Amidation Reaction Research Articles

Clearance of Intracellular Pathogens with Hyaluronic Acid Nanomicelles Responsive to H2S and pH

Hyaluronic acid (HA) is an acidic mucopolysaccharide of animal origin composed of repeating disaccharide units of N-acetylglucosamine and glucuronic acid. Due to its excellent biocompatibility, biodegradability, and selective affinity for CD44 receptors on cell surfaces, HA is widely employed as a drug carrier. In our study, we aimed to target subcellular bacteria by grafting cystamine onto HA scaffolds through an amide reaction, producing a linker responsive to H2S and pH changes. Subsequently, hydrophobic dodecylamine was attached to HA, forming amphiphilic molecules. These amphiphilic entities can self-assemble into nanomicelles in an aqueous solution, thereby encapsulating the antibacterial agent triclosan (TCS). The resulting HA-based system (HASS-TCS) can be internalized via CD44-mediated endocytosis, releasing substantial amounts of streptomycin and TCS in H2S-rich and acidic environments. Additionally, HASS-TCS has demonstrated effectiveness in eradicating biofilms and addressing intracellular infections caused by Salmonella. This study underscores a novel pH-sensitive hyaluronic acid-based drug delivery system with significant potential for the effective treatment of intracellular infections.

Red-light Emitting Orthogonally Trireactive Gold Nanoclusters for the Synthesis of Multifunctionalized Nanomaterials.

For the development of highly multifunctionalized nanomaterials, the introduction of functional molecules on gold nanoclusters containing thiols preinstalled with connecting groupsconstitutes a promising approach. However, the uniform introduction of multiple connecting groups while avoiding side reactions is a challenging task. Herein, the synthesis of gold nanoclusters (ca. 1nm) coated with thiol peptides bearing azido, amino, and aminooxy groups is reported. These nanoclusters emit red-light before and after the functionalization, enabling application to cell imaging. A detailed structure analysis using transmission electron microscope and X-ray absorption spectroscopy reveals the formation of Aun(SR)m nanoclusters as promising motifs for red-light emission. The sequential modification of the trireactive nanoclusters with RGD (Arg-Gly-Asp) peptides, metal chelators, and anticancer drugs via [3+2] cycloaddition, oximation, and amidation reactions at each functional group furnish red-light-emissive nanomaterials exhibiting remarkable toxicity against A549 human lung cancer cells. Integration of the multiligation chemistry and gold nanocluster engineering pave the way toward the development of advanced multifunctional nanomaterials for biological applications.

Recent Advances in Direct Amidation via Organocatalysis

The formation of amide bonds is essential for a wide range of applications in biological and organic systems, including proteins, pesticides, polymers, and pharmaceuticals. Moreover, it plays a critical role in the synthesis of numerous bioactive compounds with anticancer, antibacterial, and antifungal properties. Due to the limitations of conventional coupling reagents for amide synthesis, there is a growing demand for environmentally sustainable methodologies, particularly the direct formation of amides from carboxylic acids and amines. Over recent years, we have developed several catalytic reactions based on organocatalysis, advancing sustainable synthetic methods in both organic and medicinal chemistry. This review comprehensively discusses catalytic amidation reactions published up to January 2024, focusing on both organocatalysis and boron‐based catalysis for the direct condensation of carboxylic acids and amines. Additionally, it highlights our recent contributions to sustainable amidation protocols, which are progressively replacing traditional catalytic approaches in modern synthetic chemistry.

Direct Solvent‐Free Amide Bond Formation Catalyzed by Anatase‐TiO2 Surface: Insight from Modeling

Amide bond formation processes are of paramount relevance for a broad spectrum of applications. Conventional amidation protocols typically rely on drastic reaction conditions and the use/disposal of large amounts of chemicals. These limitations may be bypassed by heterogeneously catalyzed amidation at dry conditions. However, progress is hindered because the mechanisms of these processes are largely unexplored. By using ab initio metadynamics, a concerted one‐step mechanism is proposed for the solvent‐free condensation of methylamine and formic acid on TiO2(101)‐anatase, leading to methylformamide with concomitant release of molecular water. The activation barrier—14.3 kcal mol−1—is in line with the mild conditions experimentally adopted in amide bond syntheses on TiO2 nanoparticles. The mechanism disclosed herein reveals the key role of Ti4+ sites located on stoichiometric (101) anatase surfaces in promoting amide‐bond formation at the TiO2/vapor interface. The acid strength of the adsorbed HCOOH molecules may be tuned by the HCOOH surface coverage, thus influencing the outcome of the amidation reaction. These molecular‐level insights may foster further endeavors to improve/upscale TiO2‐catalyzed amide syntheses at dry conditions, while raising the interest toward amidation processes at the surface/vapor interface promoted by economically and environmentally sustainable metal oxide nanomaterials.

