Drugs possessing aryloxypropanamine pharmacophore, duloxetine, dapoxetine and propranolol, increase allopregnanolone in rat brain: Possible involvement of allopregnanolone in their central nervous system effects.

Allopregnanolone (AP) is a neurosteroid synthesized in the brain and a positive allosteric modulator of γ-aminobutyric acid (GABA) type A receptors. Some drugs possessing the aryloxypropanamine (AOPA) pharmacophore, such as fluoxetine, exert their central nervous system (CNS) effects by increasing the brain AP. Although duloxetine (DLX), dapoxetine (DPX), atomoxetine (ATX) and propranolol (PRL) also possess the AOPA pharmacophore and are used to treat some psychiatric disorders, the capabilities of these drugs to increase the brain AP and the possible involvement of AP in their CNS effects remain to be fully elucidated. To clarify these points, we first developed a method for quantifying AP in the rat brain by liquid chromatography/electrospray ionization-tandem mass spectrometry. Analysis of the changes in the brain AP levels using this method revealed that the intraperitoneal administration of DLX (10 mg/kg), DPX (10 mg/kg) and PRL (20 mg/kg) significantly increased the brain AP (DLX: < 0.40-2.74 ng/g tissue, DPX: 1.48-3.83 ng/g tissue and PRL: < 0.40-2.09 ng/g tissue) compared to the saline administration (<0.40 ng/g tissue). These results suggested the possible involvement of the GABAergic neurosteroid, AP, in the central actions of DLX, DPX and PRL. In contrast, ATX (10 mg/kg) did not affect the AP levels in the brain. In addition, the brain and serum AP levels had a remarkably high positive correlation after the administration of DLX, DPX and PRL. Thus, this study proposed the AP-related novel mechanism of actions of DLX, DPX and PRL in the CNS.

Propargylamine: an important moiety in drug discovery.

Propargylamine is a chemical moiety whose properties have made it a widely distributed group within the fields of medicinal chemistry and chemical biology. Its particular reactivity has traditionally popularized the preparation of propargylamine derivatives using a large variety of synthetic strategies, which have facilitated the access to these compounds for the study of their biomedical potential. This review comprehensively covers and analyzes the applications that propargylamine-based derivatives have achieved in the drug discovery field, both from a medicinal chemistry perspective and from a chemical biology-oriented approach. The principal therapeutic fields where propargylamine-based compounds have made an impact are identified, and a discussion of their influence and growing potential is included.

Synthesis and Characterization of Alkoxysilane-Bearing Photoreversible Cinnamic Side Groups: A Promising Building-Block for the Design of Multifunctional Silica Nanoparticles.

The present study reports on the synthesis of a new alkoxysilane-bearing light-responsive cinnamyl group and its application as a surface functionalization agent for the development of SiO2 nanoparticles (NPs) with photoreversible tails. In detail, cinnamic acid (CINN) was activated with N-hydroxysuccinimide (NHS) to obtain the corresponding NHS-ester (CINN-NHS). Subsequently, the amine group of 3-aminopropyltriethoxysilane (APTES) was acylated with CINN-NHS leading to the generation of a novel organosilane, CINN-APTES, which was then exploited for decorating SiO2 NPs. The covalent bond to the silica surface was confirmed by solid state NMR, whereas thermogravimetric analysis unveiled a functionalization degree much higher compared to that achieved by a conventional double-step post-grafting procedure. In light of these intriguing results, the strategy was successfully extended to naturally occurring sepiolite fibers, widely employed as fillers in technological applications. Finally, a preliminary proof of concept of the photoreversibility of the obtained SiO2@CINN-APTES system has been carried out through UV diffuse reflectance. The overall outcomes prove the consistency and the versatility of the methodological protocol adopted, which appears promising for the design of hybrid NPs to be employed as building blocks for photoresponsive materials with the ability to change their molecular structure and subsequent properties when exposed to different light stimuli.

Sodium Isopropyl(trimethylsilyl)amide: A Stable and Highly Soluble Lithium Diisopropylamide Mimic.

