reaction and composite mask photopolymerization, which present distinct mechanochromic sensitive due to patterns derived from different BP state, and the pattern can be reversibly erased and recurred by mechanical force and temperature. The average domain size of BPII prepared using this strategy can achieve 96µm, which is 2.5 times larger than that obtained using the conventional cooling approach. This work provides new insights into the self-assembly and selective chemochromism of functional materials and devices.

A Silica‐Supported Yttrium Triflate Packed Bed Reactor for Continuous Flow Michael Addition of Indoles to Benzylidene Malonates

AbstractThe catalytic properties of packed bed reactors filled with Y(OTf)3 immobilised onto functionalised silica have been tested in the Michael addition of indoles to benzylidene malonates under flow conditions, providing improved productivity over the batch conditions, a greater ease of recovery of the final products and a prolonged life of the catalyst. Noteworthy, the same catalytic reactor, after being used for five days, was employed to perform a different reaction, a stereoselective Diels Alder cycloaddition in flow, with a 24 times higher productivity compared to the in‐batch reaction.

Peptide-Based Covalent Inhibitors Bearing Mild Electrophiles to Target a Conserved His Residue of the Bacterial Sliding Clamp.

Peptide-based covalent inhibitors targeted to nucleophilic protein residues have recently emerged as new modalities to target protein-protein interactions (PPIs) as they may provide some benefits over more classic competitive inhibitors. Covalent inhibitors are generally targeted to cysteine, the most intrinsically reactive amino acid residue, and to lysine, which is more abundant at the surface of proteins but much less frequently to histidine. Herein, we report the structure-guided design of targeted covalent inhibitors (TCIs) able to bind covalently and selectively to the bacterial sliding clamp (SC), by reacting with a well-conserved histidine residue located on the edge of the peptide-binding pocket. SC is an essential component of the bacterial DNA replication machinery, identified as a promising target for the development of new antibacterial compounds. Thermodynamic and kinetic analyses of ligands bearing different mild electrophilic warheads confirmed the higher efficiency of the chloroacetamide compared to Michael acceptors. Two high-resolution X-ray structures of covalent inhibitor-SC adducts were obtained, revealing the canonical orientation of the ligand and details of covalent bond formation with histidine. Proteomic studies were consistent with a selective SC engagement by the chloroacetamide-based TCI. Finally, the TCI of SC was substantially more active than the parent noncovalent inhibitor in an in vitro SC-dependent DNA synthesis assay, validating the potential of the approach to design covalent inhibitors of protein-protein interactions targeted to histidine.

Hydrazone Activation in the Aminocatalytic Cascade Reaction for the Synthesis of Tetrahydroindolizines.

In this Letter, we demonstrate the usefulness of hydrazone activation for the synthesis of biologically relevant tetrahydroindolizines. A pyrrol-derived hydrazone bearing a Michael acceptor moiety in the N-alkyl side chain has been designed with the aim of participating in the aminocatalytic cascade reaction leading to the annulation of the new six-membered heterocyclic scaffold. The application of (S)-(-)-α,α-diphenyl-2-pyrrolidinemethanol trimethylsilyl ether as the aminocatalyst allows for the iminium ion-enamine-mediated cascade to proceed in a fully stereoselective manner.

Using Redox Proteomics to Gain New Insights into Neurodegenerative Disease and Protein Modification.

Antioxidant defenses in biological systems ensure redox homeostasis, regulating baseline levels of reactive oxygen and nitrogen species (ROS and RNS). Oxidative stress (OS), characterized by a lack of antioxidant defenses or an elevation in ROS and RNS, may cause a modification of biomolecules, ROS being primarily absorbed by proteins. As a result of both genome and environment interactions, proteomics provides complete information about a cell's proteome, which changes continuously. Besides measuring protein expression levels, proteomics can also be used to identify protein modifications, localizations, the effects of added agents, and the interactions between proteins. Several oxidative processes are frequently used to modify proteins post-translationally, including carbonylation, oxidation of amino acid side chains, glycation, or lipid peroxidation, which produces highly reactive alkenals. Reactive alkenals, such as 4-hydroxy-2-nonenal, are added to cysteine (Cys), lysine (Lys), or histidine (His) residues by a Michael addition, and tyrosine (Tyr) residues are nitrated and Cys residues are nitrosylated by a Michael addition. Oxidative and nitrosative stress have been implicated in many neurodegenerative diseases as a result of oxidative damage to the brain, which may be especially vulnerable due to the large consumption of dioxygen. Therefore, the current methods applied for the detection, identification, and quantification in redox proteomics are of great interest. This review describes the main protein modifications classified as chemical reactions. Finally, we discuss the importance of redox proteomics to health and describe the analytical methods used in redox proteomics.

