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This manuscript describes a mild, functional group tolerant, and metal-free C-H carboxylation that enables direct access to azole-2-carboxylic acids, followed by amide coupling in one pot. This demonstrates a significant expansion of the accessible chemical space of azole-2-amides, compared to previously known methodologies. Key to the described reactivity is the use of silyl triflate reagents, which serve as reaction mediators in C-H deprotonation and stabilizers of (otherwise unstable) azole carboxylic acid intermediates. A diverse azole substrate scope designed via machine-learning-guided analysis demonstrates the broad utility of the sequence. Density functional theory calculations provide detailed insights into the role of silyl triflates in the reaction mechanism. Transferrable applications of the protocol are successfully established: (i) A low pressure (CO

We report a combined experimental and mechanistic study on the Buchwald-Hartwig amination and C-S/S-H metathesis of aryl sulfides by selective activation of C-S bonds mediated by well-defined, air-and moisture-stable Pd(II)-NHC precatalysts, [Pd(NHC)(mu-Cl)Cl]2. This class of Pd(II)-NHC precatalysts displays excellent activity in the cross coupling of aryl sulfides. Most crucially, we unravel the unified mechanism for activation of C-S bonds in the C-N cross-coupling and C-S metathesis manifolds, where the inert C-S bond serves as a precursor to valuable amine or thioether products.

An approach for the copper-catalyzed synthesis of enantioenriched amides bearing an α-stereogenic center is disclosed. This method involves the addition of an allyl copper species to an isocyanate and allows access to α-substituted chiral amides in high yields and high-to-excellent enantioselectivities. The utility of α-vinyl β-boryl amides in synthesis is highlighted by the diversification of products to afford highly useful scaffolds. DFT calculations reveal that the catalyst preferentially coordinates to the oxygen of the isocyanate. Enantiocontrol arises from the steric repulsion between the boryl group and the stereodirecting phenyl of the chiral ligand.

Several classes of ribosomally synthesized and post-translationally modified peptides (RiPPs) are composed of multiple macrocycles. The enzymes that assemble these macrocycles must surmount the challenge of installing a single specific set of linkages out of dozens of distinct possibilities. One class of RiPPs that includes multiple macrocycles are the graspetides, named after the ATP-grasp enzymes that install ester or amide linkages between pairs of nucleophilic and electrophilic side chains. Here, using heterologous expression and NMR spectroscopy, we characterize the connectivity and structure of amycolimiditide, a 29 aa graspetide with a stem-loop structure. The stem includes four esters and extends over 20 Å. The loop of amycolimiditide is distinguished by the presence of an aspartimide moiety, installed by a dedicated

Despite several synthetic approaches that have been developed for α-deuterated amino acids, the synthesis of β-deuterated amino acids has remained a challenge. Herein, we disclose a palladium catalyzed H/D exchange protocol for a β-deuterated N-protected amino amide, which can be converted to a β-deuterated amino acid simply by removal of protecting groups. This protocol is highly efficient, simply manipulated, and appliable for deuterium-labeling of many amino amides. In addition, deuterium labeling of phenylalanine derivatives was also successful when pivalic acid served as an additive to promote the H/D exchange process.

Amide bond reduction is a versatile transformation offering access to various alcohols and amines which could be used as valuable precursors in the chemical and pharmaceutical industries, e.g. for manufacturing plastics, textiles, dyes, agrochemicals, etc. Over the last two decades, catalytic amide hydrogenation employing homogenous catalysis has gained more attention due to the atom efficiency and low environmental impact of this transformation. Owing to the inherent strength of amide bonds, amide hydrogenation procedures often involve high temperatures and pressures, which is why efforts are being channeled to finding protocols with lower energy input. Here, we report a mild amide hydrogenation method involving commercially available precursors Ru(acac)3 and 1,2-bis(di-tert-butylphosphinomethyl)benzene (L4), which under basic conditions, at 80 ˚C and under 30 bar of H2 can selectively hydrogenate a series of 2˚-benzamides to anilines and alcohols with yields ranging from 36–98% and 29–92%, respectively. Additionally, 1˚- and 3˚-amides proved to be appropriate substrates, however, low to moderate yields were obtained. The catalyst is believed to operate via an inner-sphere mechanism with a hemiaminal being the likely intermediate during the hydrogenation process.

