Two Preparation Methods for Peptide Thioester Containing Tyr(SO3H) Residue(s) without the Use of Protecting Group for Sulfate Moiety.

We report two methods for the preparation of peptide thioesters containing Tyr(SO3H) residue(s), without use of a protecting group for the sulfate moiety. The first was based on direct thioesterification using carbodiimide on a fully protected peptide acid, prepared on a 2-chlorotrityl (Clt) resin with fluoren-9-ylmethoxycarbonyl (Fmoc)-based solid-phase peptide synthesis (Fmoc-SPPS). Subsequent deprotection of the protecting groups with trifluoroacetic acid (TFA) (0 °C, 4 h) yielded peptide thioesters containing Tyr(SO3H) residue(s). Peptide thioesters containing one to three Tyr(SO3H) residue(s), prepared by this method, were used as building blocks for the synthesis of the Nα-Fmoc-protected N-terminal part of P-selectin glycoprotein ligand 1 (PSGL-1) (Fmoc-PSGL-1(43-74)) via silver-ion mediated thioester segment condensation. The other method was based on the thioesterification of peptide azide, derived from a peptide hydrazide prepared on a NH2NH-Clt-resin with Fmoc-SPPS. Peptide thioester containing two Tyr(SO3H) residues, prepared via this alternative method, was used as a building block for the one-pot synthesis of the N-terminal extracellular portion of CC-chemokine receptor 5 (CCR5(9-26)) by native chemical ligation (NCL). The two methods for the preparation of peptide thioesters containing Tyr(SO3H) residue(s) described herein are applicable to the synthesis of various types of sulfopeptides.

Induced genetic diversity through mutagenesis in wheat gene pool and significant use of SCoT markers to underpin key agronomic traits.

BACKGROUND: This research explores the efficacy of mutagenesis, specifically using sodium azide (SA) and hydrazine hydrate (HZ) treatments, to introduce genetic diversity and enhance traits in three wheat (Triticum aestivum L.) genotypes. The experiment entails subjecting the seeds to different doses of SA and HZ and cultivating them in the field for two consecutive generations: M1 (first generation) and M2 (second generation). We then employed selective breeding techniques with Start Codon Targeted (SCoT) markers to select traits within the wheat gene pool. Also, the correlation between SCoT markers and specific agronomic traits provides insights into the genetic mechanisms underlying mutagenesis-induced changes in wheat. RESULTS: In the study, eleven genotypes were derived from parent varieties Sids1, Sids12, and Giza 168, and eight mutant genotypes were selected from the M1 generation and further cultivated to establish the M2 generation. The results revealed that various morphological and agronomical characteristics, such as plant height, spikes per plant, spike length, spikelet per spike, grains per spikelet, and 100-grain weight, showed increases in different genotypes from M1 to M2. SCoT markers were employed to assess genetic diversity among the eleven genotypes. The bioinformatics analysis identified a correlation between SCoT markers and the transcription factors ABSCISIC ACID INSENSITIVE3 (ABI3) and VIVIPAROUS1 (VP1), crucial for plant development, growth, and stress adaptation. A comprehensive examination of genetic distance and the function identification of gene-associated SCoT markers may provide valuable insights into the mechanisms by which SA and HZ act as mutagens, enhancing wheat agronomic qualities. CONCLUSIONS: This study demonstrates the effective use of SA and HZ treatments to induce gene diversity through mutagenesis in the wheat gene pool, resulting in the enhancement of agronomic traits, as revealed by SCoT markers. The significant improvements in morphological and agronomical characteristics highlight the potential of mutagenesis techniques for crop improvement. These findings offer valuable information for breeders to develop effective breeding programs to enhance wheat quality and resilience through increased genetic diversity.

Cyclic Peptide Conjugate Vaccines and Physically Mixed Cyclic Peptide Vaccines for Subcutaneous Immunization.

