Positions C3 Research Articles

Direct C4 and C2 C-H Amination of Heteroarenes Using I(III) Reagents via a Cross Azine Coupling.

Aminated nitrogen heterocycles are valuable motifs across numerous chemical industries, perhaps most notably in small molecule drug discovery. While numerous strategies for installing nitrogen atoms onto azaarenes exist, most require prefunctionalization and methods for direct C-H amination are almost entirely limited to position C2. Herein, we report a method for the direct C2 and C4 C-H amination of fused azaarenes via in situ activation with a bispyridine-ligated I(III) reagent, [(Py)2IPh]2OTf, or Py-HVI. Unlike commonly used N-oxide chemistry, the method requires no preoxidation of the azaarene and provides unprecedented direct access to C4 amination products. The resulting N-heterocyclic pyridinium salts can be isolated via simple trituration. The free amine can be liberated under mild Zincke aminolysis, or the amination and cleavage can be telescoped to a one-pot process. The scope of the method is broad; the conditions are mild and operationally simple, and the aminated products are produced in good to excellent yields. Computational studies provide insights into the mechanism of activation, which involves an unusual direct nucleophilic functionalization of an I(III) ligand, as well as a kinetic basis for the observed C2 and C4 amination products.

Flavonoid as a Potent Antioxidant: Quantitative Structure-Activity Relationship Analysis, Mechanism Study, and Molecular Design by Synergizing Molecular Simulation and Machine Learning.

In this work, a quantitative structure-antioxidant activity relationship of flavonoids was performed using a machine learning (ML) method. To achieve lipid-soluble, highly antioxidant flavonoids, 398 molecular structures with various substitute groups were designed based on the flavonoid skeleton. The hydrogen dissociation energies (ΔG1, ΔG2, and ΔG3) related to multiple hydrogen atom transfer processes and the solubility parameter (δ) of flavonoids were calculated using molecular simulation. The group decomposition results and the calculated antioxidant parameters constituted the ML data set. The artificial neural network and random forest models were constructed to predict and analyze the contribution of the substitute groups and positions to the antioxidant activity. The results showed the hydroxyl group at positions B4', B5', and B6' and the branched alkyl group at position C3 in the flavonoid skeleton were the optimal choice for improving antioxidant activity and compatibility with apolar organic materials. Compared to the pyrogallol group-grafted flavonoid, the designed potent flavonoid decreased ΔG1 and δ by 2.2 and 15.1%, respectively, while ΔG2 and ΔG3 kept the favorable lower values. These findings suggest that an efficient flavonoid prefers multiple ortho-phenolic hydroxyl groups and suitable sites with hydrophobic groups. The combination of molecular simulation and the ML method may offer a new research approach for the molecular design of novel antioxidants.

Investigation of using amine and acetylamine functional units on naphthalimide dyes for photovoltaic devices

Purpose The purpose of this paper is to introduce four new organic dyes based on naphthalimide for dye-sensitized solar cells (DSSCs). Design/methodology/approach Four new dyes based on naphthalimide with substitutions of amine and acetylamine in position C4 were designed in conjugation with substituted carbazole as donor–acceptor (D-A) architecture. The absorption and emission characteristics of the prepared dyes were evaluated in H2O, DMF and their mixture (DMF:H2O = 1:1). The feasibility of electron transfer in the DSSCs structure and energy levels were evaluated using electrochemical and density functional theory, which confirm the use of dyes in the DSSCs structure. The DSSCs were prepared using an individual strategy and their optical properties were investigated under the light of AM 1.5. Findings The prepared dyes exhibit orange color with strong emission at λem = 530–570 nm due to charge transfer with a positive solvatochromic effect. The efficiency of DSSCs based on Dye1-4 1 is: 3.69%, 3.71%, 4.69% and 4.76%. Therefore, the power efficiency increases by about 29 % in the presence of acetylamine group. Practical implications The design of new structures of organic dyes should be accompanied by the development of optical and electrical properties. In other words, in addition to the continuous production of electrons, efficient dyes must also be resistant to light to increase the life of the device. Social implications Organic dyes play a key role in the production of electrons in the DSSCs structure. The engineering of these structures and the introduction of widely used but low cost types can play an important role in the development of clean energy production. Originality/value The application of organic dyes based on naphthalimide was evaluated in the DSSCs structure and its photovoltaic properties were investigated.

