Reactive Groups Research Articles

Nuclear long diameter as a new criterion to distinguish high-grade urothelial carcinoma cells from benign reactive cells.

Recently, the nuclear area has attracted attention as a morphological parameter to differentiate high-grade urothelial carcinoma (HGUC) cells from benign reactive cells. The nuclear long diameter (NLD) strongly correlates with the nuclear area and is easy to subjectively estimate. Therefore, this study examined the usefulness of the NLD-to-neutrophil diameter ratio for detecting HGUC cells in urine cytology. This study included 29, 26 and 18 patients with HGUC, glomerular disease and urolithiasis respectively. An image analysis system was used to measure the NLD of HGUC and benign reactive cells (reactive renal tubular cells and reactive urothelial cells) and the neutrophil diameter that appeared in the voided urine in these cases. The NLD index was calculated using the NLD-to-neutrophil diameter ratio. We subsequently compared HGUC and benign reactive cells with respect to NLD and NLD indices. In addition, the HGUC cell group and benign reactive cell group were compared by selecting the five cells with the largest NLD and NLD index on each slide. The NLD and NLD indices of HGUC cells were significantly higher than those of benign reactive cells in all cells and in the five cells with the largest NLD and NLD indices. The cut-off value of the NLD index for detecting HGUC cells was 1.25 in all cells and 1.80 in the five cells with the largest NLD index. The NLD index is a useful parameter that can be introduced into routine microscopic examinations to differentiate HGUC cells from benign reactive cells.

Mechanistic insights into C(sp2)-H activation in 1-Phenyl-4-vinyl-1H-1,2,3-triazole derivatives: a theoretical study with palladium acetate catalyst.

The activation of C-H bonds is a fundamental process in synthetic organic chemistry, which enables their replacement by highly reactive functional groups. Coordination compounds serve as effective catalysts for this purpose, as they facilitate chemical transformations by interacting with C-H bonds. A comprehensive understanding of the mechanism of activation of this type of bond lays the foundation for the development of efficient protocols for cross-coupling reactions. We explored the activation of C(sp2)-H bonds in 1-Phenyl-4-vinyl-1H-1,2,3-triazole derivatives with CH3, OCH3, and NO2 substituents in the para position of the phenyl ring, using palladium acetate as catalyst. The studied reaction is the first step for subsequent conjugation of the triazoles with naphthoquinones in a Heck-type reaction to create a C-C bond. The basic nitrogen atoms of the 1,2,3-triazole coordinate preferentially with the cationic palladium center to form an activated species. A concerted proton transfer from the terminal vinyl carbon to one of the acetate ligands with low activation energy is the main step for the C(sp2)-H activation. This study offers significant mechanistic insights for enhancing the effectiveness of C(sp2)-H activation protocols in organic synthesis. All calculations were performed using the Gaussian 09 software package and density functional theory (DFT). The structures of all reaction path components were fully optimized using the CAM-B3LYP functional with the Def2-SVP basis set. The optimized geometries were analyzed by computing the second-order Hessian matrix to confirm that the corresponding minimum or transition state was located. To account for solvent effects, the Polarizable Continuum Model of the Integral Equation Formalism (IEFPCM) with water as the solvent was used.

Kinetic Characterization and Identification of Key Active Site Residues of the L-aspartate N-hydroxylase, CreE.

CreE is a flavin-dependent monooxygenase (FMO) that catalyzes three sequential nitrogen oxidation reactions of L-aspartate to produce nitrosuccinate, contributing to the biosynthesis of the antimicrobial and antiproliferative nautral product, cremeomycin. This compound contains a highly reactive diazo functional group in which the reaction of CreE is essential to its formation. Nitro and diazo functional groups can serve as potent electrophiles, important in some challenging nucleophilic addition reactions. Formation of these reactive groups positions CreE as a promising candidate for biomedical and synthetic applications. Here, we present the catalytic mechanism of CreE and the identification of active site residues critical to binding L-aspartate, aiding in future enzyme engineering efforts. Steady-state analysis demonstrated that CreE is very specific for NADPH over NADH and performs a highly coupled reaction with L-aspartate. Analysis of the rapid-reaction kinetics showed that flavin reduction is very fast, along with the formation of the oxygenating species, the C4a-hydroperoxyflavin. The slowest step observed was the dehydration of the flavin. Structural analysis and site-directed mutagenesis implicated T65, R291, and R440 in the binding L-aspartate. The data presented describes the catalytic mechanism and the active site architecture of this unique FMO.