Molecular catalysts for ammonia oxidation to dinitrogen represent enabling components to utilize ammonia as a fuel and/or source of hydrogen. Ammonia oxidation requires not only the breaking of multiple strong N-H bonds, but also controlled N-N bond formation. We report a novel β-diketiminato copper complex [iPr2NNF6]Cu-NH3 ([Cu(I)]-NH3 (2)) as a robust electrocatalyst for NH3 oxidation in acetonitrile under homogeneous conditions. Complex 2 operates at a moderate overpotential (700 mV) with a TOFmax = 940 h-1 as determined from CV data in 1.3 M NH3 MeCN solvent. Prolonged (>5 h) controlled potential electrolysis (CPE) reveals the stability and robustness of the catalyst under electrocatalytic conditions. Detailed mechanistic investigations indicate that electrochemical oxidation of [Cu(I)]-NH3 forms {[Cu(II)]-NH3}+ (4) which undergoes deprotonation by excess NH3 to form reactive copper(II)-amide [Cu(II)]-NH2 (6) unstable towards N-N bond formation to give the dinuclear hydrazine complex [Cu(I)]2(mu-N2H4). Electrochemical studies reveal that the bisammine complex [Cu(I)](NH3)2 (7) forms at high ammonia concentration as part of the {[Cu(II)](NH3)2}+/[Cu(I)](NH3)2 redox couple that is electrocatalytically inactive. DFT analysis reveals a much higher thermodynamic barrier for deprotonation of {[Cu(II)](NH3)2}+ (8) by NH3 to give the four-coordinate copper(II) amide [Cu(II)](NH2)(NH3) (9) (dG = 31.7 kcal/mol) as compared to deprotonation of the three coordinate {[Cu(II)]-NH3}+ by NH3 to provide the reactive three coordinate parent amide [Cu(II)]-NH2 (dG = 18.1 kcal/mol) susceptible to N-N coupling to form [Cu(I)]2(mu-N2H4) (dG = -11.8 kcal/mol).

Yb(III) complexes of macrocyclic ligands based on1,4,7,10-tetraazacyclododecane were synthesized. The ligands carried a carbostyril chromophore for Yb(III) sensitization, and carboxylate or carbamide donors for metal binding, forming complexes of 0, +1, +2, or +3 overall charge. The coordination geometry was little affected by the replacement of carboxylates with amides, as shown by paramagnetic 1H NMR spectroscopy. The Yb(III)/Yb(II) reduction potentials were dependent on the nature of the metal binding site, and the more positively charged complexes were easier to reduce. Carbostyril excitation resulted in Yb(III) luminescence in every complex. The residual carbostyril fluorescence quantum yields were smaller in complexes containing more reducible Yb(III) centers decreasing from 5.9% for uncharged complexes to 3.1−4.4% in +3 charged species, suggesting photoinduced electron transfer (PeT) from the antenna to the Yb(III). The relative Yb(III) luminescence quantum yields were identical within the experimental error, except for the +3 charged complex with fully methylated coordinating amides, which was the most intense Yb(III) emitter of the series in water. Quenching of the Yb(III) excited state by NH vibrations proved to limit Yb(III) emission. No clear improvement of the Yb(III) sensitization efficiency was shown upon faster PeT. This result can be explained by the concomitant sensitization of Yb(III) by phonon-assisted energy transfer (PAEnT) from the antenna triplet excited state, which was completely quenched in all of the Yb complexes. Depopulation of the triplet by PeT quenching of the donor singlet excited state would be compensated by the sensitizing nature of the PeT pathway, thus resulting in a constant overall sensitization efficiency across the series.

Synthesis of drug metabolites, which often have complex structures, is an integral step in the evaluation of drug candidate metabolism, pharmacokinetic (PK) properties, and safety profiles. Frequently, such synthetic endeavors entail arduous, multiple-step de novo synthetic routes. Herein, we present the one-step Shono-type electrochemical synthesis of milligrams of chiral α-hydroxyl amide metabolites of two orexin receptor antagonists, MK-8133 and MK-6096, as revealed by a small-scale (pico- to nano-mole level) reaction screening using a lab-built online electrochemistry (EC)/mass spectrometry (MS) (EC/MS) platform. The electrochemical oxidation of MK-8133 and MK-6096 was conducted in aqueous media and found to produce the corresponding α-piperidinols with exclusive regio- and stereoselectivity, as confirmed by high-resolution nuclear magnetic resonance (NMR) characterization of products. Based on density functional theory (DFT) calculations, the exceptional regio- and stereoselectivity for this electrochemical oxidation are governed by more favorable energetics of the transition state, leading to the preferred secondary carbon radical α to the amide group and subsequent steric hindrance associated with the U-shaped conformation of the cation derived from the secondary α-carbon radical, respectively.

The preparation, structure, physical properties, and reactivities of sodium isopropyl(trimethylsilyl)amide (NaPTA) are described. Solubilities at room temperature range from n-heptane (0.55 M), n-hexane (0.60 M), toluene (0.65 M), MTBE (1.7 M), Et(3)N (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. The manuscript focuses on NaPTA/THF solutions. (29)Si 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 the pK(b) 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 pK(b) of NaPTA limits the substrates. Metalation of pseudoephedrate-based carboxamides to form disodiated Myers enolates solves several challenging technical problems.