Insights to Design New Drugs against Human African Trypanosomiasis Targeting Rhodesain using Covalent Docking, Molecular Dynamics Simulations, and MM-PBSA Calculations.

Neglected tropical diseases (NTDs) are parasitic and bacterial diseases that affect approximately 149 countries, mainly the poor population without basic sanitation. Among these, African Human Trypanosomiasis (HAT), known as sleeping sickness, shows alarming data, with treatment based on suramin and pentamidine in the initial phase and melarsoprol and eflornithine in the chronic phase. Thus, to discover new drugs, several studies point to rhodesain as a promising drug target due to the function of protein degradation and intracellular transport of proteins between the insect and host cells and is present in all cycle phases of the parasite. Here, based on the previous studies by Nascimento et al. (2021) that show the main rhodesain inhibitors development in the last decade, molecular docking and dynamics were applied in these inhibitors datasets to reveal crucial information that can be into drug design. Thus, conventional and covalent docking was employed and highlighted the presence of Michael acceptors in the ligands in a peptidomimetics scaffold, and interaction with Gly19, Gly23, Gly65, Asp161, and Trp184 is essential to the inhibiting activity. Also, our findings using MD simulations and MM-PBSA calculations confirmed Gly19, Gly23, Gly65, Asp161, and Trp184, showing high binding energy (ΔGbind between -72.782 to -124.477 kJ.mol-1). In addition, Van der Waals interactions have a better contribution (-140,930 to -96,988 kJ.mol-1) than electrostatic forces (-43,270 to -6,854 kJ.mol-1), indicating Van der Waals interactions are the leading forces in forming and maintaining ligand-rhodesain complexes. Furthermore, the Dynamic Cross-Correlation Maps (DCCM) show more correlated movements for all complexes than the free rhodesain and strong interactions in the regions of the aforementioned residues. Principal Component Analysis (PCA) demonstrates complex stability corroborating with RMSF and RMSD. This study can provide valuable insights that can guide researchers worldwide to discover a new promising drug against HAT.

Direct Construction of C-Alkyl Glycosides from Non-Activated Olefins via Nickel-Catalyzed C(sp3)─C(sp3) Coupling Reaction.

Among C-glycosides, C-alkyl glycosides are significant building blocks for natural products and glycopeptides. However, research on efficient construction methods for C-alkyl glycosides remains relatively limited. Compared with Michael acceptors, non-activated olefins are more challenging substrates and have rarely been employed in the construction of C-glycosides. Here, a highly efficient and convenient approach for the synthesis of C-alkyl glycosides through a nickel-catalyzed C(sp3)-C(sp3) coupling reaction is presented. A distinctive feature of this method is its utilization of non-activated olefins as the anomeric radical acceptors for hydroalkylation, allowing for the direct formation of C-glycoside bonds in a single step. Furthermore, this method demonstrates excellent compatibility with a broad scope of highly reactive functional groups. Mechanistic investigations suggest that the reaction proceeds via a free radical pathway, leading predominantly to the formation of products with α-configuration. Overall, this innovative methodology offers a versatile and practical approach for the synthesis of C-alkyl glycosides, offering new avenues for the production of intricate glycosides with potential applications in drug discovery and chemical biology.

Trapping of a Polyketide Synthase Module after C-C Bond Formation Reveals Transient Acyl Carrier Domain Interactions.

Modular polyketide synthases (PKSs) are giant assembly lines that produce an impressive range of biologically active compounds. However, our understanding of the structural dynamics of these megasynthases, specifically the delivery of acyl carrier protein (ACP)-bound building blocks to the catalytic site of the ketosynthase (KS) domain, remains severely limited. Using a multipronged structural approach, we report details of the inter-domain interactions after C-C bond formation in a chain-branching module of the rhizoxin PKS. Mechanism-based crosslinking of an engineered module was achieved using a synthetic substrate surrogate that serves as a Michael acceptor. The crosslinked protein allowed us to identify an asymmetric state of the dimeric protein complex upon C-C bond formation by cryo-electron microscopy (cryo-EM). The possible existence of two ACP binding sites, one of them a potential "parking position" for substrate loading, was also indicated by AlphaFold2 predictions. NMR spectroscopy showed that a transient complex is formed in solution, independent of the linker domains, and photochemical crosslinking/mass spectrometry of the standalone domains allowed us to pinpoint the interdomain interaction sites. The structural insights into a branching PKS module arrested after C-C bond formation allows a better understanding of domain dynamics and provides valuable information for the rational design of modular assembly lines.