Ligand-Enabled C6-Selective C-H Arylation of Pyrrolo[2,3-d] Pyrimidine Derivatives with Pd Catalysts: An Approach to the Synthesis of EGFR Inhibitor AEE-788.

Herein, we report the Pd(II)-catalyzed direct C-H arylation of pyrrolo[2,3-d]pyrimidine derivatives with aryl iodides, which is enabled by bidentate pyridine-pyridine ligands. A range of aryl iodides proved to be suitable coupling partners affording the desired products in good yields with high levels of C6 selectivity. This protocol features good tolerance of reactive functional groups, mild reaction conditions, and a simple reaction system, which provides an expeditious route to an essential class of 6-arylpyrrolo[2,3-d]pyrimidines frequently found in bioactive compounds, and provides a step-economical access to the second-generation EGFR inhibitor AEE-788.

A facile strategy for tuning the density of surface-grafted biomolecules for melt extrusion-based additive manufacturing applications

AbstractMelt extrusion-based additive manufacturing (ME-AM) is a promising technique to fabricate porous scaffolds for tissue engineering applications. However, most synthetic semicrystalline polymers do not possess the intrinsic biological activity required to control cell fate. Grafting of biomolecules on polymeric surfaces of AM scaffolds enhances the bioactivity of a construct; however, there are limited strategies available to control the surface density. Here, we report a strategy to tune the surface density of bioactive groups by blending a low molecular weight poly(ε-caprolactone)5k (PCL5k) containing orthogonally reactive azide groups with an unfunctionalized high molecular weight PCL75k at different ratios. Stable porous three-dimensional (3D) scaffolds were then fabricated using a high weight percentage (75 wt.%) of the low molecular weight PCL5k. As a proof-of-concept test, we prepared films of three different mass ratios of low and high molecular weight polymers with a thermopress and reacted with an alkynated fluorescent model compound on the surface, yielding a density of 201–561 pmol/cm2. Subsequently, a bone morphogenetic protein 2 (BMP-2)-derived peptide was grafted onto the films comprising different blend compositions, and the effect of peptide surface density on the osteogenic differentiation of human mesenchymal stromal cells (hMSCs) was assessed. After two weeks of culturing in a basic medium, cells expressed higher levels of BMP receptor II (BMPRII) on films with the conjugated peptide. In addition, we found that alkaline phosphatase activity was only significantly enhanced on films containing the highest peptide density (i.e., 561 pmol/cm2), indicating the importance of the surface density. Taken together, these results emphasize that the density of surface peptides on cell differentiation must be considered at the cell-material interface. Moreover, we have presented a viable strategy for ME-AM community that desires to tune the bulk and surface functionality via blending of (modified) polymers. Furthermore, the use of alkyne–azide “click” chemistry enables spatial control over bioconjugation of many tissue-specific moieties, making this approach a versatile strategy for tissue engineering applications. Graphic abstract

Runaway transition in irreversible polymer condensation with cyclization

The process of polymer condensation, i.e., the formation of bonds between reactive end groups, is ubiquitous in both industry and biology. Here we study generic systems undergoing polymer condensation in competition with cyclization. Using a generalized Smoluchowski theory, molecular dynamics simulations and experiments with DNA and ATP-consuming T4 ligase, we find that this system displays a transition, from a ring-dominated regime with finite-length chains at infinite time to a linear-polymers-dominated one with chains that keep growing in time. Finally, we show that fluids prepared close to the transition may have widely different compositions and rheology at large condensation times. Published by the American Physical Society 2024

Homogeneous multi-payload antibody-drug conjugates.