This manuscript reports the effect of hydrogen-bonding functionality on the supramolecular assembly of naphthalene-diimide (NDI)-derived amphiphilic building blocks in water. All the molecules contain a central NDI chromophore, functionalized with a hydrophilic oligo-oxyethylene (OE) wedge in one arm and a phenyl group on the opposite arm. They differ by a single H-bonding functionality, which links the NDI chromophore and the phenyl moiety. The H-bonding functionalities are amide, thioamide, urea, and urethane in NDI-A, NDI-TA, NDI-U, and NDI-UT, respectively. All of these molecules exhibit π-stacking in water, as evident from their distinct UV/vis absorption spectra when compared to that of the monomeric dye in THF. However, among these four, only NDI-A and NDI-TA show hydrogelation, while the other two precipitate out of the medium. The NDI-A hydrogel also exhibits transient stability and leads to a crystalline precipitate within ∼5 h. Only NDI-TA produces stable transparent hydrogel with the entangled fibrillar morphology that is typical for gelators. Both NDI-A and NDI-TA showed a thermoresponsive property with a lower critical solution temperature of about 41-42 °C. Powder XRD studies show a parallel orientation for NDI-A and an antiparallel orientation for NDI-TA. Computational studies support this experimental observation and indicate that the NDI-A assembly is highly stabilized by strong H-bonding among the amide groups and π-stacking interaction in the parallel orientation. On the other hand, due to weak H-bonding among the thioamide groups, the binding energy of the parallelly oriented NDI-TA was significantly lower and the optimized structure was disordered. Instead, its antiparallel orientation was more stable, with criss-cross aligned H-bonding interactions and π-π interactions between adjacent aromatic rings. The NDI-TA hydrogel with less ordered OE chains on the surface showed prominent adsorption of serum protein BSA. In sharp contrast, NDI-A did not exhibit any notable interaction with BSA, as evident from the ITC studies.

Amino acids are important nitrogen-containing compounds and organic carbon components that exist widely in the atmosphere. The formation of atmospheric aerosols is affected by their interactions with amides. The dimers formed by glutamic acid (Glu) or protonated glutamic acid (Glu

An iron-catalyzed four-component sulfonylthiocyanation between α,β-unsaturated amides/esters, TMSNCS, aryldiazonium tetrafluoroborates, and sulfur dioxide (from SOgen) is demonstrated. This protocol is characterized by mild reaction conditions, good functional group compatibility, broad substrate scope, and good to excellent yields, providing a feasible method for the preparation of

Fe(II) and Ni(II) paraCEST contrast agents containing the di-pyridine macrocyclic ligand 2,2',2″-(3,7,10-triaza-1,5(2,6)-dipyridinacycloundecaphane-3,7,10-triyl)triacetamide (DETA) are reported here. Both [Fe(DETA)]

We herein report the use of phenyl trimethylammonium iodide (PhMesub3/subNI) as a safe, nontoxic, and easy-to-handle reagent for an absolutely monoselective N-methylation of amides and related compounds as well as for the N-methylation of indoles. In addition, we expanded the method to N-ethylation using PhEtsub3/subNI. The ease of operational setup, high yields of ≤99%, high functional group tolerance, and especially the excellent monoselectivity for amides make this method attractive for late-stage methylation of bioactive compounds.

This paper describes a mild strategy to promote amide arylations. Photoinduced oxidation of a Ni(II) aryl amido intermediate is proposed to facilitate the challenging C-N reductive elimination step at moderate temperatures. Notably, the mildly basic conditions employed facilitate access to a broad scope including protected amino acids, heterocycles, phenols, and sterically hindered substituents. Hence, this work presents an attractive strategy to enable late-stage functionalization of pre-existing amide moieties in commercial drugs and natural products.