Copper‐Mediated C−H Functionalization of Amines, Imines, and Amides: Recent Developments and Synthetic Applications

AbstractCopper‐mediated C−H functionalization has emerged as a powerful strategy for the selective modification of nitrogen‐containing molecules, offering significant advancements in organic synthesis. This review provides a comprehensive overview of recent developments in copper‐catalyzed C−H functionalization reactions of amines, imines, and amides, from 2013 to present, emphasizing their synthetic applications and mechanistic insights. It also discusses the impact of these methodologies on the construction of complex molecular architectures, including pharmaceuticals and natural products. This review aims to provide valuable guidance for researchers seeking to leverage copper‐mediated strategies in their synthetic endeavors by creating current knowledge and identifying future directions. We have highlighted the new bonds formed through C−H functionalizations for the convenience of readers.

Enhancing Methylene Blue Adsorption Performance of Ti3C2Tx@Sodium Alginate Foam Through Pore Structure Regulation.

Pore structural regulation is expected to be a facile way to enhance the adsorption performance of MXene. In this work, spherical foam composites consisting of Ti3C2Tx and sodium alginate (SA) were synthesized via a vacuum freeze-drying technique. By varying the solution volume of Ti3C2Tx, four distinct Ti3C2Tx@SA spherical foams with honeycomb-like and lamellar structures with a pore diameter in the range of 100-300 μm were fabricated. Their methylene blue (MB) adsorption performances were then systematically compared. The results revealed that the honeycomb-like porous-structured spherical foams have a significantly higher adsorption capacity than their lamellar counterparts. Notably, the Ti3C2Tx@SA honeycomb-like porous foam exhibited a remarkable maximum adsorption capacity (qm) of 969 mg/g, positioning it at the forefront of MB adsorbent materials. Respective analysis of the adsorption kinetics, thermodynamics, and isotherm model indicated that this MB adsorption of Ti3C2Tx@SA honeycomb-like porous foam is characterized to be a physical, endothermic, and monolayer adsorption. The Ti3C2Tx@SA honeycomb-like porous foam also demonstrated excellent resistance to ion interference and good reusability, further attesting to its substantial potential for practical applications. X-ray photoelectron spectroscopy (XPS) analysis was employed to elucidate the adsorption mechanism, which was found to involve the synergistic effect of electrostatic adsorption and amidation reaction. This work not only offers new avenues for the development of high-performance adsorption materials but also provides crucial insights into the structural design and performance optimization of porous materials.

Hypoxia-responsive liposome enhances intracellular delivery of photosensitizer for effective photodynamic therapy

Liposomes, especially polyethylene glycol (PEG)-modified long-circulating liposomes, have been approved for market use, due to good biocompatibility, passive tumor targeting, and sustained drug release. PEG-modified long-circulating liposomes address issues such as poor stability and rapid clearance by the reticuloendothelial system. However, they still face challenges like hindering drug uptake by tumor cells and preventing tumor penetration. Inspired by the hypoxic tumor microenvironment, we constructed a hypoxia-responsive liposome (PAO-L) to enhance the intracellular uptake and photodynamic therapy (PDT) effect of chlorin e6 (Ce6). The intelligent hypoxia-cleavable PEG-AZO-OA (PAO) was prepared by coupling PEG and octadecylamine (OA) to hypoxia-sensitive azobenzene-4,4′-dicarboxylic acid (AZO) through amide reaction. The synthesized PAO was further incorporated into Ce6-loaded liposomes to enhance the circulation stability, while promote the tumor penetration and internalization by the responsive shedding of PEG from liposome surface upon reaching the hypoxic tumor tissue. PAO-L mediated PDT significantly inhibited the growth of B16F10 and 4T1 tumors, as well as lung metastasis of 4T1 breast cancer. The excellent therapeutic effect and good tolerability make PAO-L a promising candidate for enhanced PDT.

Copper-Catalyzed γ-C(sp3)-H Lactamization and Iminolactonization.

Despite extensive efforts to develop γ-lactamization reactions for pyrrolidinone synthesis using either cyclometallation, C-H insertion, or radical C-H abstraction strategies, γ-lactamization reactions of aliphatic amides using practical catalysts and common protecting groups remain extremely rare. Herein we report copper-catalyzed γ-C(sp3)-H lactamization and iminolactonization of tosyl-protected aliphatic amides using inexpensive Selectfluor as the sole oxidant. A switchable selectivity of γ-lactams or γ-iminolactones can be obtained by using two different sets of reaction conditions. Notably, structurally diverse spiro-, fused-, and bridged-lactams and iminolactones, as well as isoindolinones are accessible by this method. Further derivatization of the γ-lactam products enables the synthesis of a range of biologically important motifs, including γ-amino acids, δ-amino alcohols, and pyrrolidines.