The preparation, structure, physical properties, and reactivities of sodium isopropyl(trimethylsilyl)amide (NaPTA) are described. The solubilities at room temperature range from n-heptane (0.55 M), n-hexane (0.60 M), toluene (0.65 M), MTBE (1.7 M), Et3N (3.2 M), and THF (>6.0 M). The half-life to destruction in neat THF is >1 year at 25 °C and 7 days at 70 °C, which compares favorably to 2.5 months and 1.5 days, respectively, for LDA in neat THF. This study focuses on NaPTA in THF. 29Si NMR spectroscopy shows exclusively a mixture of cis and trans stereoisomeric dimers in 0.10-12 M THF in hexane. Density functional theory (DFT) computations suggest that the pKb is intermediate between dimeric sodium diisopropylamide (NaDA) and dimeric sodium hexamethyldisilazide (NaHMDS). Metalations of arenes, epoxides, ketones, hydrazones, alkenes, and alkyl halides show higher reactivities than LDA (kNaPTA/LDA = 1-30). While the rates of arene metalation are high, the lower pKb of NaPTA limits the substrates. Metalation of pseudoephedrate-based carboxamides to form disodiated Myers enolates solves several challenging technical problems.

N-Methylpropargylamine-Conjugated Hydroxamic Acids as Dual Inhibitors of Monoamine Oxidase A and Histone Deacetylase for Glioma Treatment.

Glioma treatment remains a challenge with a low survival rate due to the lack of effective therapeutics. Monoamine oxidase A (MAO A) plays a role in glioma development, and MAO A inhibitors reduce glioma growth. Histone deacetylase (HDAC) inhibition has emerged as a promising therapy for various malignancies including gliomas. We have synthesized and evaluated N-methylpropargylamine-conjugated hydroxamic acids as dual inhibitors of MAO A and HDAC. Compounds display potent MAO A inhibition with IC50 from 0.03 to <0.0001 µM and inhibit HDAC isoforms and cell growth in the micromolar to nanomolar IC50 range. These selective MAO A inhibitors increase histone H3 and α-tubulin acetylation and induce cell death via nonapoptotic mechanisms. Treatment with 15 reduced tumor size, reduced MAO A activity in brain and tumor tissues, and prolonged the survival. This first report on dual inhibitors of MAO A and HDAC establishes the basis of translational research for an improved treatment of glioma.

Markedly improved hydrophobicity of cellulose film via a simple one-step aminosilane-assisted ball milling.

Most cellulose products lack water resistance due to the existence of abundant hydroxyl groups. In this work, microfibrillated cellulose (MFC) was modified via 3-aminopropyltriethoxysilane (APTES)-assisted ball milling. Under the synergism between high-energy mechanical force field and APTES-modification, the fibrillation and hydrophobization of MFC were achieved simultaneously. Free-standing translucent cellulose films made of modified MFC were fabricated. The original crystal form of cellulose is maintained. The hydrophobicity of cellulose film markedly increases and the water contact angle goes up to 133.2 ± 3.4°, which might be ascribed to the combined effects of APTES-modification and rough film surface. In addition, the thermostability and mechanical properties of cellulose film are also improved via mechanochemical modification. This work provides a novel one-step fibrillation-hydrophobization method for cellulose.

Antioxidant Activity of Bioactive Peptide Fractions from Germinated Soybeans Conjugated to Fe3O4 Nanoparticles by the Ugi Multicomponent Reaction.

