Diversifying Amino Acids and Peptides via Deaminative Reductive Cross-Couplings Leveraging High-Throughput Experimentation.

A deaminative reductive coupling of amino acid pyridinium salts with aryl bromides has been developed to enable efficient synthesis of noncanonical amino acids and diversification of peptides. This method transforms natural, commercially available lysine, ornithine, diaminobutanoic acid, and diaminopropanoic acid to aryl alanines and homologated derivatives with varying chain lengths. Attractive features include ability to transverse scales, tolerance of pharma-relevant (hetero)aryls and biorthogonal functional groups, and the applicability beyond monomeric amino acids to short and macrocyclic peptide substrates. The success of this work relied on high-throughput experimentation to identify complementary reaction conditions that proved critical for achieving the coupling of a broad scope of aryl bromides with a range of amino acid and peptide substrates including macrocyclic peptides.

The construction of garlic diallyl disulfide nano-emulsions and their effect on the physicochemical properties and heterocyclic aromatic amines formation in roasted pork.

Garlic diallyl disulfide (DAD) nano-emulsions consisting of soy proteins were constructed, and their effects on physicochemical properties and heterocyclic aromatic amines (HAAs) formation in roasted pork were investigated. DAD was well encapsulated by soy proteins with a mean particle of 400-700 nm. Applying DAD nano-emulsions to pork patties significantly altered the color and texture of roasted pork, with a slight increase in brightness and decreases in redness and yellowness. The flavor determination demonstrated that sulfur-containing compound levels in encapsulated DAD were significantly reduced, particularly 7S group compounds, indicating an effective shielding effect on the irritating odor of garlic oil by protein. The levels of three HAAs (MeIQx, PhIP, and Harman) were significantly reduced by DAD nano-emulsion exposure (51.84 %, 76.80 %, and 48.70 %, respectively). This study provides a new method for inhibiting HAA formation and improving the sensory qualities of meat products.

Remote and Proximal Hydroaminoalkylation of Alkenes Enabled by Photoredox/Nickel Dual Catalysis.

A mild and site-selective hydroaminoalkylation of activated and unactivated alkenes via dual photoredox/Ni catalysis is developed. This dual catalytic strategy enables exclusive access to α-selective products, which is complementary to previously reported photocatalytic hydroaminoalkylation of activated alkenes that provides the ß-selective products. The chain-walking of a Ni-H intermediate toward a carbonyl allows for the hydroaminoalkylation of unactivated alkenes at remote sp3 C-H sites. This method tolerates a broad substrate scope of both amines and alkenes as well as providing a streamlined synthesis of value-added ß-amino acid derivatives from readily available starting materials.

Design and synthesis of novel nitrothiazolacetamide conjugated to different thioquinazolinone derivatives as anti-urease agents.

The present article describes the design, synthesis, in vitro urease inhibition, and in silico molecular docking studies of a novel series of nitrothiazolacetamide conjugated to different thioquinazolinones. Fourteen nitrothiazolacetamide bearing thioquinazolinones derivatives (8a-n) were synthesized through the reaction of isatoic anhydride with different amine, followed by reaction with carbon disulfide and KOH in ethanol. The intermediates were then converted into final products by treating them with 2-chloro-N-(5-nitrothiazol-2-yl)acetamide in DMF. All derivatives were then characterized through different spectroscopic techniques (1H, 13C-NMR, MS, and FTIR). In vitro screening of these molecules against urease demonstrated the potent urease inhibitory potential of derivatives with IC50 values ranging between 2.22 ± 0.09 and 8.43 ± 0.61 µM when compared with the standard thiourea (IC50 = 22.50 ± 0.44 µM). Compound 8h as the most potent derivative exhibited an uncompetitive inhibition pattern against urease in the kinetic study. The high anti-ureolytic activity of 8h was confirmed against two urease-positive microorganisms. According to molecular docking study, 8h exhibited several hydrophobic interactions with Lys10, Leu11, Met44, Ala47, Ala85, Phe87, and Pro88 residues plus two hydrogen bound interactions with Thr86. According to the in silico assessment, the ADME-Toxicity and drug-likeness profile of synthesized compounds were in the acceptable range.