Copper‐Catalyzed γ‐C(sp3)−H Lactamization and Iminolactonization

AbstractDespite extensive efforts to develop γ‐lactamization reactions for pyrrolidinone synthesis using either cyclometallation, C−H insertion, or radical C−H abstraction strategies, γ‐lactamization reactions of aliphatic amides using practical catalysts and common protecting groups remain extremely rare. Herein we report copper‐catalyzed γ‐C(sp3)−H lactamization and iminolactonization of tosyl‐protected aliphatic amides using inexpensive Selectfluor as the sole oxidant. A switchable selectivity of γ‐lactams or γ‐iminolactones can be obtained by using two different sets of reaction conditions. Notably, structurally diverse spiro‐, fused‐, and bridged‐lactams and iminolactones, as well as isoindolinones are accessible by this method. Further derivatization of the γ‐lactam products enables the synthesis of a range of biologically important motifs, including γ‐amino acids, δ‐amino alcohols, and pyrrolidines.

Synthesis of 2‐(Pentafluoro‐λ6‐sulfanyl)acetamides and Impact of the Fluorinated Group on the Lipophilicity

AbstractThe synthesis of 2‐(pentafluoro‐λ6‐sulfanyl)acetamides is described via an amidation reaction between 2‐(pentafluoro‐λ6‐sulfanyl)acetic acid, the SF5‐containing building block, and various amines. A total of 27 examples of SF5‐containing amides were synthesized, with isolated yields going from 43 % to quantitative. We showed that a 2‐(pentafluoro‐λ6‐sulfanyl)acetamide could be converted to a N‐(2‐SF5‐ethyl)amine and a SF5‐containing oxadiazoles. Finally, the effect of the SF5 substituent on the lipophilicity of the amide of a model compound was evaluated.

Tunable Activated Esters Enable Lysine-Selective Protein Labeling and Profiling.

Lysine residues on protein surfaces are abundant and often found in enzyme active sites, making them critical targets for studying undruggable proteins. However, the varied microenvironment surrounding lysine residues results in a wide range of pKa values, complicating site-specific covalent binding. In this study, we address the challenges posed by the diverse reactivity of amino side chains by modulating the amide reaction activity of heteroaromatic activated esters. By fine-tuning the type, position, and number of heteroatoms, we successfully rationalized the regulation of their amide reaction activity, leading to the design of probes for selective lysine labeling within the proteome for profiling purposes. Systematic optimization of these esters' reactivity and selectivity has yielded a series of effective probes suitable for both in vitro and cellular applications. These findings significantly enhance our understanding of protein functions and mechanisms, facilitated by the precise identification and analysis of protein labeling and profiling.

A pH-responsive phase-transition bi-affinity nanopolymer-assisted exosome metabolomics for early screening of osteoarthritis

Exosomes, emerging as ideal non-invasive biomarkers for disease diagnosis and monitoring, have seldom been explored based on metabolite levels. In this study, we designed and synthesized a pH-responsive phase-transition bifunctional affinity nanopolymer (pH-BiAN) that could efficiently and homogeneously separate exosomes from urine. Specifically, poly-4-vinylpyridine (P4VP) was chosen as the pH-responsive polymer and simultaneously modified with two exosome-affinity components CD63 aptamer and distearoyl phosphoethanolamine (DSPE) through a one-step amide reaction at room temperature. By utilizing two distinct but synergistic affinity mechanisms—the immune affinity between CD63 aptamer and exosomal CD63 proteins, and hydrophobic interactions between the DSPE and the exosomal lipids—pH-BiAN can enable efficient and specific exosome separation. Moreover, during the urine exosome capture procedure, the pH-BiAN outperforms conventional solid exosome separation materials by remaining soluble in the urine sample, significantly enhancing mass transfer and contact efficiency. After exosome capture, pH-BiAN can quickly aggregate and convert to solid upon pH adjustment, allowing for easy centrifugation separation. Afterwards, multiple machine learning models were established by combining liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) untargeted metabolomics for isolated exosomes, and the clinical accuracy of the training and test sets was more than 0.919, which could well distinguish early osteoarthritis patients from healthy people.

Cascade Reactions of Alkynyl Ketones and Amides to Generate Unsaturated Oxacycles and Aromatic Carbocycles.