Synthetic Modification and Insecticidal Activity of 4-epi-cis-Dihydroagarofuran Derivatives.

To synthesize the fundamental framework of dihydroagarofuran, a novel strategy was devised for constructing the C-ring through a dearomatization reaction using 6-methoxy-1-tetralone as the initial substrate. Subsequently, the dihydroagarofuran skeleton was assembled via two consecutive Michael addition reactions. The conjugated diene and trans-dihydroagarofuran skeleton were modified. The insecticidal activities of 33 compounds against Mythimna separata were evaluated. Compounds 11-5 exhibited an LC50 value of 0.378 mg/mL. The activity exhibited a remarkable 29-fold increase compared to positive control Celangulin V, which was widely recognized as the most renowned natural dihydroagarofuran polyol ester insecticidal active compound. Docking experiments between synthetic compounds and target proteins revealed the shared binding sites with Celangulin V. Structure-activity relationship studies indicated that methyl groups at positions C4 and C10 significantly improved insecticidal activity, while ether groups with linear chains displayed enhanced activity; in particular, the allyl ether group demonstrated optimal efficacy. Furthermore, a three-dimensional quantitative structure-activity relationship model was established to investigate the correlation between the skeletal structure and activity. These research findings provide valuable insights for discovering and developing dihydroagarofuran-like compounds.

Fucoidan modulates gut microbiota and immunity in Peyer's patches against inflammatory bowel disease

Although fucoidan has potential use as an anti-inflammatory agent, the specific mechanisms by which it influences signaling and immunomodulatory pathways between gut microbiota and Peyer's patches remain unclear. Therefore, the aim of this study was to investigate the therapeutic potential of fucoidan in a dextran sulfate sodium (DSS)-induced mouse model of inflammatory bowel disease (IBD) by examining the effects on gut microbiota and the underlying anti-inflammatory mechanisms. Purified fucoidan, which upon characterization revealed structural fragments comprising →3)-β-D-Galp-(1→, →4)-α-L-Fucp-(1→, and →3)-α-L-Fucp-(1→ residues with a sulfation at position C2 was used. Treatment of the mice with fucoidan significantly alleviated the symptoms of IBD and restored the diversity of gut microbiota by enhancing the abundance of Bacteroidetes and reducing the proportion of Firmicutes. The administration of fucoidan also elevated levels of short-chain fatty acids while reducing the levels of pro-inflammatory cytokines, including interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ. Most importantly, fucoidan attenuated the expression of integrin α4β7/MAdCAM-1 and CCL25/CCR9, which are involved in homing intestinal lymphocytes within Peyer's patches. These findings indicate that fucoidan is a promising gut microbiota modulator and an anti-inflammatory agent for IBD.

Structural and electronic properties of 1,10-phenantroline derivatives in complex with Sm, Gd and Tm lanthanides: Insights from calculations

In the present work, outcomes from a density functional theory investigation on the effect of lanthanides (Lns)-containing 1,10 phenanthroline complexes are discussed. Starting from the recently synthetized [Sm(L1)3]3+ (L1 = 1,10 phenanthroline), the effect of metal center replacement and of functionalization in position C5 and C6 of the ligand is examined. In detail, the comparative analysis of electronic and structural properties proceeds testing the presence of Gd3+ and Tm3+ instead of Sm3+, in combination with 1,10 phenanthroline-5,6 dione (L2), 5,6 dimethyl 1,10 phenanthroline (L3) and 1,10 phenatroline-5,6 diamine (L4) ligands. From deeper analysis, it turns out that the lanthanides do not affect the geometrical structure of the complexes, since slight variations of metal–ligand distances are observed. On the other hand, combination of ligands and metals lead to an improvement of the calculated electronic absorption for all the compounds with respect to the available experimental data, linked to the different nature of the frontier orbitals. In particular, for all complexes expected [Gd(L1)3]3+ a near-IR absorption is observed and discussed, thus opening to the possible adoption of such complexes for future photoinduced medical applications.