Self-assembled nanotechnology is a promising strategy for improving the effective utilization of pesticides due to its distinct advantages. Herein, an amide-bonded prodrug conjugate based on pyrimethanil (PYR) and butyric acid (BA) was successfully synthesized by the nucleophilic substitution reaction and subsequently self-assembled into spherical nanoparticles (PB NPs) with an average size of 85 nm through the solvent exchange method without using any toxic adjuvant. The results showed that PB NPs based on PYR and BA had a synergistic antimicrobial activity against

Colloidal organo-mineral associations contribute to soil organic matter (OM) preservation and mainly occur in two forms: (i) as water-dispersible colloids that are potentially mobile (free colloids) and (ii) as building units of soil microaggregates that are occluded inside them (occluded colloids). However, the way in which these two colloidal forms differ in terms of textural characteristics and chemical composition, together with the nature of their associated OM, remains unknown. To fill these knowledge gaps, free and occluded fine colloids220 nm were isolated from arable soils with comparable organic carbon (C

Two diastereomers of the protonated diketopiperazine (DKP) dipeptide cyclo(Tyr-Tyr), namely, cyclo(LTyr-LTyr)H

ConspectusEnantiopure atropisomers have become increasingly important in asymmetric synthesis and catalysis, pharmaceutical science, and material science since the discovery of inherent features of axial chirality originating from rotational restriction. Despite the advances made in this field to date, it remains highly desirable to construct structurally diverse atropisomers with potentially useful functions. We propose superposition to match axial and point chirality as a potentially useful strategy to access structurally complex and diverse building blocks for organic synthesis and pharmaceutical science because merging atropisomeric backbones with one or more extra chiral elements can topologically broaden three-dimensional environments to create complex scaffolds with multiple tunable parameters. Over the past decade, we have successfully implemented a strategic design for the superposition of axial and point chirality to develop a series of enantiopure atropisomers and have utilized the synergistic functions of these molecules to enhance chirality transfer in various catalytic asymmetric transformations.In this Account, we present several novel atropisomers with superposed axial and point chirality developed in our laboratory. In our studies, this superposition strategy was used to design and synthesize both biaryl and non-biaryl atropisomers from commercially available chiral sources. Consequently, these atropisomers were used to demonstrate the importance of the synergetic functions of axial and point chirality in specific enantioselective reactions. For example, aromatic amide-derived atropisomers, simplified as Xing-Phos arrays, were broadly employed in Ag-catalyzed [3 + 2] cycloaddition by a series of reactions of aldiminoesters with activated alkenes and imines, as well as being used as chiral solvating agents for the discrimination of optically active mandelic acid derivatives. Considering the powerful potential of non-biaryl atropisomers for asymmetric catalysis, we also explored the transition-metal-catalyzed enantioselective construction of a novel backbone of non-biaryl atropisomers (Ar-alkene, Ar-N axis) bearing both axial and point chirality for the design and synthesis of chiral ligands and functional molecules.The studies presented herein are expected to stimulate further research efforts on the development of functional atropisomers by superposition of matching axial and point chirality. In addition to tunable electron and stereohindrance effects, the synergy between matching chiral elements of axial/point chirality and functional groups is proven to be a special function that cannot be ignored for promoting reactivity and chirality-transfer efficiency in enantioselective synthesis. Consequently, our novel types of scaffolds with superposed axial and point chirality that are capable of versatile coordination with various metal catalysts in asymmetric catalysis highlight the power of the superposition of matching axial and point chirality for the construction of synthetically useful atropisomers.

The chemo- and site-selective reaction at the particular C─N amide bond among a sea of other amides is a significant and long-standing challenge. Although the use of twisted amides has been demonstrated for modifications of inert C─N amide bonds, none of these methods can selectively activate a particular amide bond for C─C bond formation in the presence of similar amides. Using density functional theory as a guide, we report the first site-selective C─C bond modification of a particular C─N amide bond in polyamides with a low twist angle by combining ground-state steric distortion with electronic activation.

Through a modified Kinugasa reaction, a novel method of amidation on terminal oligo alkyne conjugates by copper-promoted oxidation with nitrones has been developed. Unprotected bifunctional carboxylic acid-amine reagents can be transformed directly to the respective amide products under these edited Kinugasa reaction conditions. 3-Cycle DNA-encoded libraries (DELs) can be built in three steps of chemical conversion.

The Protein Data Bank (PDB) file format developed at Brookhaven National Laboratory is the most popular file format to store biological data and is widely supported by many software programs for the editing and visualization of macromolecular structures. Unfortunately, many of these structures have variety of issues ranging from missing side chains and/or atoms to alternate locations (rotamers). To fix these flaws, one has to learn a new program, compile modules, and install libraries. To overcome these challenges, we present Protein Repair and Analysis Server (PRAS), an easy-to-use web server to repair protein structures and add missing atoms. The PRAS program flow has two main sections. In the first section, several subroutines are called to deal with sequence microheterogeneity, rotamers, missing side chains, heavy atoms, or hydrogen atoms. A log file is generated detailing irregularities and their fixes as carried out by the program. In the later section, the program uses the error-corrected protein structure to assign secondary structure elements based on amide-amide interactions of the backbone. Plots of four Ramachandran types (general, glycine, proline, and pre-proline) and percentage of secondary structure elements; a log file and the error-corrected PDB file can be downloaded by clicking on the download link generated by the server. The server is freely available and is accessed through its web address at www.protein-science.com. Alternatively, users can download the source code from the server or install the program on their local machines following the instructions at https://pypi.org/project/Pras-Server/ or https://github.com/osita-sunday-nnyigide/Pras_Server. While the present work focuses on the repair of structural data in the PDB format, the server is capable of fixing similar errors in the extensible and newly adopted mmCIF format.