Secondary Amine Pendant ß-Peptide Polymers Displaying Potent Antibacterial Activity and Promising Therapeutic Potential in Treating MRSA-Induced Wound Infections and Keratitis.

Interest in developing antibacterial polymers as synthetic mimics of host defense peptides (HPDs) has accelerated in recent years to combat antibiotic-resistant bacterial infections. Positively charged moieties are critical in defining the antibacterial activity and eukaryotic toxicity of HDP mimics. Most examples have utilized primary amines or guanidines as the source of positively charged moieties, inspired by the lysine and arginine residues in HDPs. Here, we explore the impact of amine group variation (primary, secondary, or tertiary amine) on the antibacterial performance of HDP-mimicking ß-peptide polymers. Our studies show that a secondary ammonium is superior to either a primary ammonium or a tertiary ammonium as the cationic moiety in antibacterial ß-peptide polymers. The optimal polymer, a homopolymer bearing secondary amino groups, displays potent antibacterial activity and the highest selectivity (low hemolysis and cytotoxicity). The optimal polymer displays potent activity against antibiotic-resistant bacteria and high therapeutic efficacy in treating MRSA-induced wound infections and keratitis as well as low acute dermal toxicity and low corneal epithelial cytotoxicity. This work suggests that secondary amines may be broadly useful in the design of antibacterial polymers.

Effect of olive leaf extract marination on heterocyclic aromatic amine formation in pan-fried salmon.

BACKGROUND: In this study, the reducing effects of varying levels of olive leaf extract (0%, 0.25%, 0.5%, 1% and 2%) on the formation of heterocyclic aromatic amines (HAAs) in pan-cooked salmon at 180 and 220 °C were examined. RESULTS: All salmon samples were analyzed for ten HAAs: IQx, IQ, MeIQx, MeIQ, 4,8-DiMeIQx, 7,8-DiMeIQx, PhIP, AαC, MeAαC and Trp-P-2. The most abundant HAA was MeIQ (≤2.98 ng g-1 ) followed by Trp-P-2 (≤2.40 ng g-1 ), MeIQx (≤0.83 ng g-1 ), IQ (≤0.41 ng g-1 ), 7,8-DiMeIQx (≤0.29 ng g-1 ), 4,8-DiMeIQx (≤0.16 ng g-1 ) and IQx (≤0.06 ng g-1 ). However, PhIP, AαC and MeAαC were undetectable in all samples. In the control samples, HAAs were found at levels ranging from not detected to 2.40 ng g-1 . Total HAA content was between 0.81 and 4.03 ng g-1 . The olive leaf extracts reduced the total HAA levels at all certain concentration levels at 180 °C and the reducing effects were found to be 32.78-77.69%. CONCLUSION: The current study displayed that olive leaf extracts could be efficient when added in up to 1% concentration prior to cooking for reducing HAA formation without changing organoleptic characteristics of salmon. © 2021 Society of Chemical Industry.

The effect of onion and garlic on non-polar heterocyclic aromatic amines (α-, ß-, γ- and δ-carbolines) formation in pan-fried meat and gravy.

Thermal treatment of protein-rich food can lead to the formation of biologically active heterocyclic aromatic amines (HAAs). One of the methods to learn how to reduce the content as well as the influence of these compounds on heath is the study of factors inhibiting their synthesis. In the current investigation, the effect of onion and garlic on the formation of six possibly carcinogenic non-polar HAAs (α-, γ- and δ-carbolines) and two co-mutagenic ß-carbolines (harmane and norharmane) was evaluated by comparing their contents in meat and gravy samples obtained from pan-fried pork dishes prepared in the presence and absence of these vegetables. Carbolines were isolated from food samples by solid phase extraction. The quantitative analysis was performed by high-performance liquid chromatography with fluorescence detection. The concentrations of individual compounds in dishes prepared without added vegetables ranged from 0.02 ng g-1 (3-amino-1,4-dimethyl-5 H-pyrido(4,3-b)indole; Trp-P-1) to 10.1 ng g-1 of meat (2-amino-9 H-pyrido[2,3-b]indole; AαC). Onion (30 g/100 g of meat) and garlic (15 g/100 g of meat) lowered the total content (in meat and gravy) of the α-, δ- and γ-carbolines in the range from 52% to 87%. In contrast, onion caused an increase in the norharmane concentration both in meat and gravy. The percentage of carbolines in the gravies (assuming that their total content in meat and gravy is 100%) was higher in dishes prepared with onion and garlic than in dishes without these seasonings.