The conjugation of biomolecules to magnetic nanoparticles has emerged as promising approach in biomedicine as the treatment of several diseases, such as cancer. In this study, conjugation of bioactive peptide fractions from germinated soybeans to magnetite nanoparticles was achieved. Different fractions of germinated soybean peptides (>10 kDa and 5-10 kDa) were for the first time conjugated to previously coated magnetite nanoparticles (with 3-aminopropyltriethoxysilane (APTES) and sodium citrate) by the Ugi four-component reaction. The crystallinity of the nanoparticles was corroborated by X-ray diffraction, while the particle size was determined by scanning transmission electron microscopy. The analyses were carried out using infrared and ultraviolet-visible spectroscopy, dynamic light scattering, and thermogravimetry, which confirmed the coating and functionalization of the magnetite nanoparticles and conjugation of different peptide fractions on their surfaces. The antioxidant activity of the conjugates was determined by the reducing power and hydroxyl radical scavenging activity. The nanoparticles synthesized represent promising materials, as they have found applications in bionanotechnology for enhanced treatment of diseases, such as cancer, due to a higher antioxidant capacity than that of fractions without conjugation. The highest antioxidant capacity was observed for a >10 kDa peptide fraction conjugated to the magnetite nanoparticles coated with APTES.

Molecularly Imprinted Silica-Coated CdTe Quantum Dots for Fluorometric Determination of Trace Chloramphenicol.

A dual recognition system with a fluorescence quenching of quantum dots (QDs) and specific recognition of molecularly imprinted polymer (MIP) for the detection of chloramphenicol (CAP) was constructed. MIP@SiO2@QDs was prepared by reverse microemulsion method with 3-aminopropyltriethoxysilane (APTS), tetraethyl orthosilicate (TEOS) and QDs being used as the functional monomer, cross-linker and signal sources, respectively. MIP can specifically recognize CAP, and the fluorescence of QDs can be quenched by CAP due to the photo-induced electron transfer reaction between CAP and QDs. Thus, a method for the trace detection of CAP based on MIP@SiO2@QDs fluorescence quenching was established. The fluorescence quenching efficiency of MIP@SiO2@QDs displayed a desirable linear response to the concentration of CAP in the range of 1.00~4.00 × 102 µmol × L-1, and the limit of detection was 0.35 µmol × L-1 (3σ, n = 9). Importantly, MIP@SiO2@QDs presented good detection selectivity owing to specific recognition for CAP, and was successfully applied to quantify CAP in lake water with the recovery ranging 102.0~104.0%, suggesting this method has the promising potential for the on-site detection of CAP in environmental waters.

Functionalization of mesoporous silica as an effective composite carrier for essential oils with improved sustained release behavior and long-term antibacterial performance.

In this work, a novel composite carrier system for loading essential oils was developed by using tetraethyl orthosilicate (TEOS) and (3-aminopropyl) triethoxysilane (APTES) as silica precursors and cetyl trimethyl ammonium bromide (CTAB) as a template, and the resultant aminated mesoporous silica was further chemically modified by polyacrylic acid (PAA). The obtained composite carriers exhibited a high loading capability toward tea tree oil (TTO), and they also significantly improved the release behavior of TTO due to the steric hindrance of silica mesopore and the polymer restriction. Besides, it was found that the release behavior followed the First-Order kinetic model, revealing that the release of TTO was driven by the concentration gradient. In addition, these composite carriers with essential oil-loaded demonstrated remarkable antibacterial performance againstE. coliandS. aureus, and they could retain antibacterial performance even after 50 d. Moreover, the antibacterial mechanism was also elucidated with the assistance of nucleic acid and conductivity measurements. Therefore, this work provides a facile and environmentally friendly approach to preparing effective composite carriers for improving the sustained release of essential oils, and the long-term antibacterial performance of these essential oil-loaded composite carriers makes them tremendously potential for practical applications.

Novel propargylamine-based inhibitors of cholinesterases and monoamine oxidases: Synthesis, biological evaluation and docking study.