We describe novel amine-mediated transformation of alkynyl ketones and amides to generate 2-methylene-2H-pyrans, substituted 3-hydroxy-9H-fluoren-9-ones, and amine-incorporated arenes. These cascade processes are initiated by conjugate addition of secondary amine followed by hydrolysis of the enamine/vinylogous amide intermediates. The product distribution is highly sensitive to the steric and electronic effects of the substituents on both the alkyne moieties, the tether structure connecting them, and the nature of the amine. Alkynyl amide participates in the Alder-ene reaction favorably to generate more reactive allene amide that reacts with amine to generate amine-incorporated arene products. These metal-free cascade reactions are a useful synthetic method that can be exploited for the construction of various hetero- and carbocyclic systems.

Serotonin-functionalized starch-based hemostatic sponges enhance platelet activation in the management of non-compressible hemorrhage

Massive hemorrhage poses a serious threat to human health and even life. Access to rapid and potent hemostatic materials is crucial for lowering mortality rates. Starch-based materials exhibit good biocompatibility and are extensively utilized in hemostatic. However, existing starch-based hemostatic products suffer from limited hemostatic efficacy. Serotonin, an indoleamine naturally occurring in the human body, is recognized for its potent platelet-activating properties. Therefore, this study focused on enhancing the procoagulant activity of starch by incorporating serotonin into the starch backbone via esterification and amidation reactions, yielding a novel serotonin-loaded starch-based hemostatic sponge (SLS sponge). The SLS sponges featured exceptional porosity (≥80 %) and water absorption capacity (≥2000 %), which rapidly initiated the coagulation cascade reaction, promoted the adhesion and aggregation of red blood cells and platelets, and intensified platelet activation. This multifaceted approach synergistically enhanced hemostasis via both active and passive coagulation mechanisms. Notably, the SLS sponges adhered firmly to the wound surfaces without pressure. Compared with gelatin sponges, the SLS sponges significantly reduced blood loss by approximately 40.5 % and shortened the time to achieve hemostasis by approximately 28.9 %. These findings indicate that the newly developed SLS sponges are a promising active hemostatic material, particularly effective in managing non-compressible hemorrhages.

Copper‐Catalyzed Carboamination of Unactivated Alkenes to Synthesize β‐Lactams with Trichloroacetonitrile

ABSTRACTβ‐Lactams, as nitrogen‐containing heterocycles with distinctive biological activities, have made significant contributions to the treatment of infectious diseases. This study which used inexpensive copper salts as catalysts, trichloroacetonitrile as a radical precursor, and potassium carbonate as base offers a concise route for the synthesis of β‐lactam compounds substituted with potentially pharmacologically active dichloroacetyl moieties. Preliminary mechanistic studies indicate that unactivated alkenes undergo sequential intermolecular radical addition and intramolecular amidation reactions. The copper salts undergo catalytic cycles involving Cu(I)/Cu(II)/Cu(III) species.

VEGF-loaded ROS-responsive nanodots improve the structure and function of sciatic nerve lesions in type II diabetic peripheral neuropathy

Diabetic peripheral neuropathy (DPN) is a prevalent complication of diabetes mellitus (DM), significantly contributing to the risk of amputation and mortality. Reactive oxygen species (ROS) can induce both neurological and structural harm through direct impact and pyroptosis, underscoring the critical role of ROS regulation in mitigating DPN. In this research endeavor, we propose harnessing the inherent antioxidant properties of sulfhydryl groups by grafting them onto gold nanodots through an amidation reaction, resulting in the creation of ROS-responsive AuNDs. Additionally, we aim to synthesize AuNDs-VEGF, wherein VEGF is attached to AuNDs via electrostatic interactions, as a therapeutic strategy for addressing DPN in rat models. The results of in vivo experiments showed that AuNDs and AuNDs-VEGF nanoparticles could increase the nerve conduction velocity, shorten the latency of nerve conduction in the sciatic nerve, promote the regeneration of nerve trophectodermal vessels, improve the structure and function of the sciatic nerve, reduce the apoptosis of neural cells, and alleviate the atrophy of the gastrocnemius muscle. Thus, VEGF-loaded ROS-responsive nanodots present a promising avenue for ameliorating diabetic peripheral neuropathy. This innovative approach not only extends the application possibilities of nanodots but also introduces a novel avenue for the treatment of diabetic neuropathy.

Chemoselective Pd-Based Dyotropic Rearrangement: Fluorocyclization and Regioselective Wacker Reaction of Homoallylic Amides.