Many systemic cancer chemotherapies comprise a combination of drugs, yet all clinically used antibody-drug conjugates (ADCs) contain a single-drug payload. These combination regimens improve treatment outcomes by producing synergistic anticancer effects and slowing the development of drug-resistant cell populations. In an attempt to replicate these regimens and improve the efficacy of targeted therapy, the field of ADCs has moved towards developing techniques that allow for multiple unique payloads to be attached to a single antibody molecule with high homogeneity. However, the methods for generating such constructs-homogeneous multi-payload ADCs-are both numerous and complex owing to the plethora of reactive functional groups that make up the surface of an antibody. Here, by summarizing and comparing the methods of both single- and multi-payload ADC generation and their key preclinical and clinical results, we provide a timely overview of this relatively new area of research. The methods discussed range from branched linker installation to the incorporation of unnatural amino acids, with a generalized comparison tool of the most promising modification strategies also provided. Finally, the successes and challenges of this rapidly growing field are critically evaluated, and from this, future areas of research and development are proposed.

Synthesis and Biological Applications of Coumarinyl-Chalcones

Abstract: This survey provides information on the synthesis and biological applications of coumarinylchalcones. Chalcones are unsaturated ketones involving the reactive keto-ethylenic group (CO-CH=CH). Chalcones are naturally abundant in many medical plants, including vegetables, fruits, and foods. Natural and synthetic chalcone compounds exhibit a broad spectrum of biological properties like anticancer, antiinflammatory, anti-HIV, antioxidant, antimalarial, and antimicrobial. Some conventional, microwave, and grinding techniques have been utilized for the synthesis of chalcones. Noteworthy, the Claisen-Schmidt condensation reaction remains the most popular and effective method for synthesis. It summarizes information about its synthetic methods as building blocks in some reactions like cyclization reactions and medical applications. This review article presents an overview of approaches and biological data for chalcones bearing a coumarin scaffold.

Characterization and the physical properties of nano-sized Bi2O3/polymer for energy and high-refractive index applications

The present work focuses on developing nanocomposites for optoelectronics and energy storage devices leveraging the unique physicochemical features of bismuth (III) oxide (Bi2O3) using a polyvinyl pyrrolidone/polyvinyl alcohol matrix (PV(A/P)). Bi2O3 nanofillers (NF) and Bi2O3/PV(A/P) nanocomposite (NC) films were prepared by facile chemical solution approaches. The X-ray (XRD) data and a transmission electron image revealed that the NF exhibits a monoclinic phase, resembling slightly deformed agglomerated spheres. In the FTIR spectrum, different stretching vibrations of Bi-O-Bi bonds were found, along with their complexation and interaction with the reactive groups in the matrix. The SEM revealed a uniform distribution of Bi2O3 NF loading up to 1.5 wt% on the sample’s surface. Thermal analyses (TGA and DSC thermograms) were used to study the thermal stability, melting, and decomposition temperatures of the NC films. The dielectric features were studied under frequencies between 2 × 103 and 8 × 106 Hz and heating from 293 to 393 K. The dielectric constant and energy density were increased with Bi2O3 NF content. This implies that we can utilize the prepared NC for the fabrication of energy storage devices. The influences of the Bi2O3 NF doping level on the transmittance, band gap, Urbach energy, refractive index, conductivity, and other physical parameters were discussed. The modifications induced in the dielectric/optical parameters make the prepared NC films the best candidates for applications requiring a high refractive index, such as optical coatings and integrated photonic devices.

Translational Research of the Acute Effects of Negative Emotions on Vascular Endothelial Health: Findings From a Randomized Controlled Study.

Provoked anger is associated with an increased risk of cardiovascular disease events. The underlying mechanism linking provoked anger as well as other core negative emotions including anxiety and sadness to cardiovascular disease remain unknown. The study objective was to examine the acute effects of provoked anger, and secondarily, anxiety and sadness on endothelial cell health. Apparently healthy adult participants (n=280) were randomized to an 8-minute anger recall task, a depressed mood recall task, an anxiety recall task, or an emotionally neutral condition. Pre-/post-assessments of endothelial health including endothelium-dependent vasodilation (reactive hyperemia index), circulating endothelial cell-derived microparticles (CD62E+, CD31+/CD42-, and CD31+/Annexin V+) and circulating bone marrow-derived endothelial progenitor cells (CD34+/CD133+/kinase insert domain receptor+ endothelial progenitor cells and CD34+/kinase insert domain receptor+ endothelial progenitor cells) were measured. There was a group×time interaction for the anger versus neutral condition on the change in reactive hyperemia index score from baseline to 40 minutes (P=0.007) with a mean±SD change in reactive hyperemia index score of 0.20±0.67 and 0.50±0.60 in the anger and neutral conditions, respectively. For the change in reactive hyperemia index score, the anxiety versus neutral condition group by time interaction approached but did not reach statistical significance (P=0.054), and the sadness versus neutral condition group by time interaction was not statistically significant (P=0.160). There were no consistent statistically significant group×time interactions for the anger, anxiety, and sadness versus neutral condition on endothelial cell-derived microparticles and endothelial progenitor cells from baseline to 40 minutes. In this randomized controlled experimental study, a brief provocation of anger adversely affected endothelial cell health by impairing endothelium-dependent vasodilation.