Immune stimulants (adjuvants) enhance immune system recognition to provide an effective and individualized immune response when delivered with an antigen. Synthetic cyclic deca-peptides, co-administered with a toll-like receptor targeting lipopeptide, have shown self-adjuvant properties, dramatically boosting the immune response in a murine model as a subunit peptide-based vaccine containing group A Streptococcus peptide antigens.Here, we designed a novel peptide and lipid adjuvant system for the delivery of group A Streptococcus peptide antigen and a T helper peptide epitope. Following linear peptide synthesis on 2-chlorotrityl chloride resin, the linear peptide was cleaved and head-to-tail cyclized in solution. The selective arrangement of amino acids in the deca-peptide allowed for selective conjugation of lipids and/or peptide antigens following cyclisation. Using both solution-phase peptide chemistry and copper-catalyzed azide-alkyne cycloaddition reaction were covalently (and selectively) ligated lipid and/or peptide antigens onto the cyclic deca-peptide core. Subcutaneous administration of the vaccine design to mice resulted in the generation of a large number of serum immunoglobulin (Ig) G antibodies.

Unveiling Route for the Synthesis of Tröger's Bases Through Azide Rearrangement.

This study introduces a novel method for producing Tröger's bases by utilizing the rearrangement chemistry of benzyl azide. This method offers a convenient and adaptable pathway for synthesizing these important molecular structures with potential for further advancements. By reacting benzyl azide derivatives with TfOH under the presence of water, this process generates iminium ion, formaldehyde, and aniline intermediates in situ. Notably, this conversion is reversible under acidic conditions, allowing for the regeneration of the iminium ion and ultimately leading to the formation of the desired Tröger's base product. Additionally, this method could decrease the risk of exposure to an excess amount of formaldehyde.

Synthesis of substituted triazole-pyrazole hybrids using triazenylpyrazole precursors.

A synthesis route to access triazole-pyrazole hybrids via triazenylpyrazoles was developed. Contrary to existing methods, this route allows the facile N-functionalization of the pyrazole before the attachment of the triazole unit via a copper-catalyzed azide-alkyne cycloaddition. The developed methodology was used to synthesize a library of over fifty new multi-substituted pyrazole-triazole hybrids. We also demonstrate a one-pot strategy that renders the isolation of potentially hazardous azides obsolete. In addition, the compatibility of the method with solid-phase synthesis is shown exemplarily.

In vitro α-glucosidase, docking and density functional theory studies on novel azide metal complexes.

Aim: The goal of this study is to synthesize new metal complexes containing N-methyl-1-(pyridin-2-yl)methanimine and azide ligands as α-glucosidase inhibitors for Type 2 diabetes. Materials & methods: The target complexes (12-16) were synthesized by reacting N-methyl-1-(pyridin-2-yl)methanimine (L1) with sodium azide in the presence of corresponding metal salts. The investigation of target protein interactions, vibrational, electronic and nonlinear optical properties for these complexes was performed by molecular docking and density functional theory studies. Results: Among these complexes, complex 13 (IC50 = 0.2802 ± 0.62 µM) containing Hg ion showed the highest α-glucosidase inhibitory property. On the other hand, significant results were detected for complexes containing Cu and Ag ions. Conclusion: Complex 13 may be an alternate anti-diabetic inhibitor according to in vitro/docking results.

[Box: see text].

Gamma rays and sodium azide induced variations in bio-physiological and agronomical traits in linseed (Linum usitatissimum L.).

Linseed is a valuable oilseed crop with huge therapeutic importance due to its high content of omega-3 fatty acids in the form of Alpha-linolenic acid (ALA). It is a self-pollinated crop with a low-yielding potential that restricts its improvement endeavors. To overcome low-yielding potential, individual and combination treatments of gamma rays and sodium azide were employed in widely grown linseed varieties. The results revealed a dose-dependent decline in seed germination, seedling height, pollen fertility, chlorophyll, and carotenoid contents and a dose-independent decline in carbonic anhydrase activity. Bio-physiological parameters decreased substantially in combination treatments compared to individual treatments of gamma rays and sodium azide. In contrast, lower doses of gamma rays, sodium azide, and their combinations effectively increased mean values of yield and yield-attributing traits in a few putative mutants. Such putative mutants represent a valuable genetic resource that could be used in future breeding programs for the genetic improvement of linseed and related medicinal plants.