Ab initio simulations of black and blue phosphorene functionalised with chemical groups for biomolecule anchoring.

Black and blue phosphorene (2D-dimensional allotropes of phosphorus) have shown fascinating electronic, optical, and magnetic properties, with promising technological applications. In this work, we studied the adsorption of amine, hydroxyl, amide, and carboxyl groups onto both black and blue phosphorenes, in order to analyse the effects of biomolecule anchoring on the structural and electronic properties of phosphenes, using density functional simulations. Analyses were carried out of six different configurations for each chemical group functionalised on black and blue phosphorene. We observed that the radicals interacted via a chemisorption regime with the nanostructures, with binding energies that varied from 1.42 to 3.78 eV. The electronic properties showed that the presence of the chemical groups altered the energy gaps for both black and blue phosphorenes, due to a presence of a half-filled level when a single radical was adsorbed. We were able to observe that functionalised two-dimensional phosphorene showed promising characteristics in terms of anchoring molecules, and particularly those of biological interest, due to its high surface area, strong coupling between phosphorene and chemical groups, and the possibility of chemically manipulating radicals.

Soybean-Oil-Based CO2-Switchable Surfactants with Multiple Heads.

Oligomeric surfactants display the novel properties of low surface activity, low critical micellar concentration and enhanced viscosity, but no CO2 switchable oligomeric surfactants have been developed so far. The introduction of CO2 can convert tertiary amine reversibly to quaternary ammonium salt, which causes switchable surface activity. In this study, epoxidized soybean oil was selected as a raw material to synthesize a CO2-responsive oligomeric surfactant. After addition and removal of CO2, the conductivity analyzing proves that the oligomeric surfactant had a good response to CO2 stimulation. The viscosity of the oligomeric surfactant solution increased obviously after sparging CO2, but returned to its initial low viscosity in the absence of CO2. This work is expected to open a new window for the study of bio-based CO2-stimulated oligomeric surfactants.

In silico, theoretical biointerface analysis and in vitro kinetic analysis of amine compounds interaction with acetylcholinesterase and butyrylcholinesterase.

Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are considered important target for drug design against Alzheimer's disease. In the present study in silico analysis; theoretical analysis of biointerface between ligand and interacting amino acid residues of proteins; and in vitro analysis of enzyme inhibition kinetics were carried out to delineate the inhibitory property of amine compounds against AChE/BChE. High throughput virtual screening of amine compounds identified three compounds (2-aminoquinoline, 2-aminobenzimidazole and 2-amino-1-methylbenzimidazole) that best interacted with AChE/BChE. Molecular docking analysis revealed the interaction of these compounds in the active site gorge of AChE/BChE, in particular with amino acid residues present in the peripheral anionic site. Molecular dynamics simulation confirmed the stable binding of these compounds with AChE/BChE. Binding energy calculated through MMGBSA method identified the non-covalent interactions (electrostatic and Van der Waals interactions) have contributed to the stable binding of the amine compounds with the AChE/BChE. Biointerface between amine compounds and AChE/BChE were visualized through Hirshfeld surface analysis. The inter-fragment interaction energies for the possible contacts between amine compounds and amino acid residues were carried out for the first time. All the amine compounds showed mixed-type of inhibition with moderate Ki value in in vitro analysis.

Mediator-Enabled Electrocatalysis with Ligandless Copper for Anaerobic Chan-Lam Coupling Reactions.