Structure of the type 38 Streptococcus pneumoniae capsular polysaccharide

Streptococcus pneumoniae is one of the globally important encapsulated human pathogens and more than 100 different serotypes have been identified. Despite very extensive genetic and immune-serological studies, the capsular polysaccharide repeating unit structure of several serotypes has not been determined yet, including the type 38 (type 38 in Danish nomenclature; type 71 in US nomenclature). Physicochemical data revealed that type 38 polysaccharide is composed of a pentasaccharide repeat unit →3)-[β-D-Galf(1 → 2)]-β-D-GalpA6(L-Ser)-(1 → 3)-α-D-GlcpNAc-(1 → 3)-α-D-Sugp-(1 → 4)-α-D-Galp(2OAc)-(1 → . The polysaccharide is O-acetylated at position C2 of the α-Gal residue at approximately (68–87 %) of the repeat units.

The Influence of the Alkylamino Group on the Solvatochromic Behavior of 5-(4-substituted-arylidene)-1,3-dimethylpyrimidine-2,4,6-triones: Synthesis, Spectroscopic and Computational Studies.

Advances in electronics and medical diagnostics have made organic dyes extremely popular as key functional materials. From a practical viewpoint, it is necessary to assess the spectroscopic and physicochemical properties of newly designed dyes. In this context, the condensation of 1,3-dimethylbarbituric acid with electron-rich alkylaminobenzaldehyde derivatives has been described, resulting in a series of merocyanine-type dyes. These dyes exhibit intense blue-light absorption but weak fluorescence. An electron-donating alkylamino group at position C4 is responsible for the solvatochromic behavior of the dyes since the lone electron pair of the nitrogen atom is variably delocalized toward the barbituric ring, which exhibits electron-withdrawing properties. This was elucidated, taking into account the different geometry of the amino group. The intramolecular charge transfer in the molecules is responsible for the relatively high redshift in absorption and fluorescence spectra. Additionally, an increase in solvent polarity moves the absorption and fluorescence to lower energy regions. The observed solvatochromism is discussed in terms of the four-parameter Catalán solvent polarity scale. The differences in the behavior of the dyes were quantified with the aid of time-dependent density functional theory calculations. The obtained results made it possible to find regularities linking the basic spectroscopic properties of the compounds with their chemical structure. This is important in the targeted search for new, practically important dyes.

Study of Direct N7 Regioselective tert-Alkylation of 6-Substituted Purines and Their Modification at Position C6 through O, S, N, and C Substituents.

A new N7 direct regioselective method allowing the introduction of tert-alkyl groups into appropriate 6-substituted purine derivatives is developed. This method is based on a reaction of N-trimethylsilylated purines with a tert-alkyl halide using SnCl4 as a catalyst. In this work, we study the structure and optimal reaction conditions leading to the N7 isomer and in some cases also to the N9 isomer. The main goal is devoted to preparing 7-(tert-butyl)-6-chloropurine as a suitable compound for other purine transformations. The stability of the tert-butyl group at the N7 position is tested for classic model reactions, leading to the preparation of new 6,7-disubstituted purine derivatives, which is also interesting from the point of view of possible biological activity.