Nanomedicine-based and unmodified drug interventions to address COVID-19 have evolved over the course of the pandemic as more information is gleaned and virus variants continue to emerge. For example, some early therapies (e.g., antibodies) have experienced markedly decreased efficacy. Due to a growing concern of future drug resistant variants, current drug development strategies are seeking to find effective drug combinations. In this study, we used IDentif.AI, an artificial intelligence-derived platform, to investigate the drug-drug and drug-dose interaction space of six promising experimental or currently deployed therapies at various concentrations: EIDD-1931, YH-53, nirmatrelvir, AT-511, favipiravir, and auranofin. The drugs were tested

Renin is the rate-limiting enzyme in the renin-angiotensin-aldosterone system (RAAS) which regulates blood pressure and renal function and hence is an attractive target for the treatment of hypertension and cardiovascular/renal diseases. However, the development of direct renin inhibitors (DRIs) with favorable oral bioavailability has been a longstanding challenge for many years. This problem was thought to be because most of the reported DRIs were peptide-like structures or nonpeptide-like structures with a molecular weight (MW) of600. Therefore, we tried to find nonpeptidomimetic DRIs with a MW of500 and discovered the promising 2-carbamoyl morpholine derivative

Carbonylation reactions involving CO as readily available C1 synthons have become one of the most important tools for the construction of carbonyl compounds from feedstock chemicals. Despite numerous catalytic methods for carbonylation reactions proceeding via ionic or radical pathways, an inherent limitation to these methods is the need to control switchable single and double carbonylative formation of value-added products from the same and simple starting materials. Here, we describe a new strategy that exploits photoredox catalysis to regulate the philicity of amine coupling partners to drive switchable radical carbonylation reactions. In double carbonylation, amines were first transformed into nitrogen radical cations by single-electron transfer-oxidation and coupled with CO to form carbamoyl radicals, which further underwent radical cross-coupling with the incipient cyanoalkyl acyl radicals to afford the double carbonylation products. Upon the addition of stoichiometric 4-dimethylaminopyridine (DMAP), DMAP competitively traps the initially formed cyanoalkyl acyl radical to form the relatively stabilized cyanoalkyl acyl-DMAP salts that engaged in the subsequent substitution with the nucleophilic amines to produce the single carbonylation products. The reaction proceeded smoothly with excellent selectivity in the presence of various amine nucleophiles at room temperature, generating valuable amides and α-ketoamides in a versatile and controlled fashion. Combined experimental and computational studies provided mechanistic insights into the possible pathways.

The quinazolinone template offers an exciting potential for transforming molecules into useful bioactivity. Herein, we report the first regioselective C-5 alkenylation of quinazolinone-coumarin conjugates via ruthenium(II) catalyst using amide as a weak directing group. This methodology permits excellent regioselectivity, extensive substrate tolerance, and mild reaction conditions. In addition, it generates interesting fluorophores that show positive solvatochromism in the range from 404 nm (toluene) to 541 nm (methanol).

The ability to exploit carbonyl groups to measure electric fields in enzymes and other complex reactive environments by using the vibrational Stark effect has inspired growing interest in how these fields can be measured, tuned, and ultimately designed. Previous studies have concentrated on the role of the solvent in tuning the fields exerted on the solute. Here, we explore instead the role of the solute electronic structure in modifying the local solvent organization and electric field exerted on the solute. By measuring the infrared absorption spectra of amide-containing molecules, as prototypical peptides, and contrasting them with non-amide carbonyls in a wide range of solvents, we show that these solutes experience notable differences in their frequency shifts in polar solvents. Using vibrational Stark spectroscopy and molecular dynamics simulations, we demonstrate that while some of these differences can be rationalized by using the distinct intrinsic Stark tuning rates of the solutes, the larger frequency shifts for amides and dimethylurea primarily result from the larger solvent electric fields experienced by their carbonyl groups. These larger fields arise due to their stronger