Simple copper salts serve as catalysts to effect C-X bond-forming reactions in some of the most utilized transformations in synthesis, including the oxidative coupling of aryl boronic acids and amines. However, these Chan-Lam coupling reactions have historically relied on chemical oxidants that limit their applicability beyond small-scale synthesis. Despite the success of replacing strong chemical oxidants with electrochemistry for a variety of metal-catalyzed processes, electrooxidative reactions with ligandless copper catalysts are plagued by slow electron-transfer kinetics, irreversible copper plating, and competitive substrate oxidation. Herein, we report the implementation of substoichiometric quantities of redox mediators to address limitations to Cu-catalyzed electrosynthesis. Mechanistic studies reveal that mediators serve multiple roles by (i) rapidly oxidizing low-valent Cu intermediates, (ii) stripping Cu metal from the cathode to regenerate the catalyst and reveal the active Pt surface for proton reduction, and (iii) providing anodic overcharge protection to prevent substrate oxidation. This strategy is applied to Chan-Lam coupling of aryl-, heteroaryl-, and alkylamines with arylboronic acids in the absence of chemical oxidants. Couplings under these electrochemical conditions occur with higher yields and shorter reaction times than conventional reactions in air and provide complementary substrate reactivity.

Bio-based Poly(hydroxy urethane)s: Synthesis and Pre/Post-Functionalization.

New and emerging demand for polyurethane (PU) continues to rise over the years. The harmful isocyanate binding agents and their integrated PU products are at the height of environmental concerns, in particular PU (macro and micro) pollution and their degradation problems. Non-isocyanate poly(hydroxy urethane)s (NIPUs) are sustainable and green alternatives to conventional PUs. Since the introduction of NIPU in 1957, the market value of NIPU and its hybridized materials has increased exponentially in 2019 and is expected to continue to rise in the coming years. The secondary hydroxyl groups of these NIPU's urethane moiety have revolutionized them by allowing for adequate pre/post functionalization. This minireview highlights different strategies and advances in pre/post-functionalization used in biobased NIPU. We have performed a comprehensive evaluation of the development of new ideas in this field to achieve more efficient synthetic biobased hybridized NIPU processes through selective and kinetic understanding.

The Formation of Methyl Ketones during Lipid Oxidation at Elevated Temperatures.

Lipid oxidation and the resulting volatile organic compounds are the main reasons for a loss of food quality. In addition to typical compounds, such as alkanes, aldehydes and alcohols, methyl ketones like heptan-2-one, are repeatedly described as aroma-active substances in various foods. However, it is not yet clear from which precursors methyl ketones are formed and what influence amino compounds have on the formation mechanism. In this study, the formation of methyl ketones in selected food-relevant fats and oils, as well as in model systems with linoleic acid or pure secondary degradation products (alka-2,4-dienals, alken-2-als, hexanal, and 2-butyloct-2-enal), has been investigated. Elevated temperatures were chosen for simulating processing conditions such as baking, frying, or deep-frying. Up to seven methyl ketones in milk fat, vegetable oils, and selected model systems have been determined using static headspace gas chromatography-mass spectrometry (GC-MS). This study showed that methyl ketones are tertiary lipid oxidation products, as they are derived from secondary degradation products such as deca-2,4-dienal and oct-2-enal. The study further showed that the position of the double bond in the precursor compound determines the chain length of the methyl ketone and that amino compounds promote the formation of methyl ketones to a different degree. These compounds influence the profile of the products formed. As food naturally contains lipids as well as amino compounds, the proposed pathways are relevant for the formation of aroma-active methyl ketones in food.

Fabrication of New Demulsifiers Employing the Waste Polyethylene Terephthalate and their Demulsification Efficiency for Heavy Crude Oil Emulsions.

Two novel amphiphilic polyethylene amine terephthalate have been prepared via the glycolsis of polyethylene terephthalate (PET). The product, bis (2-hydroxyethyl terephthalate) (BHET), was converted to the corresponding dialkyl halide, bis(2-chloroethyl) terephthalate (BCET), using thionyl chloride (TC). This dialkyl compound was used for alkylation of dodecyl amine (DOA) and tetraethylenepentamine (TEPA) or pentaethylenehexamine (PEHA) to form the corresponding polyethylene amine terephthalate, i.e., DOAT and DOAP, respectively. Their chemical structure, surface tension, interfacial tension (IFT), and dynamic light scattering (DLS) were determined using different techniques. The efficiency of the prepared polyethylene amine terephthalate to demulsify water in heavy crude (W/O) emulsions was also determined and found to increase as their concentrations increased. Moreover, DOAT showed faster and higher efficiency, and cleaner separation than DOAP.