Changes in the Serum and Tissue Levels of Free and Conjugated Sialic Acids, Neu5Ac, Neu5Gc, and KDN in Mice after the Oral Administration of Edible Bird’s Nests: An LC–MS/MS Quantitative Analysis

Edible bird’s nests have a variety of biological activities, the main components of which are sialic acids. Sialic acids are a group of nine-carbon N-acetylated derivatives of neuraminic acid containing a keto group at position C2 and play important roles in many biological processes. To verify whether the oral administration of edible bird’s nests would change the content and distribution of sialic acid components in vivo, a liquid chromatography–mass spectrometry method for the quantitative analysis of sialic acid levels in serum and tissues was developed. In the negative ion mode, the mobile phases consist of 0.1% formic acid in water (A) and acetonitrile (v/v) (B). Isocratic elution was performed with 60% B for 0−15 min. The chromatographic separation was performed on a Morphling HILIC Amide column (2.1 mm × 150 mm, 5 μm) at a flow rate of 0.5 mL min−1. The results showed that the correlation coefficients of the typical calibration curves were all higher than 0.995, exhibiting good linearity. The levels of free and conjugated forms of N-glycolylneuraminic acid (Neu5Gc), N-acetylneuraminic acid (Neu5Ac), and 2-keto-3-deoxy-D-glycero-D-galactonononic acid (KDN) in the serum and different tissues were simultaneously detected after the oral administration of the edible bird’s nests at a daily dose of 300 and 700 mg Kg−1 for seven days in mice. Our study found that the oral administration of edible bird’s nests can significantly increase the concentration of total sialic acids (Neu5Gc + Neu5Ac + KDN) in serum and spleen and lungs tissues, which may be related to the anti-inflammatory and immune function of edible bird’s nest, but further studies are needed to verify this. Neu5Ac was the dominant sialic acid in brain tissue, and Neu5Gc was the dominant sialic acid in serum and other tissues, including heart, liver, spleen, lungs, and kidney. Moreover, we found that the forms of Neu5Ac and Neu5Gc were mainly conjugated in all groups except liver tissue. In conclusion, the method we established had good linearity and accuracy; it allowed the analytes to be effectively separated from the matrix and endogenous substances in serum or tissues, so it could effectively detect the distribution and concentration of free and conjugated forms of sialic acids in serum and tissues, which was beneficial to the research and exploitation of edible bird’s nests and sialic acids.

Adjusting UV-Vis Spectrum of Alizarin by Insertion of Auxochromes.

First synthesized in 1868, alizarin became one of the first synthetic dyes and was widely used as a red dye in the textile industry, making it more affordable and readily available than the traditional red dyes derived from natural sources. Despite extensive both experimental and computational analyses on the electronic effects of substituents on the shape of the visible spectrum of alizarin and alizarin Red S, no previous systematic work has been undertaken with the aim to fine tune the dominant absorption region defining its color by introducing other electron-withdrawing or electron-donor groups. For such, we have performed a comprehensive study of electronic effects of substituents in position C3 of alizarin by means of a time dependent DFT approach. These auxochromes attached to the chromophore are proven to alter both the wavelength and intensity of absorption. It is shown that the introduction of an electron-donor group in alizarin causes the transition bands to be significantly red-shifted whereas electron-withdrawing groups cause a minor blue-shifting.

COQ4 is required for the oxidative decarboxylation of the C1 carbon of coenzyme Q in eukaryotic cells

Coenzyme Q (CoQ) is a redox lipid that fulfills critical functions in cellular bioenergetics and homeostasis. CoQ is synthesized by a multi-step pathway that involves several COQ proteins. Two steps of the eukaryotic pathway, the decarboxylation and hydroxylation of position C1, have remained uncharacterized. Here, we provide evidence that these two reactions occur in a single oxidative decarboxylation step catalyzed by COQ4. We demonstrate that COQ4 complements an Escherichia coli strain deficient for C1 decarboxylation and hydroxylation and that COQ4 displays oxidative decarboxylation activity in the non-CoQ producer Corynebacterium glutamicum. Overall, our results substantiate that COQ4 contributes to CoQ biosynthesis, not only via its previously proposed structural role but also via the oxidative decarboxylation of CoQ precursors. These findings fill a major gap in the knowledge of eukaryotic CoQ biosynthesis and shed light on the pathophysiology of human primary CoQ deficiency due to COQ4 mutations.

Synthesis of C3-Substituted N1-tert-Butyl 1,2,4-Triazinium Salts via the Liebeskind-Srogl Reaction for Fluorogenic Labeling of Live Cells.