Cetyltrimethylammonium-chloride assisted in situ metabolic incorporation of nano-sized ROS-generating cascade-reaction containers in Gram-positive and Gram-negative peptidoglycan layers for the control of bacterially-induced sepsis.

Cascade-reaction containers generating reactive oxygen species (ROS) as an alternative for antibiotic-based strategies for bacterial infection control, require endogenous oxygen-sources and ROS-generation close to or preferably inside target bacteria. Here, this is achieved by cetyltrimethylammonium-chloride (CTAC) assisted in situ metabolic labeling and incorporation of mesoporous SiO2-nanoparticles, dual-loaded with glucose-oxidase and Fe3O4-nanoparticles as cascade-reaction containers, inside bacterial cell walls. First, azide-functionalized d-alanine (D-Ala-N3) was inserted in cell wall peptidoglycan layers of growing Gram-positive pathogens. In Gram-negatives, this could only be achieved after outer lipid-membrane permeabilization, using a low concentration of CTAC. Low concentrations of CTAC had no adverse effect on in vitro blood clotting or hemolysis nor on the health of mice when blood-injected. Next, dibenzocyclooctyne-polyethylene-glycol modified, SiO2-nanoparticles were in situ click-reacted with d-Ala-N3 in bacterial cell wall peptidoglycan layers. Herewith, a two-step cascade-reaction is facilitated inside bacteria, in which glucose-oxidase generates H2O2 at endogenously-available glucose concentrations, while subsequently Fe3O4-nanoparticles catalyze generation of •OH from the H2O2 generated. Generation of •OH inside bacterial cell walls by dual-loaded mesoporous SiO2-nanoparticles yielded more effective in vitro killing of both planktonic Gram-positive and Gram-negative bacteria suspended in 10 % plasma than SiO2-nanoparticles solely loaded with glucose-oxidase. Gram-positive or Gram-negative bacterially induced sepsis in mice could be effectively treated by in situ pre-treatment with tail-vein injected CTAC and d-Ala-N3, followed by injection of dual-loaded cascade-reaction containers without using antibiotics. This makes in situ metabolic incorporation of cascade-reaction containers as described attractive for further investigation with respect to the control of other types of infections comprising planktonic bacteria. STATEMENT OF SIGNIFICANCE: In situ metabolic-incorporation of cascade-reaction-containers loaded with glucose-oxidase and Fe3O4 nanoparticles into bacterial cell-wall peptidoglycan is described, yielding ROS-generation from endogenous glucose, non-antibiotically killing bacteria before ROS inactivates. Hitherto, only Gram-positives could be metabolically-labeled, because Gram-negatives possess two lipid-membranes. The outer membrane impedes direct access to the peptidoglycan. This problem was solved by outer-membrane permeabilization using a quaternary-ammonium compound. Several studies on metabolic-labeling perform crucial labeling steps during bacterial-culturing that in real-life should be part of a treatment. In situ metabolic-incorporation as described, can be applied in well-plates during in vitro experiments or in the body as during in vivo animal experiments. Surprisingly, metabolic-incorporation proceeded unhampered in blood and a murine, bacterially-induced sepsis could be well treated.

Ultrasound-assisted Cu(II) Strecker-functionalized organocatalyst for green azide-alkyne cycloaddition and Ullmann reactions.

A new aminonitrile-functionalized Fe3O4 has been synthesized via the Strecker reaction, the designed aminonitrile ligand on the surface of the magnetic core coordinated to copper(II) to obtain the final new catalyst. The fabricated nanocatalyst was characterized by Fourier transform Infrared (FT-IR), Field Emission Scanning Electron Microscopy (FESEM), Energy-Dispersive X-ray spectroscopy (EDX), Transmission Electron Microscopy (TEM), Vibrating-Sample Magnetometer (VSM), Inductively Coupled Plasma Optical Emission Spectroscopy (ICP-OES), and Thermogravimetric Analysis (TGA). The high tendency of nitrogens in the aminonitrile functional group to make a complex with Cu(II) has caused the practical activity of this nucleus in this catalyst. This nanocatalyst performance was investigated in azide-alkyne Huisgen cycloaddition (3 + 2) reaction for achieving to 1,4-disubstituted 1,2,3-triazoles in water as a green media at room temperature. In another try, Classic Ullmann Reaction was investigated for the synthesis of biaryls at 85 °C promoted by ultrasonic condition (37 kHz). The reaction scope was explored using different reactants and the results of using this developed catalytic system demonstrated its capacity to reduce the reaction time and enhance the reaction efficiency to provide good to excellent product yield. Conversely, the simple recycling and reusability of this catalyst for at least six times without any noticeable leaching of copper makes it a potential future catalyst for synthesizing such compounds.