Trapping of a Polyketide Synthase Module after C−C Bond Formation Reveals Transient Acyl Carrier Domain Interactions

AbstractModular polyketide synthases (PKSs) are giant assembly lines that produce an impressive range of biologically active compounds. However, our understanding of the structural dynamics of these megasynthases, specifically the delivery of acyl carrier protein (ACP)‐bound building blocks to the catalytic site of the ketosynthase (KS) domain, remains severely limited. Using a multipronged structural approach, we report details of the inter‐domain interactions after C−C bond formation in a chain‐branching module of the rhizoxin PKS. Mechanism‐based crosslinking of an engineered module was achieved using a synthetic substrate surrogate that serves as a Michael acceptor. The crosslinked protein allowed us to identify an asymmetric state of the dimeric protein complex upon C−C bond formation by cryo‐electron microscopy (cryo‐EM). The possible existence of two ACP binding sites, one of them a potential “parking position” for substrate loading, was also indicated by AlphaFold2 predictions. NMR spectroscopy showed that a transient complex is formed in solution, independent of the linker domains, and photochemical crosslinking/mass spectrometry of the standalone domains allowed us to pinpoint the interdomain interaction sites. The structural insights into a branching PKS module arrested after C−C bond formation allows a better understanding of domain dynamics and provides valuable information for the rational design of modular assembly lines.

Synthesis, Reactivity and Application of Vinyl Sulfoximines and Vinyl Aminosulfoxonium Salts

AbstractThe combination of a sulfonimidoyl and aminosulfoxonium group with a double bond renders vinyl sulfoximines and vinyl aminosulfoxonium salts particularly versatile classes of compounds in organic synthesis. The discussion of vinyl sulfoximines includes in addition to the synthesis, the Michael reaction and its application in asymmetric synthesis, the synthesis, structure and application of α‐lithiovinyl sulfoximines, the nickel‐catalyzed and copper‐mediated anionic cross‐coupling reaction of α‐metallovinyl sulfoximines, the synthesis of acyclic and cyclic dienyl vinyl sulfoximines and the ring‐closing metathesis, the hydroalumination and reductive Pauson‐Khand reaction, the nickel‐catalyzed cross‐coupling reaction, the vinyl‐allyl isomerization, the cycloaddition, and the cyclization. The discussion of vinyl aminosulfoxonium salts includes in addition to the synthesis, the Michael reaction, the ethylenation of protic nucleophiles, the synthesis of allyl aminosulfoxonium salts and the nucleophilic substitution, the synthesis of allyl aminosulfoxonium ylides and the imino ester aziridination, the synthesis of vinyl aminosulfoxonium ylides, the synthesis of alkynes and dihydrofurans, the nickel‐catalyzed cross‐coupling reaction, and the intramolecular substitution of the amino group.

Engineering a pH-responsive polymeric micelle co-loaded with paclitaxel and triptolide for breast cancer therapy.

Breast cancer has overtaken lung cancer as the number one cancer worldwide. Paclitaxel (PTX) is a widely used first-line anti-cancer drug, but it is not very effective in clinical breast cancer therapy. It has been reported that triptolide (TPL) can enhance the anticancer effect of paclitaxel, and better synergistic therapeutic effects are seen with concomitant administration of PTX and TPL. In this study, we developed pH-responsive polymeric micelles for co-delivery of PTX and TPL, which disassembling in acidic tumour microenvironments to target drug release and effectively kill breast cancer cells. Firstly, we synthesized amphiphilic copolymer mPEG2000-PBAE through Michael addition reaction, confirmed by various characterizations. Polymer micelles loaded with TPL and PTX (TPL/PTX-PMs) were prepared by the thin film dispersion method. The average particle size of TPL/PTX-PMs was 97.29 ± 1.63 nm, with PDI of 0.237 ± 0.003 and Zeta potential of 9.57 ± 0.80 mV, LC% was 6.19 ± 0.21%, EE% was 88.67 ± 3.06%. Carrier material biocompatibility and loaded micelle cytotoxicity were assessed using the CCK-8 method, demonstrating excellent biocompatibility. Under the same drug concentration, TPL/PTX-PMs were the most toxic to tumour cells and had the strongest proliferation inhibitory effect. Cellular uptake assays revealed that TPL/PTX-PMs significantly increased intracellular drug concentration and enhanced antitumor activity. Overall, pH-responsive micellar co-delivery of TPL and PTX is a promising approach for breast cancer therapy.