We recently described the development and application of a new bioorthogonal conjugation, the triazinium ligation. To explore the wider application of this reaction, in this work, we introduce a general method for synthesizing C3-substituted triazinium salts based on the Liebeskind-Srogl cross-coupling reaction and catalytic thioether reduction. These methods enabled the synthesis of triazinium derivatives for investigating the effect of different substituents on the ligation kinetics and stability of the compounds under biologically relevant conditions. Finally, we demonstrate that the combination of a coumarin fluorophore attached to position C3 with a C5-(4-methoxyphenyl) substituent yields a fluorogenic triazinium probe suitable for no-wash, live-cell labeling. The developed methodology represents a promising synthetic approach to the late-stage modification of triazinium salts, potentially widening their applications in bioorthogonal reactions.

Selective C2 and C3 phosphorylmethylation of indoles with a phosphorylmethyl dibenzothiophenium reagent

A novel electrophilic phosphorylmethylating reagent with excellent selectivity for the formation of indole C(sp2)–CH2PO(OEt)2 bonds at position C2 with a photoredox catalyst and at position C3 with a copper catalyst has been developed.

Theoretical analysis of the OH-initiated atmospheric oxidation reactions of imidazole.

Imidazoles are present in Earth's atmosphere in both the gas-phase and in aerosol particles, and have been implicated in the formation of brown carbon aerosols. The gas-phase oxidation of imidazole (C3N2H4) by hydroxyl radicals has been shown to be preferentially initiated via OH-addition to position C5, producing the 5-hydroxyimidazolyl radical adduct. However, the fate of this adduct upon reaction with O2 in the atmospheric gas-phase is currently unknown. We employed an automated approach to investigate the reaction mechanism and kinetics of imidazole's OH-initiated gas-phase oxidation, in the presence of O2 and NOx. The explored mechanism included reactions available to first-generation RO2 radicals, as well as alkoxyl radicals produced from RO2 + NO reactions. Product distributions were obtained by assembling and solving a master equation, under conditions relevant to the Earth's atmosphere. Our calculations show a complex, branched reaction mechanism, which nevertheless converges to yield two major closed-shell products: 4H-imidazol-4-ol (4H-4ol) and N,N'-diformylformamidine (FMF). At 298 K and 1 atm, we estimate the yields of 4H-4ol and FMF from imidazole oxidation initiated via OH-addition to position C5 to be 34 : 66, 12 : 85 and 2 : 95 under 10 ppt, 100 ppt and 1 ppb of NO respectively. This work also revealed O2-migration pathways between the α-N-imino peroxyl radical isomers. This reaction channel is fast for the first-generation RO2 radicals, and may be important during the atmospheric oxidation of other unsaturated organic nitrogen compounds as well.

Design, synthesis and biological evaluation of the positional isomers of the galactose conjugates able to target hepatocellular carcinoma cells via ASGPR-mediated cellular uptake and cytotoxicity

Galactose as a recognizing motif for asialoglycoprotein receptor (ASGPR) is a widely accepted vector to deliver cytotoxic agents in the therapy of hepatocellular carcinoma (HCC), however, the individual hydroxyl group of galactose (Gal) contributed to recognizing ASGPR is obscure and remains largely unanswered in the design of glycoconjugates. Herein, we designed and synthesized five positional isomers of Gal-anthocyanin Cy5.0 conjugates and three Gal-doxorubicin (Dox) isomers, respectively. The fluorescence intensity of Gal-Cy5.0 conjugates accumulated in cancer cells hinted the optimal modification sites of positions C2 and C6. Comparing to the cytotoxicity of other conjugates, C2-Gal-Dox (11) was the most potent. Moreover, Gal-Dox conjugates significantly the toxicity of Dox. A progressively lower internalization capacity and siRNA technology implied the cellular uptake and cytotoxicity directly related to the ASGPR expression level. Accordingly, position C2 of galactose may be the best substitution site via ASGPR mediation in the design of anti-HCC glycoconjugates.