Emerging and Re-emerging Warheads for Targeted Covalent Inhibitors: An Update.

Covalent inhibitors and other types of covalent modalities have seen a revival in the past two decades, with a variety of new targeted covalent drugs having been approved in recent years. A key feature of such molecules is an intrinsically reactive group, typically a weak electrophile, which enables the irreversible or reversible formation of a covalent bond with a specific amino acid of the target protein. This reactive group, often called the "warhead", is a critical determinant of the ligand's activity, selectivity, and general biological properties. In 2019, we summarized emerging and re-emerging warhead chemistries to target cysteine and other amino acids (Gehringer, M.; Laufer, S. A. J. Med. Chem. 2019, 62, 5673-5724; DOI: 10.1021/acs.jmedchem.8b01153). Since then, the field has rapidly evolved. Here we discuss the progress on covalent warheads made since our last Perspective and their application in medicinal chemistry and chemical biology.

Investigating of epoxy nanocomposites structure and properties that contain both pristine and aminosilane-treated silicon carbide (SiC) particles

This article presents a methodology for functionalization of silicon carbide (SiC) through chemical modification using γ-aminopropyltriethoxysilane (APTES) and its subsequent dispersion in an epoxy composition. The research revealed that functionalizing SiC particles with γ-aminopropyltriethoxysilane (SiC(APTES)) enhanced their chemical compatibility with the epoxy composition, facilitating the dispersion of SiC particles. Furthermore, it was observed that the functionalization of the filler had a profound impact on the structure, curing kinetics, and physical and mechanical properties of epoxy nanocomposites. The addition of SiC(APTES) into the epoxy composition resulted in a significant reinforcement of the material. Specifically, the flexural stress and flexural modulus of elasticity increased by 179% and 74%, respectively, while the impact strength experienced a remarkable improvement of 462%. Additionally, the tensile strength and tensile modulus of elasticity increased by 83% and 70%, respectively, compared to the epoxy composite without SiC. The application of SiC(APTES) also played a crucial role in initiating the polymerization process through the involvement of reactive amino groups, leading to a reduction in the initial curing temperature and an amplification of the thermal effects of the polymerization reaction. Moreover, the presence of functionalized SiC significantly influenced the structure of the epoxy composite, thereby contributing to its enhanced strength. In summary, the inclusion of SiC in the epoxy composition not only bolstered the material but also improved its thermal stability.

Robust mechanical strength and high colorfastness of amorphous photonic crystals on fabrics with durable antibacterial and anti-static properties

The technique of utilizing structural color dyeing presents a sustainable and energy-conserving approach to textile dyeing. However, the coating with structural coloration always exhibited cracks and inadequate colorfastness attributed to the presence of capillary tension. In this study, we employed a hydrophilic silane called 3-aminopropyltriethoxysilane (KH550) to chemically modify the fabric. This method endowed the fabric with reactive amino groups, thereby augmenting the interfacial bonding strength between polydopamine (PDA)@SiO2@Ag+/Ag NPs and the fabric substrate through metal coordination and covalent bonds. Additionally, by utilizing catechol complexation, we successfully loaded Ag ions onto the PDA coating of composite microspheres. These Ag ions acted as linkers during self-assembly of microspheres. The active amino groups on the surface of chemically modified cotton fabric reacted with PDA at a specific temperature, resulting in the formation of robust covalent bonds simultaneously. The resulting fabric demonstrated excellent water resistance as well as efficient antibacterial and anti-static properties, which were confirmed through various mechanical tests such as washing, folding, and rubbing experiments. This research presents an innovative approach for creating durable structural colored fabrics with multifunctional properties based on metal coordination and covalent bonds that can be effectively applied in textile printing and dyeing.