Fluorocyclization of alkenes tethered with a pronucleophile is an efficient transformation that converts easily accessible starting materials to fluorinated heterocycles in a single step. We report herein an unprecedented Pd(II)-catalyzed oxidative domino process that transforms homoallylic amides to 5,6-dihydro-4H-1,3-oxazines through a domino oxypalladation/PdII-oxidation/dyotropic rearrangement/reductive elimination sequence. Three chemical bonds are created under these operationally simple conditions. Taking advantage of the facile hydrolysis of the α-fluoro tertiary alkyl ether under acidic conditions, a one-pot conversion of homoallylic amides to homologated ketones is subsequently developed, which represents a rare example of regioselective Wacker oxidation reaction of 1,1-disubstituted alkenes.

A novel type of quantum-delivery system (salicylic acid conjugation based on ZnO quantum dots) alleviates the bacterial fruit blotch disease of melon plants by activating defense response

The use of nano-pesticide delivery systems to suppress crop disease has great potential in sustainable agriculture. Herein, a pH-responsive salicylic acid (SA) conjugation based on aminopropyl-functionalized ZnO quantum dots (SA-ZnO QDs) with a loading capacity of 13.4 wt% was prepared by an amidation reaction. Results indicated that SA-ZnO QDs could release SA rapidly in an acidic condition, which corresponded to the pH of the water-soaked lesions where the bacterial fruit blotch disease often spread. The antibacterial activity of the synthesized SA-ZnO QDs was about 1.6 times and 1.3 times higher than that of SA and aminopropyl-functionalized ZnO QDs, respectively. A pot experiment showed that foliar application of SA-ZnO QDs could reduce the incidence of bacterial fruit blotch disease (54.46%) by increasing the antioxidant defense systems (44.33–79.59%) and nutrient absorption (23.19–26.95%). More importantly, we observed that, after the application of SA-ZnO QDs, the systemic acquired resistance and flavone biosynthesis were activated in infected melon seedlings, which was revealed by metabolomics. This work demonstrates the important role of the quantum-delivery system in improving crop disease suppression for sustainable agriculture.

Metal‐Free Direct Synthesis of N‐Sulfonyl Amidines from Thioamides and Electron Deficient N‐Sulfonylamides

AbstractA metal‐free, efficient synthesis of N‐sulfonyl amidines has been demonstrated from easily accessible thioamides and electron‐deficient sulfonyl amides. The amidation reaction is facile at room temperature with low sulfonyl amide loading. The reaction with thioamides is illustrated with various thioamides and electron‐deficient sulfonyl amides with broad substrate scope. The utility of N‐sulfonyl amidine synthesis is validated with late‐stage drug functionalization.

Lignin‐based nitrogen and phosphorus‐containing polylactic acid with flame‐retardant performances

AbstractPolylactic acid (PLA) is a new type of biodegradable material that has been applied in many fields such as extrusion, injection molding, film drawing, and spinning. In contrary, it does not have flame retardancy. In this paper, N‐PCDL was synthesized by amidation reaction between COOH of PCDL and NH2 of tetraethylenepentamine (TEPA), followed by an Atherton‐Todd reaction of unreacted NH2 at the other end of TEPA with PH of DOPO to prepare a novel lignin‐based flame retardant containing nitrogen and phosphorus (NP‐PCDL). The Fourier transform infrared spectroscopy (FT‐IR) and nuclear magnetic hydrogen spectroscopy (1H NMR) analysis results showed that proton peaks of CONH, PN, and NH appeared in the NP‐PCDL spectrum, while the characteristic absorption peak of PH bond disappeared in DOPO, the X‐ray photoelectron spectroscopy (XPS) results showed that the degraded lignin consisted of elements C and O, while NP‐PCDL consisted of elements C, O, N and P. The above results indicated that NP‐PCDL was successfully prepared. NP‐PCDL accounted for 3% (mass percentage, the same below), 5% and 10% of PLA, then lignin based flame‐retardant PLA composites were prepared by internal mixing and injection molding. Thermogravimetric analysis (TGA) showed that the residual carbon of PLA/3% NP‐PCDL, PLA/5% NP‐PCDL and PLA/10% NP‐PCDL at 800°C were higher than that of pure PLA, with the increase of 56.56%, 97.54%, and 301.64%, respectively; The analysis of SEM, XPS, and Raman showed that PLA/NP‐PCDL formed dense, regular and highly graphitized residual carbon with phosphorus nitrogen structure during the combustion process. At the same time, NH3, H2O and PO˙ free radicals were released, which could dilute combustible gases, destroy free radical chain reaction, isolate combustible gases and heat, so as to play a flame‐retardant role.