Variable swelling behavior of and drug encapsulation in a maleimide-modified hyaluronic acid nanogel-based hydrogel

Hyaluronic acid (HA) has garnered much attention in the development of novel hydrogels. Hydrogels, as drug delivery systems, are very important in tissue engineering applications. In this study, we developed a novel HA nanogel containing a cholesterol and maleimide derivative (HAMICH) and its corresponding crosslinked hydrogel (HAMICH gel) to encapsulate drugs for their subsequent release. HAMICH gels self-assemble into nanoparticles via hydrophobic interactions. Dynamic light scattering analysis of HAMICH revealed that the particle size tended to decrease with increasing degree of cholesterol moiety substitution. The HAMICH gel was prepared through a Michael addition reaction between HAMICH and pentaerythritol tetra(mercaptoethyl)polyoxyethylene. The concentration of HAMICH needed for gelation depends on the degree of cholesterol moiety substitution; the higher the substitution degree is, the greater the concentration of HAMICH needed. The HAMICH gel exhibited less swelling and a smaller volume change than the gel with an unmodified cholesterol moiety in phosphate-buffered saline (pH 7.4). The HAMICH gel displayed enhanced peptide and protein trapping abilities without hydrogel swelling, suggesting its potential as a HA hydrogel for biomedical applications.

Tetraaniline-modified Co-MOF-PDA for anti-corrosive reinforcement of waterborne epoxy coating

The main aim of this study was to exploit the advantages of dopamine and tetraaniline (TA) to enhance the physical barrier properties and active anti-corrosion performance of composite coatings; in this study, the growth of polydopamine on the surface of Co-MOF enhanced its compatibility with waterborne epoxy, and Co-MOF-PDA-TA (MP-TA) was successfully synthesised by adding dopamine and tetraaniline via Michael addition, confirmed through characterisation methods such as Fourier-transform infrared spectroscopy, X-ray diffraction and scanning electron microscopy. MP-TA can be added as a nanofiller additive to water-based epoxy coatings, and a detailed study on the corrosion resistance of the prepared composite coatings showed that the composite coating containing 0.50wt% MP-TA/WEC exhibits good anti-corrosion performance with an impedance modulus at low frequency (0.01 Hz) of 7.253 × 109 Ω cm2 because TA not only prolongs the time required for corrosion ions to reach the interface but also forms a passivation film on the steel surface. Moreover, the reduced TA can be oxidised to EB or even LEB by releasing two electrons, which further promotes the formation of a passivation film, providing a good pathway for the application of MP-TA as a multifunctional additive.

Patterned immobilization of polyoxometalate-loaded mesoporous silica particles via amine-ene Michael additions on alkene functionalized surfaces

Polyoxometalates (POM) are anionic oxoclusters of early transition metals that are of great interest for a variety of applications, including the development of sensors and catalysts. A crucial step in the use of POM in functional materials is the production of composites that can be further processed into complex materials, e.g. by printing on different substrates. In this work, we present an immobilization approach for POMs that involves two key processes: first, the stable encapsulation of POMs in the pores of mesoporous silica nanoparticles (MSPs) and, second, the formation of microstructured arrays with these POM-loaded nanoparticles. Specifically, we have developed a strategy that leads to water-stable, POM-loaded mesoporous silica that can be covalently linked to alkene-bearing surfaces by amine-Michael addition and patterned into microarrays by scanning probe lithography (SPL). The immobilization strategy presented facilitates the printing of hybrid POM-loaded nanomaterials onto different surfaces and provides a versatile method for the fabrication of POM-based composites. Importantly, POM-loaded MSPs are useful in applications such as microfluidic systems and sensors that require frequent washing. Overall, this method is a promising way to produce surface-printed POM arrays that can be used for a wide range of applications.

Enhancement of the Surface Hydrophilicity of Poly(Vinyl Chloride) Using Hyperbranched Polylysine with Polydopamine