A combination of several pharmacophores in one molecule has been successfully used for multi-target-directed ligands (MTDL) design. New propargylamine substituted derivatives combined with salicylic and cinnamic scaffolds were designed and synthesized as potential cholinesterases and monoamine oxidases (MAOs) inhibitors. They were evaluated invitro for inhibition of acetyl- (AChE) and butyrylcholinesterase (BuChE) using Ellman's method. All the compounds act as dual inhibitors. Most of the derivatives are stronger inhibitors of AChE, the best activity showed 5-bromo-N-(prop-2-yn-1-yl)salicylamide 1e (IC50 = 8.05 µM). Carbamates (4-bromo-2-[(prop-2-yn-1-yl)carbamoyl]phenyl ethyl(methyl)carbamate 2d and 2,4-dibromo-6-[(prop-2-yn-1-yl)carbamoyl]phenyl ethyl(methyl)carbamate 2e were selective and the most active for BuChE (25.10 and 26.09 µM). 4-Bromo-2-[(prop-2-yn-1-ylimino)methyl]phenol 4a was the most potent inhibitor of MAOs (IC50 of 3.95 and ≈10 µM for MAO-B and MAO-A, respectively) along with a balanced inhibition of both cholinesterases being a real MTDL. The mechanism of action was proposed, and binding modes of the hits were studied by molecular docking on human enzymes. Some of the derivatives also exhibited antioxidant properties. Insilico prediction of physicochemical parameters affirm that the molecules would be active after oral administration and able to reach brain tissue.

Reactions of Sodium Diisopropylamide: Liquid-Phase and Solid-Liquid Phase-Transfer Catalysis by N,N,N',N″,N″-Pentamethyldiethylenetriamine.

Sodium diisopropylamide (NaDA) in N,N-dimethylethylamine (DMEA) and DMEA-hydrocarbon mixtures with added N,N,N',N″,N″-pentamethyldiethylenetriamine (PMDTA) reacts with alkyl halides, epoxides, hydrazones, arenes, alkenes, and allyl ethers. Comparisons of PMDTA with N,N,N',N'-tetramethylethylenediamine (TMEDA) accompanied by detailed rate and computational studies reveal the importance of the trifunctionality and κ2-κ3 hemilability. Rate studies show exclusively monomer-based reactions of 2-bromooctane, cyclooctene oxide, and dimethylresorcinol. Catalysis with 10 mol % PMDTA shows up to >30-fold accelerations (kcat > 300) with no evidence of inhibition over 10 turnovers. Solid-liquid phase-transfer catalysis (SLPTC) is explored as a means to optimize the catalysis as well as explore the merits of heterogeneous reaction conditions.

Anchor and bridge functions of APTES layer on interface between hydrophilic starch films and hydrophobic soyabean oil coating.

One of the well-recognized weaknesses of starch-based materials is their sensitivity to moisture, which limits their expanding applications. Natural materials, soyabean oils have been used as a coating for starch film, but the poor interface between hydrophilic starch and hydrophobic soyabean oil needs to be improved. In this work, (3-Aminopropyl) triethoxysilane (APTES) was used to reinforce the bonding between starch matrix and the coating of bio-based acrylated epoxidized soyabean oil (AESO). Study results show that APTES interacted effectively with both starch films via hydrogen bonding, and chemical bonds with AESO through the Michael addition reaction. Pull adhesion and cross-cutting tests demonstrated that the interfacial adhesion was significantly improved after treating their surface with APTES. The interfacial adhesion strength increased over 4 times after treating with 1.6 wt% APTES. The starch films treated with APTES and AESO coating were intact after soaking in water for more than 2 h.

Reconstitution and Structural Analysis of a HECT Ligase-Ubiquitin Complex via an Activity-Based Probe.

Ubiquitin activity-based probes have proven invaluable in elucidating structural mechanisms in the ubiquitin system by stabilizing transient macromolecular complexes of deubiquitinases, ubiquitin-activating enzymes, and the assemblies of ubiquitin-conjugating enzymes with ubiquitin ligases of the RING-Between-RING and RING-Cysteine-Relay families. Here, we demonstrate that an activity-based probe, ubiquitin-propargylamine, allows for the preparative reconstitution and structural analysis of the interactions between ubiquitin and certain HECT ligases. We present a crystal structure of the ubiquitin-linked HECT domain of HUWE1 that defines a catalytically critical conformation of the C-terminal tail of the ligase for the transfer of ubiquitin to an acceptor protein. Moreover, we observe that ubiquitin-propargylamine displays selectivity among HECT domains, thus corroborating the notion that activity-based probes may provide entry points for the development of specific, active site-directed inhibitors and reporters of HECT ligase activities.