Synthesis and Antioxidant Activity of New Selenium-Containing Quinolines.

BACKGROUND: Quinoline derivatives have been attracted much attention in drug discovery, and synthetic derivatives of these scaffolds present a range of pharmacological activities. Therefore, organoselenium compounds are valuable scaffolds in organic synthesis because of their pharmacological activities and their use as versatile building blocks for regio-, chemo-and stereoselective reactions. Thus, the synthesis of selenium-containing quinolines has great significance, and their applicability range from simple antioxidant agents, to selective DNA-binding and photocleaving agents. OBJECTIVE: In the present study, we describe the synthesis and antioxidant activity in vitro of new 7- chloro-N(arylselanyl)quinolin-4-amines 5 by the reaction of 4,7-dichloroquinoline 4 with (arylselanyl)- amines 3. METHODS: For the synthesis of 7-chloro-N(arylselanyl)quinolin-4-amines 5, we performed the reaction of (arylselanyl)-amines 3 with 4,7-dichloroquinoline 4 in the presence of Et3N at 120 °C in a sealed tube. The antioxidant activities of the compounds 5 were evaluated by the following in vitro assays: 2,2- diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity, 2,2-azinobis-3- ethylbenzothiazoline-6-sulfonic acid (ABTS), ferric ion reducing antioxidant power (FRAP), nitric oxide (NO) scavenging and superoxide dismutase-like activity (SOD-Like). RESULTS: 7-Chloro-N(arylselanyl)quinolin-4-amines 5a-d have been synthesized in yields ranging from 68% to 82% by the reaction of 4,7-dichloroquinoline 4 with arylselanyl-amines 3a-d using Et3N as a base, at 120 °C, in a sealed tube for 24 hours and tolerates different substituents, such as -OMe and -Cl, in the arylselanyl moiety. The obtained compounds 5a-d presented significant results concerning the antioxidant potential, which had an effect in the tests of inhibition of radical's DPPH, ABTS+ and NO, as well as in the analysis that evaluates the capacity (FRAP) and in the superoxide dismutase-like activity assay (SOD-Like). It is worth mentioning that 7-chloro- N(arylselanyl)quinolin-4-amine 5b presented excellent results, demonstrating a better antioxidant capacity when compared to the others. CONCLUSION: According to the obtained results, 7-chloro-N(arylselanyl)quinolin-4-amines 5 were synthesized in good yields by the reaction of 4,7-dichloroquinoline with arylselanyl-amines and tolerated different substituents in the arylselanyl moiety. The tested compounds presented significant antioxidant potential in the tests of inhibition of DPPH, ABTS+, and NO radicals, as well as in the FRAP and superoxide dismutase-like activity assays (SOD-Like).

Exploring the relationship between potato components and Maillard reaction derivative harmful products using multivariate statistical analysis.

The correlation between potato components and Maillard reaction derivative harmful products (MRDHPs) formation during heat-processing was assessed in nine commercial potato varieties in China. Principal component analysis (PCA) combined with canonical correlation analysis (CCA) approach was performed to explore their relationships. The variables contributing most to the PCA results were extracted for CCA, and the results indicated that several amino acids, including lysine, tryptophan, alanine, phenylalanine, aspartate, and glutamate, have significant impacts on acrylamide and ß-carboline heterocyclic amine formation. Moreover, 5-O-caffeoylquinic acid, 3-O-caffeoylquinic acid, α-solanine, and α-chaconine were also important factors associated with acrylamide and ß-carboline heterocyclic amine formation. Optimally using raw potato varieties based on the impacts of these factors can help control MRDHP formation during thermal processing. For the first time, such approach was applied, which may be a useful tool for discovering the correlation of food components and MRDHPs.

A non-perturbative pairwise-additive analysis of charge transfer contributions to intermolecular interaction energies.