Conjugated molecularly imprinted polymers based on covalent organic frameworks: Fluorescent sensing platform for specific capture of urea and elimination of ethyl carbamate.

This study described the preparation of an azide covalent organic framework-embedded molecularly imprinted polymers (COFs(azide)@MIPs) platform for urea adsorption and indirect ethyl carbamate (EC) removal from Chinese yellow rice wine (Huangjiu). By modifying the pore surface of COFs using the copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction, COFs(azide) with a high fluorescence quantum yield and particular recognition ability were inventively produced. In order to selectively trap urea, the COFs(azide) were encased in an imprinted shell layer via imprinting technology. With a detection limit (LOD) of 0.016 µg L-1 (R2 = 0.9874), the COFs(azides)@MIPs demonstrated a good linear relationship with urea in the linear range of 0-5 µg L-1. Using real Huangjiu samples, the spiking recovery trials showed the viability of this sensing platform with recoveries ranging from 88.44 % to 109.26 % and an RSD of less than 3.40 %. The Huangjiu processing model system achieved 38.93 % EC reduction by COFs(azides)@MIPs. This research will open up new avenues for the treatment of health problems associated with fermented alcoholic beverages, particularly Huangjiu, while also capturing and removing hazards coming from food.

Recent Progress on Synthesis of Functionalized 1,5-Disubstituted Triazoles.

Immediately after the invention of 'Click Chemistry' in 2002, the regioselective 1,2,3- triazole scaffolds resulted from respective organic azides and terminal alkynes under Cu(I) catalysis have been well recognized as the functional heterocyclic core at the centre of modern organic chemistry, medicinal chemistry, and material sciences. This CuAAC reaction has several notable features including excellent regioselectivity, high-to-excellent yields, easy to execute, short reaction time, modular in nature, mild condition, readily available starting materials, etc. Moreover, the resulting regioselective triazoles can serve as amide bond isosteres, a privileged functional group in drug discovery and development. More than hundreds of reviews had been devoted to the 'Click Chemistry' in special reference to 1,4-disubstituted triazoles, while only little efforts were made for an opposite regioisomer i.e., 1,5-disubstituted triazole. Herein, we have presented various classical approaches for an expeditious synthesis of a wide range of biologically relevant 1,5- disubstituted 1,2,3-triazole analogues. The syntheses of such a class of diversly functionalized triazoles have emerged as a crucial investigation in the domain of chemistry and biology. This tutorial review covers the literature assessment on the development of various synthetic protocols for the functionalized 1,5-disubstituted triazoles reported during the last 12 years.

Fast detection of tryptamine in meat products with azide-functionalized covalent organic frameworks confined in molecularly imprinted polymers.

Tryptamine is a biogenic amine that affects organoleptic quality through the generation of off-odours in foods. Herein, imine-based covalent organic frameworks (COFs) were synthesized via Schiff base reactions and postmodified with click chemistry to generate azide-functionalized COFs with tunable azide units on the walls. The combination of molecular imprinting with COFs enabled the specific recognition of the targets. The resulting optosensing system (azide-functionalized COFs@MIPs) was used as a sample-to-answer analyser for detecting tryptamine (detection time within 10 min). A linear relationship was observed for the fluorescence response to tryptamine concentrations in the range of 3-120 µg L-1, with a limit of detection of 1.74 µg L-1. The recoveries for spiked samples were satisfactory, with relative standard deviations <9.90%. The optosensing system is a potential tool for the quantitative detection of tryptamine in meat products because of its lower cost, shorter processing time, and simpler processing steps compared to conventional chromatographic techniques.