Gold nanoparticles (AuNPs) are currently intensively exploited in the biomedical field as they possess interesting chemical and optical properties. Although their synthesis is well-known, their controlled surface modification with defined densities of ligands such as peptides, DNA, or antibodies remains challenging and has generally to be optimized case by case. This is particularly true for applications like in vivo drug delivery that require AuNPs with multiple ligands, for example a targeting ligand and a drug in well-defined proportions. In this context, we aimed to develop a calixarene-modification strategy that would allow the controlled orthogonal conjugation of AuNPs, respectively, via amide bond formation and copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC). To do this, we synthesized a calix[4]arene-tetradiazonium salt bearing four PEG chains ended by an alkyne group (

It is very appealing to synthesize functional soft materials from natural and abundant plant diterpenes because they have conformationally rigid and chiral properties. Herein, dehydroabietic-based monoamide (DA-1) and diamide (DA-2) were designed by introducing device interactions, π-π stacking and hydrogen bonding, with an aromatic group, C═O, and N-H. DA-1 and DA-2 can be gelled in a mixed solvent and a single solvent, respectively. Several novel supramolecular organic gels including highly entangled three-dimensional networks composed of rods or fibers were constructed. Interestingly, DA-2 forms a helical structure that is right-handed under the cooperative control of the solvent and the rigid structure of rosin. Gel formation was primarily driven by hydrogen bonding, π-π stacking, and van der Waals force. Combined with Gaussian calculation and X-ray diffraction (XRD), we established pack patterns for each system, revealing the roles played by rosin and amide groups. Moreover, the carbon tetrachloride gel of DA-2 can effectively remove Congo red in an aqueous solution, and the removal rate can reach 98.4%. This research explores an efficient organic gel for adsorbing Congo red dye with the secretions of pine trees.

Amphotericin B (AMB

Total internal reflection tip-enhanced Raman spectroscopy (TIR-TERS) has recently emerged as a promising technique for noninvasive nanoscale chemical characterization of biomolecules. We demonstrate that the TERS enhancement achieved in this experimental configuration is nearly 30 times higher than that in linear polarization and 8 times higher than that in radial polarization using traditional bottom-illumination geometry. TIR-TERS is applied to the study of Tau amyloid fibrils formed with the human full-length Tau protein mixed with heparin. This technique reveals the possibility to perform TERS imaging with 1-4 nm axial and 5-10 nm lateral spatial optical resolution. In these Tau/heparin fibrils, spectral signatures assigned to aromatic amino acid residues (phenylalanine, histidine, and tyrosine) and nonaromatic ones (e.g., cysteine, lysine, arginine, asparagine, and glutamine) are distinctly observed. Amide I and amide III bands can also be detected. In a fibril portion, it is shown that antiparallel β-sheets and fibril core β-sheets are abundant and are often localized in amino acid-rich regions where parallel β-sheets and random coils are present in lower proportions. This first TIR-TERS study on a nonresonant biological sample paves the way for future nanoscale chemical and structural characterization of biomolecules using this performant and original technique.

An approach to diverse cross-benzoin and α-siloxy ketone products which leverages a simple yet underutilized C-C bond disconnection strategy is reported. Acyl substitution of readily accessible α-siloxy Weinreb amides with organolithium compounds enables access to a broad scope of aryl, heteroaryl, alkyl, alkenyl, and alkynyl derivatives. Enantiopure benzoins can be accessed via a chiral pool approach, and the utility of accessible cross-benzoins and α-siloxy ketones is highlighted in a suite of downstream synthetic applications.

The two RNA-dependent RNA polymerase inhibitors remdesivir and favipiravir were originally developed and approved as broad-spectrum antiviral drugs for the treatment of harmful viral infections such as Ebola and influenza. With the outbreak of the global SARS-CoV-2 pandemic, the two drugs were repurposed for the treatment of COVID-19 patients. Clinical studies suggested that the efficacy of the drugs is enhanced in the case of an early or even prophylactic application. Because the contact between drug molecules and the plasma membrane is essential for a successful permeation process of the substances and therefore for their intracellular efficiency, drug-induced effects on the membrane structure are likely and have already been shown for other substances. We investigated the impact of remdesivir and favipiravir on lipid bilayers in model and cell membranes via several biophysical approaches. The measurements revealed that the embedding of remdesivir molecules in the lipid bilayer results in a disturbance of the membrane structure of the tested phospholipid vesicles. Nevertheless, in a cell-based assay, the presence of remdesivir induced only weak hemolysis of the treated erythrocytes. In contrast, no experimental indication for an effect on the structure and integrity of the membrane was detected in the case of favipiravir. Regarding potential prophylactic or accompanying use of the drugs in the therapy of COVID-19, the physiologically relevant impacts associated with the drug-induced structural modifications of the membrane might be important to understand side effects and/or low effectivities.