Impedimetric cardiac biomarker determination in serum mediated by epoxy and hydroxyl of reduced graphene oxide on gold array microelectrodes.

A label-free chemical bonding strategy mediated by reduced graphene oxide (rGO) basal plane functional groups has been developed for cardiac Troponin I (cTnI) detection. Four different chemical strategies on respective electrode sensing surface were precedingly examined using electrochemical impedance spectroscopy. The impedimetric assessment was carried out by sweeping frequency at the range 0.1-500 kHz perturbated at a small amplitude of AC voltage (25 mV). The chemical strategy-4 denoted as S-4 shows a significant analytical performance on cTnI detection in spiked buffer and human serum, whereby the pre-mixture of rGO and (3-Aminopropyl)triethoxysilane (APTES) creates a large number of amine sites (-NH2), which significantly enhanced the antibody immobilization without excessive functionalization. The as-fabricated immunosensor exhibited an ultra-low limit of detection of 6.3 ag mL-1 and the lowest antigen concentration measured was at 10 ag mL-1. The immunosensor showed a linear and wide range of cTnI detection (10 ag mL-1-100 ng mL-1) in human serum with a regression coefficient of 0.9716, rapid detection (5 min of binding time), and stable and highly reproducible bioelectrode response with RSD < 5%. Hence, the demonstrated S-4 strategy is highly recommended for other downstream biosensors applications.

Recombinant SARS-CoV-2 envelope protein traffics to the trans-Golgi network following amphipol-mediated delivery into human cells.

The severe acute respiratory syndrome coronavirus 2 envelope protein (S2-E) is a conserved membrane protein that is important for coronavirus (CoV) assembly and budding. Here, we describe the recombinant expression and purification of S2-E in amphipol-class amphipathic polymer solutions, which solubilize and stabilize membrane proteins, but do not disrupt membranes. We found that amphipol delivery of S2-E to preformed planar bilayers results in spontaneous membrane integration and formation of viroporin cation channels. Amphipol delivery of the S2-E protein to human cells results in plasma membrane integration, followed by retrograde trafficking to the trans-Golgi network and accumulation in swollen perinuclear lysosomal-associated membrane protein 1-positive vesicles, likely lysosomes. CoV envelope proteins have previously been proposed to manipulate the luminal pH of the trans-Golgi network, which serves as an accumulation station for progeny CoV particles prior to cellular egress via lysosomes. Delivery of S2-E to cells will enable chemical biological approaches for future studies of severe acute respiratory syndrome coronavirus 2 pathogenesis and possibly even development of "Trojan horse" antiviral therapies. Finally, this work also establishes a paradigm for amphipol-mediated delivery of membrane proteins to cells.

N-Propargylamine-hydroxypyridinone hybrids as multitarget agents for the treatment of Alzheimer's disease.

AD is a progressive brain disorder. Because of the lack of remarkable single-target drugs against neurodegenerative disorders, the multitarget-directed ligand strategy has received attention as a promising therapeutic approach. Herein, we rationally designed twenty-nine hybrids of N-propargylamine-hydroxypyridinone. The designed hybrids possessed excellent iron-chelating activity (pFe3+ = 17.09-22.02) and potent monoamine oxidase B inhibitory effects. Various biological evaluations of the optimal compound 6b were performed step by step, including inhibition screening of monoamine oxidase (hMAO-B IC50 = 0.083 ± 0.001 µM, hMAO-A IC50 = 6.11 ± 0.08 µM; SI = 73.5), prediction of blood-brain barrier permeability and mouse behavioral research. All of these favorable results proved that the N-propargylamine-hydroxypyridinone scaffold is a promising structure for the discovery of multitargeted ligands for AD therapy.

Fabrication of a Kagomé-type MOF Membrane by Seeded Growth on Amino-functionalized Porous Al2 O3 Substrate.