One-pot Ugi-azide and Heck reactions for the synthesis of heterocyclic systems containing tetrazole and 1,2,3,4-tetrahydroisoquinoline.

A new method for the synthesis of heterocyclic systems containing tetrazole and tetrahydroisoquinoline is developed via the performance of one-pot Ugi-azide and Heck cyclization reactions. The integration of the multicomponent and post-condensation reactions in one-pot maximizes the pot-, atom-, and step-economy (PASE).

A New Insight Into The Huisgen Reaction: Heterogeneous Copper Catalyzed Azide-Alkyne Cycloaddition for the Synthesis of 1,4-Disubstituted Triazole (From 2018-2023).

The Huisgen cycloaddition, often referred to as 1,3-Dipolar cycloaddition, is a well-established method for synthesizing 1,4-disubstituted triazoles. Originally conducted under thermal conditions [3+2] cycloaddition reactions were limited by temperature, prolonged reaction time, and regioselectivity. The introduction of copper catalyzed azide-alkyne cycloaddition (CuAAC) revitalized interest, giving rise to the concept of "click chemistry". The CuAAC has emerged as a prominent method for producing 1,2,3-triazole with excellent yields and exceptional regioselectivity even in unfavorable conditions. Copper catalysts conventionally facilitate azide-alkyne cycloadditions, but challenges include instability and recycling issues. In recent years, there has been a growing demand for heterogeneous and porous catalysts in various chemical reactions. Chemists have been more interested in heterogenous catalysts as a result of the difficulties in separating homogenous catalysts from reaction products. These catalysts are favored for their abundant active sites, extensive surface area, easy separation from reaction mixtures, and the ability to be reused. Heterogeneous catalysts have garnered significant attention due to their broad industrial utility, characterized by cost-effectiveness, stability, resistance to thermal degradation, and ease of removal compared to their homogeneous counterparts. The present review covers recent advancements from year 2018 to 2023 in the field of click reactions for obtaining 1,2,3-triazoles through Cu catalyzed 1,3-dipolar azide-alkyne cycloaddition and the properties of the catalyst, reaction conditions such as solvent, temperature, reaction time, and the impact of different heterogeneous copper catalysts on product yield.

Organo-Photocatalytic Anti-Markovnikov Hydroamidation of Alkenes with Sulfonyl Azides: A Combined Experimental and Computational Study.

The construction of C(sp3)-N bonds via direct N-centered radical addition with olefins under benign conditions is a desirable but challenging strategy. Herein, we describe an organo-photocatalytic approach to achieve anti-Markovnikov alkene hydroamidation with sulfonyl azides in a highly efficient manner under transition-metal-free and mild conditions. A broad range of substrates, including both activated and unactivated alkenes, are suitable for this protocol, providing a convenient and practical method to construct sulfonylamide derivatives. A synergistic experimental and computational mechanistic study suggests that the additive, Hantzsch ester (HE), might undergo a triplet-triplet energy transfer manner to achieve photosensitization by the organo-photocatalyst under visible light irradiation. Next, the resulted triplet excited state 3HE* could lead to a homolytic cleavage of C4-H bond, which triggers a straightforward H-atom transfer (HAT) style in converting sulfonyl azide to the corresponding key amidyl radical. Subsequently, the addition of the amidyl radical to alkene followed by HAT from p-toluenethiol could proceed to afford the desired anti-Markovnikov hydroamidation product. It is worth noting that mechanistic pathway bifurcation could be possible for this reaction. A feasible radical chain propagation mechanistic pathway is also proposed to rationalize the high efficiency of this reaction.

Study on the Effect of Nanoporous Copper Particle Size on Copper-Based Azide.