The high-temperature cooking of protein-rich foods represents an important but poorly constrained source of nitrogen-containing gases and particles to indoor and outdoor atmospheres. For example, panfrying meat may form and emit these nitrogen-containing compounds through complex chemistry occurring between heated proteins and cooking oils. Here, we simulate this cooking process by heating amino acids together with triglycerides. We explore their interactions across different temperatures, triglyceride types, and amino acid precursors to form amide-containing products. Ammonia, arising from the thermal degradation of amino acids, may react with a triglyceride's ester linkages, forming amides and promoting de-esterification reactions that break the triglyceride into volatilizable products. Additionally, triglycerides may thermally oxidize and fragment as they are heated, and the resulting oxygenated breakdown products may react with ammonia to form amides. We observed evidence for amide formation through both of these pathways, including gas-phase emissions of C

The prebiotic origin of catalyst-controlled peptide synthesis is fundamental to understanding the emergence of life. Building on our recent discovery that thiols catalyze the ligation of amino acids, amides, and peptides with amidonitriles in neutral water, we demonstrate the outcome of ligation depends on pH and that high p

A novel process is described for the synthesis of di- and trisubstituted cyclohexenes from an arene. These compounds are prepared from three independent nucleophilic addition reactions to a phenyl sulfone (PhSO(2)R; R = Me, Ph, NC(4)H(8)) dihapto-coordinated to the tungsten complex {WTp(NO)(PMe(3))}(Tp = trispyrazolylborate). Such coordination renders the dearomatized aryl ring susceptible to protonation at a carbon ortho to the sulfone group. The resulting arenium species readily reacts with the first nucleophile to form a dihapto-coordinated sulfonylated diene complex. This complex can again be protonated, and subsequent nucleophilic addition forms a trisubstituted cyclohexene species bearing a sulfonyl group at an allylic position. Loss of the sulfinate anion forms a π-allyl species, to which a third nucleophile can be added. The trisubstituted cyclohexene can then be oxidatively decomplexed, either before or after substitution of the sulfonyl group. Nucleophiles employed include masked enolates, cyanide, amines, amides, and hydride, with all three additions occurring to the same face of the ring, anti to the metal. Of the twelve novel functionalized cyclohexenes prepared as examples of this methodology, nine compounds meet five independent criteria for evaluating drug likeliness. Structural assignments are supported with nine crystal structures, DFT studies, and full 2D NMR analysis.

The application of agrochemicals is critical to global food safety. Nowadays, environmentally friendly green agrochemicals are the trend in field crop protection. The research and development of nematicides absorbed more attention as a typical representation of agrochemicals. This review describes the origin of recently commercialized nematicides, the application of bioisosterism and scaffold hopping in the discovery and optimization of agrochemicals, especially nematicides, and novel bioisosteric design strategies for the identification of fluensulfone analogues. Pesticide repurposing, high-throughput screening, computer-aided drug design, and incorporation of known pharmacophoric fragments have been the most successful approach for the discovery of new nematicides. As outlined, the strategies of bioisosteric replacements and scaffold hopping have been very successful approaches in the search for new nematicides for sustainable crop protection. In the exploration of novel fluensulfone analogues with nematicidal activity, bioisosteric replacement of sulfone by amide, chain extension by insertion of a methylene group, and reversal of the amide group have proven to be successful approaches and yielded new and highly active fluensulfone analogues. These attempts might result in compounds with an optimal balance of steric, hydrophobic, electronic, and hydrogen-bonding properties and contribute to deal with the complex problem during the research and development of new nematicides. Further ideas are also put forward to provide new approaches for the molecular design of nematicides.

Thionyl fluoride (SOF

Functionalized azetidines, 2,3-dihydrofurans, or the unorthodox dioxa-3-azabicyclonone-4-ene motifs are the products from transition metal-free reaction between

Biodegradable and biocompatible biomaterials have offered much more opportunities from an engineering standpoint for treating diseases and maintaining health. Poly(ester amide)s (PEAs), as an outstanding family among such biomaterials, have risen overwhelmingly in the past decades. These synthetic polymers have easily and widely available raw materials and a diversity of synthetic approaches, which have attracted considerable attention. More importantly, combining the superiorities of polyamides and polyesters, PEAs have emerged with better functions. They could have improved biodegradability, biocompatibility, and cell-material interactions. The PEAs derived from α-amino acids even allow the introduction of pendant sites for further modification or functionalization. Meanwhile, it is gradually recognized that the chemical structures are closely related to the physiochemical and biological properties of PEAs so that their properties can be precisely controlled. PEAs therefore become significant materials in the biomedical fields. This review will attempt to summarize the recent progress in the development of PEAs with respect to the preparation materials and methods, structure-property relationships along with their latest biomedical accomplishments, especially for drug delivery and tissue engineering.