Detection of Active SARS-CoV-2 3CL Protease in Infected Cells Using Activity-Based Probes with a 2,6-Dichlorobenzoyloxymethyl Ketone Reactive Warhead.

The 3CL protease (3CLpro) is a viral cysteine protease of SARS-CoV-2 and is responsible for the main processing of the viral polyproteins involved in viral replication and proliferation. Despite the importance of 3CLpro as a drug target, the intracellular dynamics of active 3CLpro, including its expression and subcellular localization in SARS-CoV-2-infected cells, are poorly understood. Herein, we report an activity-based probe (ABP) with a clickable alkyne and an irreversible warhead for the SARS-CoV-2 3CL protease. We designed and synthesized two ABPs that contain a chloromethyl ketone (probe 2) or 2,6-dichlorobenzoyloxymethyl ketone (probe 3) reactive group at the P1' site. Labeling of recombinant 3CLpro by the ABPs in the purified and proteome systems revealed that probe 3 displayed ligand-directed and selective labeling against 3CLpro. Labeling of transiently expressed active 3CLpro in COS-7 cells also validated the good target selectivity of probe 3 for 3CLpro. We finally demonstrated that endogenously expressed 3CLpro in SARS-CoV-2-infected cells can be detected by fluorescence microscopy imaging using probe 3, suggesting that active 3CLpro at 5 h postinfection is localized in the juxtanuclear region. To the best of our knowledge, this is the first report investigating the subcellular localization of active 3CLpro by using ABPs. We believe that probe 3 will be a useful chemical tool for acquiring important biological knowledge of active 3CLpro in SARS-CoV-2-infected cells.

Silver nitrate-assisted photo-crosslinking for enhancing the mechanical properties of an alginate/silk fibroin-based 3D scaffold

Scaffolds play a pivotal role in tissue engineering and serve as vital biological substitutes, providing structural support for cell adhesion and subsequent tissue development. An ideal scaffold must possess mechanical properties suitable for tissue function and exhibit biodegradability. Although synthetic polymer scaffolds offer high rigidity and elasticity owing to their reactive side groups, which facilitate tailored mechanical and rheological properties, they may lack biological cues and cause persistent side effects during degradation. To address these challenges, natural polymers have garnered attention owing to their inherent bioactivity and biocompatibility. However, natural polymers such as silk fibroin (SF) and tyramine-modified alginate (AT) have limitations, including uncontrolled mechanical properties and weak structural integrity. In this study, we developed a blend of SF and AT as a printable biomaterial for extrusion-based 3D printing. Using photocrosslinkable SF/AT inks facilitated the fabrication of complex scaffolds with high printability, thereby enhancing their structural stability. The incorporation of silver nitrate facilitated the tunability of mechanical and rheological behaviors. SF/AT scaffolds with varying stiffness in the physiologically relevant range for soft tissues (51–246 kPa) exhibited excellent biocompatibility, indicating their promising potential for diverse applications in tissue engineering.

Silicone Nanocomposites with Enhanced Thermal Resistance: A Short Review.

Continuous technological progress places significant demands on the materials used in increasingly modern devices. An important parameter is often the long-term thermal resistance of the material. The use of heat-resistant polymer materials worked well in technologically advanced products. An economically justified direction in searching for new materials is the area of polymer nanocomposite materials. It is necessary to appropriately select both the polymer matrix and the nanofillers best able to demonstrate the synergistic effect. A promising area of exploration for such nanocomposites is the use of organosilicon polymers, which results from the unique properties of these polymers related to their structure. This review presents the results of the analysis of the most important literature reports regarding organosilicon polymer nanocomposites with increased thermal resistance. Particular attention was paid to modification methods of silicone nanocomposites, focusing on increasing their thermal resistance related to the modification of siloxane molecular structure and by making nanocomposites using inorganic additives and carbon nanomaterials. Attention was also paid to such important issues as the influence of the dispersion of additives in the polymer matrix on the thermal resistance of silicone nanocomposites and the possibility of modifying the polymer matrix and permanently introducing nanofillers thanks to the presence of various reactive groups. The thermal stability mechanism of these nanocomposites was also analysed.

Copper/Zinc-Catalyzed Stitching of 2-Carbonylanilines with Bis(ynamides): Access to Pyrrolo[2,3-b]quinolines and Its Photophysical Studies.