Preparing copper-based azide by in situ reaction is well-suited for MEMS processing technology and holds promising prospects in the field of MEMS micro-initiators. This study involved the preparation of porous copper with particle sizes of approximately 30 nm, 60 nm and 100 nm through powder sintering. These were used as precursors for a gas-solid in situ azide reaction to produce copper-based azide with varying morphologies and compositions. Copper-based azide micro-initiators were designed, and their output performance was evaluated using CL-20 and HNS-IV explosives. Analytical results revealed that the product from the reaction of the 100 nm precursor exhibited a lumpy and uneven structure with a conversion rate of 90.36%. The product from the 60 nm precursor reaction had a dense surface with a conversion rate of 94.56%, while the 30 nm precursor resulted in a needle-like form with a conversion rate of 92.82%. Detonation experiments demonstrated that the copper-based azide micro-initiators prepared with 100 nm of a porous copper precursor exhibited unstable output performance, requiring a 1.6 mg charge to successfully detonate CL-20 explosives. On the other hand, copper-based azide micro-initiators prepared from 60 nm and 30 nm of porous copper precursors exhibited stable output performance. A charge of 0.8 mg was adequate for reliably and consistently detonating CL-20 and HNS-IV explosives. The reduced particle size of the precursor enhanced the output performance of the copper-based azide micro-initiators, providing increased energy redundancy during detonation and improving overall usage reliability.

A New Family of High Oxidation State Antiperovskite Nitrides: La3MN5 (M=Cr, Mn and Mo).

Three new nitrides La3MN5 (M=Cr, Mn, and Mo) have been synthesized using a high pressure azide route. These are the first examples of ternary Cs3CoCl5-type nitrides, and show that this (MN4)NLa3 antiperovskite structure type may be used to stabilise high oxidation-state transition metals in tetrahedral molecular [MN4]n- nitridometallate anions. Magnetic measurements confirm that Cr and Mo are in the M6+ state, but the M=Mn phase has an anomalously small paramagnetic moment and large cell volume. Neutron powder diffraction data are fitted using an anion-excess La3MnN5.30 model (space group I4/mcm, a=6.81587(9) Šand c=11.22664(18) Šat 200 K) in which Mn is close to the +7 state. Excess-anion incorporation into Cs3CoCl5-type materials has not been previously reported, and this or other substitution mechanisms may enable many other high oxidation state transition metal nitrides to be prepared.

A case report of sodium azide-induced myopericarditis.

Background: Sodium azide exposures are rare but can be lethal as the substance inhibits complex IV in the electron transport chain, blocking adenosine-triphosphate (ATP) synthesis. Sodium azide is mostly used as a propellant in vehicular airbags but is also used in laboratory, pharmacy, and industrial settings. No known antidote exists and its cardiotoxic effects are poorly described in the literature. Case summary: We describe the case of a 31-year-old patient with major depressive disorder presenting with altered mental status after ingestion of an unknown amount of sodium azide. Although initially chest pain free, she developed pleuritic chest pain 48 h after ingestion. This was accompanied by new diffuse ST elevations on the electrocardiogram and serum troponin elevations concerning for myopericarditis. Treatment was pursued with a 14-day course of colchicine resulting in complete symptom resolution within 4 days of treatment initiation. The patient's transthoracic echocardiogram was only notable for a preserved left ventricular ejection fraction (LVEF). Discussion: Cardiac toxicity after sodium azide ingestion usually occurs days after ingestion and has been previously described in the forms of heart failure with reduced ejection fraction complicated by cardiogenic shock. We describe the first case of sodium azide-induced myopericarditis with a preserved LVEF treated with colchicine. Colchicine is an established treatment for pericarditis, but its inhibition of endocytosis, an ATP-dependent cellular function, could be mechanistically relevant to this case.

Regioselective quinazoline C2 modifications through the azide-tetrazole tautomeric equilibrium.

2-Chloro-4-sulfonylquinazolines undergo functional group swap when treated with an azide nucleophile: 1) the azide replaces the sulfonyl group at the C4 position; 2) the intrinsic azide-tetrazole tautomeric equilibrium directs the nucleofugal sulfinate from the first step to replace chloride at the C2 position. This transformation is effective with quinazolines bearing electron-rich substituents. Therefore, the title transformations are demonstrated on the 6,7-dimethoxyquinazoline core, which is present in pharmaceutically active substances. The methodology application is showcased by transforming the obtained 4-azido-6,7-dimethoxy-2-sulfonylquinazolines into the α1-adrenoceptor blockers terazosin and prazosin by further C2-selective SNAr reaction and azide reduction.