The development of an asymmetric protocol for the reductive alkynylation of amides to access important α-stereogenic tertiary propargylic amines is reported using a tandem Ir-catalyzed hydrosilylation/enantioselective Cu-catalyzed alkynylation. The reaction utilizes a Cu/PyBox catalyst system in the alkynylation step to achieve asymmetry and affords excellent yields with moderate to good levels of enantiocontrol while employing low Ir-catalyst loadings (0.5 mol %).

Emissions of NH

NMR relaxation analysis of the mobile residues in globular proteins is sensitive to the form of the experimentally fitted internal autocorrelation function, which is used to represent that motion. Different order parameter representations can precisely fit the same set of

Translation according to the genetic code is made possible by selectivity both in aminoacylation of tRNA and in anticodon:codon recognition. In extant biology, tRNAs are selectively aminoacylated by enzymes using high-energy intermediates, but how this might have been achieved prior to the advent of protein synthesis has been a largely unanswered question in prebiotic chemistry. We have now elucidated a novel, prebiotically plausible stereoselective aminoacyl-RNA synthesis which starts from RNA-amino acid phosphoramidates and proceeds via phosphoramidate-ester intermediates which subsequently undergo conversion to aminoacyl-esters by mild acid hydrolysis. The chemistry avoids the intermediacy of high-energy mixed carboxy-phosphate anhydrides and is greatly favored under eutectic conditions, which also potentially allow for the requisite pH fluctuation through the variable solubility of CO2 in solid/liquid water.

The development of CRISPR-Cas9 mediated gene editing technology is revolutionizing molecular biology, biotechnology, and medicine. However, as with other nucleic acid technologies, CRISPR would greatly benefit from chemical modifications that optimize delivery, activity, and specificity of gene editing. Amide modifications at certain positions of short interfering RNAs have been previously shown to improve their RNAi activity and specificity, which motivated the current study on replacement of selected internucleoside phosphates of CRISPR RNAs with amide linkages. Herein, we show that amide modifications did not interfere with CRISPR-Cas9 activity when placed in the protospacer adjacent motif (PAM) distal region of CRISPR RNAs. In contrast, modification of the seed region led to a loss of DNA cleavage activity at most but not all positions. These results are encouraging for future studies on amides as backbone modifications in CRISPR RNAs.

Peptides are fundamental therapeutic modalities whose sequence-specific synthesis can be automated. Yet, modern peptide synthesis remains atom uneconomical and requires an excess of coupling agents and protected amino acids for efficient amide bond formation. We recently described the rational design of an organocatalyst that can operate on Fmoc amino acids─the standard monomers in automated peptide synthesis (

Adaptor protein 2-associated kinase 1 (AAK1) is a serine/threonine kinase that was identified as a therapeutic target for the potential treatment of neuropathic pain. Inhibition of AAK1 in the central nervous system, particularly within the spinal cord, was found to be the relevant site for achieving an antinociceptive effect. We previously reported that compound

alpha-Amino acid based polyester amides (PEAs) are promising candidates for additive manufacturing (AM), as they unite the flexibility and degradability of polyesters and good thermomechanical properties of polyamides in one structure. Introducing alpha-amino acids in the PEA structure brings additional advantages such as (i) good cytocompatibility and biodegradability, (ii) providing strong amide bonds, enhancing the hydrogen bonding network, (iii) the introduction of pendant reactive functional groups, and (iv) providing good cell-polymer interactions. However, the application of alpha-amino acid based PEAs for AM via fused deposition modeling (FDM), an important manufacturing technique with unique processing characteristics and requirements, is still lacking. With the aim to exploit the combination of these advantages in the creation, design, and function of additively manufactured scaffolds using FDM, we report the structure-function relationship of a series of alpha-amino acid based PEAs. The PEAs with three different molecular weights were synthesized via the active solution polycondensation, and their performance for AM applications was studied in comparison with a commercial biomedical grade copolymer of L-lactide and glycolide (PLGA). The PEAs, in addition to good thermal stability, showed semicrystalline behavior with proper mechanical properties, which were different depending on their molecular weight and crystallinity. They showed more ductility due to their lower glass transition temperature (T-g; 18-20 & DEG;C) compared with PLGA (57 & DEG;C). The rheology studies revealed that the end-capping of PEAs is of high importance for preventing cross-linking and further polymerization during the melt extrusion and for the steadiness and reproducibility of FDM. Furthermore, our data regarding the steady 3D printing performance, good polymer-cell interactions, and low cytotoxicity suggest that alpha-amino acid based PEAs can be introduced as favorable polymers for future AM applications in tissue engineering. In addition, their ability for formation of bonelike apatite in the simulated body fluid (SBF) indicates their potential for bone tissue engineering applications.