Energy decomposition analysis (EDA) based on absolutely localized molecular orbitals (ALMOs) decomposes the interaction energy between molecules into physically interpretable components like geometry distortion, frozen interactions, polarization, and charge transfer (CT, also sometimes called charge delocalization) interactions. In this work, a numerically exact scheme to decompose the CT interaction energy into pairwise additive terms is introduced for the ALMO-EDA using density functional theory. Unlike perturbative pairwise charge-decomposition analysis, the new approach does not break down for strongly interacting systems, or show significant exchange-correlation functional dependence in the decomposed energy components. Both the energy lowering and the charge flow associated with CT can be decomposed. Complementary occupied-virtual orbital pairs (COVPs) that capture the dominant donor and acceptor CT orbitals are obtained for the new decomposition. It is applied to systems with different types of interactions including DNA base-pairs, borane-ammonia adducts, and transition metal hexacarbonyls. While consistent with most existing understanding of the nature of CT in these systems, the results also reveal some new insights into the origin of trends in donor-acceptor interactions.

Selective separation of hibiscus acid from Roselle extracts by an amino-functionalized Metal Organic Framework.

The separation and purification of biologically-active compounds from natural sources is of interest because such molecules find wide application in the pharmaceutical sector and in other industrial areas. Roselle (Hibiscus sabdariffa) plants are a good source of anthocyanins, flavonoids, hydroxycitric acid, tartaric acid, ascorbic acid and hibiscus acid. The separation of hibiscus acid from the Roselle extract is very challenging, requiring the use of selective methods. It is accomplished here by means of the indium-bearing Metal Organic Framework MIL-68-NH2. Before and after exposure to MIL-68-NH2, the Roselle extract is analyzed by thin-layer chromatography, ultraviolet-visible spectrophotometry, gas chromatography-mass spectrometry, and high-performance liquid chromatography. The structural integrity of MIL-68-NH2 after the separations is investigated by powder X-ray diffraction, nuclear magnetic resonance and infrared spectroscopy, confirming the adsorption selectivity of MIL-68-NH2 towards hibiscus acid.

Discovery of the Potent, Selective, Orally Available CXCR7 Antagonist ACT-1004-1239.

The chemokine receptor CXCR7, also known as ACKR3, is a seven-transmembrane G-protein-coupled receptor (GPCR) involved in various pathologies such as neurological diseases, autoimmune diseases, and cancers. By binding and scavenging the chemokines CXCL11 and CXCL12, CXCR7 regulates their extracellular levels. From an original high-throughput screening campaign emerged hit 3 among others. The hit-to-lead optimization led to the discovery of a novel chemotype series exemplified by the trans racemic compound 11i. This series provided CXCR7 antagonists that block CXCL11- and CXCL12-induced ß-arrestin recruitment. Further structural modifications on the trisubstituted piperidine scaffold of 11i yielded compounds with high CXCR7 antagonistic activities and balanced ADMET properties. The effort described herein culminated in the discovery of ACT-1004-1239 (28f). Biological characterization of ACT-1004-1239 demonstrated that it is a potent, insurmountable antagonist. Oral administration of ACT-1004-1239 in mice up to 100 mg/kg led to a dose-dependent increase of plasma CXCL12 concentration.

Divergent Synthesis of γ-Amino Acid and γ-Lactam Derivatives from meso-Glutaric Anhydrides.

The first divergent synthesis of both γ-amino acid and γ-lactam derivatives from meso-glutaric anhydrides is described. The organocatalytic desymmetrisation with TMSN3 relies on controlled generation of a nucleophilic ammonium azide species mediated by a polystyrene-bound base to promote efficient silylazidation. After Curtius rearrangement of the acyl azide intermediate to access the corresponding isocyanate, hydrolysis/alcoholysis provided uniformly high yields of γ-amino acids and their N-protected counterparts. The same intermediates were shown to undergo an unprecedented decarboxylation-cyclisation cascade in situ to provide synthetically useful yields of γ-lactam derivatives without using any further activating agents. Mechanistic insights invoke the intermediacy of an unconventional γ-N-carboxyanhydride (γ-NCA) in the latter process. Among the examples prepared using this transformation are 8 APIs/molecules of considerable medicinal interest.