Herein, a one-pot desulfonylative protocol enabled by copper(II)/zinc(II) salts to access pyrrolo[2,3-b]quinolines in good to excellent yields from 2-carbonylanilines and ynamide-derived buta-1,3-diynes has been reported. Significantly, various 2-carbonylanilines carrying reactive functional groups are well tolerated. Moreover, a gram-scale synthesis and synthetic application highlight the practical utility of the current protocol. Notably, the fluorescence properties of pyrrolo[2,3-b]quinolines have been recorded, and their potential use as a fluorescent probe in the imaging of live cells has been demonstrated.

Fouling-resistant reverse osmosis membranes grafted with 2-aminoethanethiol having a low interaction energy with charged foulants

Many fouling-resistant materials have been grafted or coated on the RO membrane surface for fouling-resistance. However, these modified RO membranes still exhibit a fast flux drop towards small charged organic foulants. Herein, we creatively use the quantum chemistry method to screen the thiol group having a close to zero interaction energy with small charged organic foulants. Thus, we selected a small molecule of 2-aminoethanethiol (AET) having a fouling-resistant thiol group and a reactive amine group for RO membrane surface modification. The water permeance of the AET-grafted RO membrane increases from 2.6 ± 0.1 L m−2 h−1 bar−1 to 3.2 ± 0.05 L m−2 h−1 bar−1, 23% higher than that of the pristine membrane. Moreover, the AET-grafted RO membrane exhibits excellent fouling resistance against charged surfactants. Our study offers insights on the design of fouling-resistant molecules for antifouling surface modification of RO membranes towards small charged organic foulants.

Systematic Characterization of Cow Manure Biochar and Its Effect on Salicornia herbacea L. Growth

This study investigated the potential of biochar as a sustainable material for waste utilization and carbon sequestration in soil. Biochar was prepared from cow manure (CM) and applied to the soil. Biochar was processed by subjecting CM to various temperature ranges (400 [CMB400], 550 [CMB550], and 700 °C [CMB700]) under nitrogen gas (allowed to flow to restrict oxygen), with residence time set to 3 h. The characteristics of the biochar produced at each temperature were analyzed. The experiment was conducted for approximately 15 weeks with the laboratory temperature maintained between 24 and 26 °C. The growth rate of plants was obtained by measuring their length weekly, starting 4 weeks after crop establishment. CMB550 exhibited the highest specific surface area (117.57 m2 g−1) and well-distributed pore size; therefore, it was mixed with the soil at a specific ratio and put in pots for the planting of Salicornia herbacea L. (glasswort) in the laboratory. The results demonstrated that adding biochar to soil increased plant growth and that the biochar could store organic carbon. In addition, an investigation of heavy metals demonstrated that samples with biochar had lower heavy metal concentrations in glasswort than those without because of the potential of biochar to adsorb heavy metals. By interacting with heavy metal ions in soil solution, the reactive sites and functional groups on the surface of biochar immobilize them and lessen their potentially detrimental effects on plant growth. Overall, biochar has the potential to be a valuable resource for waste management and environmental improvement.

Active mixing of two-component viscoelastic silicone ink at molecular level for spatiotemporally controlled 3D/4D printing of cellular silicones

3D printed silicones have demonstrated great potential in diverse areas such as soft robots, tissue engineering, flexible sensors and energy dissipation. However, most silicone inks face inevitable curing issue once it is prepared. During the materials extrusion based printing process, the curing-related viscosity change in silicone inks hamper the ink stability and printing controllability, leading to complex relationship among ink properties and printing parameters, as well as printing structures and material properties of final products. Herein, this work presents active mixing of two component silicone ink to realize stable printing, achieving exact and continuous match of ink properties and printing parameters. Using a specially formulated ink containing separate starting components with reactive groups, catalyst and thixotropic agents, this work studies the active mixing process thoroughly for the first time from molecular level to materials performances under various conditions regarding inlet flow rates, impeller rotation speed and component ratios. Besides, cellular silicones with controlled distribution of component ratios and tailored gradient structures are printed, leading to integrated manufacturing of compression performance and shape morphing property. This work will pave way for active mixing and printing of two-component silicones, and provide guidance for other reactive multi-material 3D printing systems.