In this study, we report an efficient fabrication method for the membrane of a metal-organic framework (MOF) (Kgm-OEt) which is one kind of kagomé-type MOF with a two-dimensional (2D) sheet structure having one-dimensional (1D) channels suitable for separation of H2 from other larger gases. The Kgm-OEt seed layer was created on an Al2 O3 substrate using layer-by-layer (LBL) growth, then a membrane was fabricated by secondary growth. The membrane on a 3-aminopropyltriethoxysilane (APTEs)-treated substrate obtained in this method was continuous and defect-free with the crystal orientation suitable for gas transportation, while the membrane grown on an unmodified substrate was loosely packed with unfavorable crystal orientation.

Shadow Electrochemiluminescence Microscopy of Single Mitochondria.

Mitochondria are the subcellular bioenergetic organelles. The analysis of their morphology and topology is essential to provide useful information on their activity and metabolism. Herein, we report a label-free shadow electrochemiluminescence (ECL) microscopy based on the spatial confinement of the ECL-emitting reactive layer to image single living mitochondria deposited on the electrode surface. The ECL mechanism of the freely-diffusing [Ru(bpy)3 ]2+ dye with the sacrificial tri-n-propylamine coreactant restrains the light-emitting region to a micrometric thickness allowing to visualize individual mitochondria with a remarkable sharp negative optical contrast. The imaging approach named "shadow ECL" (SECL) reflects the negative imprint of the local diffusional hindrance of the ECL reagents by each mitochondrion. The statistical analysis of the colocalization of the shadow ECL spots with the functional mitochondria revealed by classical fluorescent biomarkers, MitoTracker Deep Red and the endogenous intramitochondrial NADH, validates the reported methodology. The versatility and extreme sensitivity of the approach are further demonstrated by visualizing single mitochondria, which remain hardly detectable with the usual biomarkers. Finally, by alleviating problems of photobleaching and phototoxicity associated with conventional microscopy methods, SECL microscopy should find promising applications in the imaging of subcellular structures.

Synthesis of propargylamine mycophenolate analogues and their selective cytotoxic activity towards neuroblastoma SH-SY5Y cell line.

Twenty six propargylamine mycophenolate analogues were designed and synthesized from mycophenolic acid 1 employing a key step A3-coupling reaction. Their cytotoxic activity was examined against six cancer cell lines. Compounds 6a, 6j, 6t, 6u, and 6z exhibited selective cytotoxicity towards neuroblastoma (SH-SY5Y) cancer cells and were less toxic to normal cells in comparison to the lead compound, MPA 1 and a standard drug, ellipticine. Molecular docking results suggested that compound 6a is fit well in the key amino acid of three proteins (CDK9, EGFR, and VEGFR-2) as targets in cancer therapy. The propargylamine mycophenolate scaffold might be a valuable starting point for development of new neuroblastoma anticancer drugs.

Extraction and electrochemical detection for quantification of trace-level DNA.

A novel strategy was developed to extract, detect, and quantify trace-level DNA. For the extraction step, a composite of methylene blue (MB), poly(acrylic acid) (PAA), and modified iron oxide magnetic nanoparticles (IOMNPs) (PAA/IOMNPs) was used to adsorb DNA from the sample. MB-PAA/IOMNPs with adsorbed DNA were then separated from the solution with an external magnet and MB-DNA was eluted from PAA/IOMNPs with acetic acid. In the detection step, MB-DNA was adsorbed on the surface of 3-aminopropyltriethoxysilane (APTES)-modified glassy carbon electrode via electrostatic force. DNA was quantified by measuring the oxidation peak of MB at a potential -0.13 V vs. Ag/AgCl using differential pulse voltammetry. Under the optimal experimental conditions, the DNA sensor showed linear ranges from 0.001 to 0.005 pg µL-1, 0.005 to 0.070 pg µL-1, and 0.070 to 0.400 pg µL-1 and a limit of detection of 0.87 fg µL-1. The proposed sensor detected trace DNA in real samples with recoveries that ranged from 80.4 to 90.4%.