In recent years, the application of polyvinyl chloride (PVC) material has significantly expanded within the realm of biomedical materials. However, the hydrophobicity of PVC has been found to cause many adverse reactions in patients within the biomedical field. It is imperative to urgently discover viable approaches for enhancing the hydrophilicity of PVC in order to ensure its safety in biomedical applications. In this study, the surface of PVC films was modified with a combination of hyperbranched polylysine (HBPL) and polydopamine (pDA) through either simultaneous deposition with polydopamine (PVC-pDA/HBPL) or successive deposition of pDA and HBPL (PVC-pDA-HBPL), aiming to investigate the influence of this modification method on surface hydrophilicity enhancement. The surface coatings were characterized using gravimetry, scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), Raman spectroscopy, and water contact angle measurements. The results demonstrated that the incorporation of HBPL led to a significant enhancement in both the deposition amount and stability of pDA, particularly when the mass ratio of DA/HBPL was approximately 1:1. Simultaneously, the morphology of the films exhibited an increase in roughness, while surface hydrophilicity was significantly enhanced upon incorporating pDA and HBPL, and the water contact angle was decreased to 43.2°. Moreover, the detachment of PVC-pDA/HBPL and PVC-pDA-HBPL after exposure to 1.0 M NaOH solutions was considerably lower compared to that of PVC-pDA alone, indicating improved stability under strongly basic conditions. Notably, these enhancements were more pronounced for PVC-pDA/HBPL than for PVC-pDA-HBPL, indicating that HBPL may act as a cross-linker during pDA deposition primarily through intermolecular Schiff base reactions, hydrogen bonding, or Michael addition. This work represents a pioneering effort in integrating HBPL and dopamine for hydrophilic modification of PVC materials, thereby expanding the potential applications of PVC materials. Additionally, we provide novel insights into constructing a hydrophilic surface based on bionic principles and expanding the potential applications of HBPL and pDA.

Self-reporting and Biodegradable Thermosetting Solid Polymer Electrolyte.

To date, significant efforts have been dedicated to improve their ionic conductivity, thermal stability, and mechanical strength of solid polymer electrolytes (SPEs). However, direct monitoring of physical and chemical changes in SPEs is still lacking. Moreover, existing thermosetting SPEs are hardly degradable. Herein, by overcoming the limitation predicted by Flory theory, self-reporting and biodegradable thermosetting hyperbranched poly(β-amino ester)-based SPEs (HPAE-SPEs) are reported. HPAE is successfully synthesized through a well-controlled "A2+B4" Michael addition strategy and then crosslinked it in situ to produce HPAE-SPEs. The multiple tertiary aliphatic amines at the branching sites confer multicolour luminescence to HPAE-SPEs, enabling direct observation of its physical and chemical damage. After use, HPAE-SPEs can be rapidly hydrolysed into non-hazardous β-amino acids and polyols via self-catalysis. Optimized HPAE-SPE exhibits an ionic conductivity of 1.3×10-4 S/cm at 60 °C, a Na+ transference number ( ) of 0.67, a highly stable sodium plating-stripping behaviour and a low overpotential of ≈190 mV. This study establishes a new paradigm for developing SPEs by engineering multifunctional polymers. The self-reporting and biodegradable properties would greatly expand the scope of applications for SPEs.

Copper/Ruthenium Relay Catalysis for Stereodivergent Access to δ-Hydroxy α-Amino Acids and Small Peptides.

An atom- and step-economical and redox-neutral cascade reaction enabled by asymmetric bimetallic relay catalysis by merging a ruthenium-catalyzed asymmetric borrowing-hydrogen reaction with copper-catalyzed asymmetric Michael addition has been realized. A variety of highly functionalized 2-amino-5-hydroxyvaleric acid esters or peptides bearing 1,4-non-adjacent stereogenic centers have been prepared in high yields with excellent enantio- and diastereoselectivity. Judicious selection and rational modification of the Ru catalysts with careful tuning of the reaction conditions played a pivotal role in stereoselectivity control as well as attenuating undesired α-epimerization, thus enabling a full complement of all four stereoisomers that were otherwise inaccessible in previous work. Concise asymmetric stereodivergent synthesis of the key intermediates for biologically important chiral molecules further showcases the synthetic utility of this methodology.

Copper/Ruthenium Relay Catalysis for Stereodivergent Access to δ‐Hydroxy α‐Amino Acids and Small Peptides

AbstractAn atom‐ and step‐economical and redox‐neutral cascade reaction enabled by asymmetric bimetallic relay catalysis by merging a ruthenium‐catalyzed asymmetric borrowing‐hydrogen reaction with copper‐catalyzed asymmetric Michael addition has been realized. A variety of highly functionalized 2‐amino‐5‐hydroxyvaleric acid esters or peptides bearing 1,4‐non‐adjacent stereogenic centers have been prepared in high yields with excellent enantio‐ and diastereoselectivity. Judicious selection and rational modification of the Ru catalysts with careful tuning of the reaction conditions played a pivotal role in stereoselectivity control as well as attenuating undesired α‐epimerization, thus enabling a full complement of all four stereoisomers that were otherwise inaccessible in previous work. Concise asymmetric stereodivergent synthesis of the key intermediates for biologically important chiral molecules further showcases the synthetic utility of this methodology.