Anti-Neurodegenerating Activity: Structure-Activity Relationship Analysis of Flavonoids.

An anti-neurodegeneration activity study was carried out for 80 flavonoid compounds. The structure-activity analysis of the structures was carried out by performing three different anti-neurodegeneration screening tests, showing that in these structures, the presence of a hydroxy substituent group at position C3' as well as C5' of ring B and a methoxy substituent group at the C7 position of ring A play a vital role in neuroprotective and antioxidant as well as anti-inflammatory activity. Further, we found structure (5) was the top-performing active structure out of 80 structures. Subsequently, a molecular docking study was carried out for the 3 lead flavonoid compounds (4), (5), and (23) and 21 similar hypothetical proposed structures to estimate the binding strength between the tested compounds and proteins potentially involved in disease causation. Ligand-based pharmacophores were generated to guide future drug design studies.

Developing a highly efficient CGBE base editor in watermelon.

Cytosine and adenosine base editors (CBEs and ABEs) are novel genome-editing tools that have been widely utilized in molecular breeding to precisely modify single-nucleotide polymorphisms (SNPs) critical for plant agronomic traits and species evolution. However, conventional BE editors are limited to achieve C-to-T and A-to-G substitutions, respectively. To enhance the applicability of base editing technology in watermelon, we developed an efficient CGBE editor (SCGBE2.0) by removing the uracil glycosylase inhibitor (UGI) unit from the commonly used hA3A-CBE and incorporating the uracil-DNA glycosylase (UNG) component. Seven specific guide RNAs (sgRNAs) targeting five watermelon genes were designed to assess the editing efficiency of SCGBE. The results obtained from stably transformed watermelon plants demonstrated that SCGBE2.0 could efficiently induce C-to-G mutations at positions C5-C9 in 43.2% transgenic plants (with a maximum base conversion efficiency of 46.1%) and C-to-A mutation at position C4 in 23.5% transgenic plants (with a maximum base conversion efficiency of 45.9%). These findings highlight the capability of our integrated SCGBE2.0 editor to achieve C-to-G/A mutations in a site-preferred manner, thus providing an efficient base editing tool for precise base modification and site-directed saturated mutagenesis in watermelon.

Exploring the 5-Substituted 2-Aminobenzothiazole-Based DNA Gyrase B Inhibitors Active against ESKAPE Pathogens.

We present a new series of 2-aminobenzothiazole-based DNA gyrase B inhibitors with promising activity against ESKAPE bacterial pathogens. Based on the binding information extracted from the cocrystal structure of DNA gyrase B inhibitor A, in complex with Escherichia coli GyrB24, we expanded the chemical space of the benzothiazole-based series to the C5 position of the benzothiazole ring. In particular, compound E showed low nanomolar inhibition of DNA gyrase (IC50 < 10 nM) and broad-spectrum antibacterial activity against pathogens belonging to the ESKAPE group, with the minimum inhibitory concentration < 0.03 μg/mL for most Gram-positive strains and 4-16 μg/mL against Gram-negative E. coli, Acinetobacter baumannii, Pseudomonas aeruginosa, and Klebsiella pneumoniae. To understand the binding mode of the synthesized inhibitors, a combination of docking calculations, molecular dynamics (MD) simulations, and MD-derived structure-based pharmacophore modeling was performed. The computational analysis has revealed that the substitution at position C5 can be used to modify the physicochemical properties and antibacterial spectrum and enhance the inhibitory potency of the compounds. Additionally, a discussion of challenges associated with the synthesis of 5-substituted 2-aminobenzothiazoles is presented.

Structural basis of regioselective tryptophan dibromination by the single-component flavin-dependent halogenase AetF.

The flavin-dependent halogenase (FDH) AetF successively brominates tryptophan at C5 and C7 to generate 5,7-dibromotryptophan. In contrast to the well studied two-component tryptophan halogenases, AetF is a single-component flavoprotein monooxygenase. Here, crystal structures of AetF alone and in complex with various substrates are presented, representing the first experimental structures of a single-component FDH. Rotational pseudosymmetry and pseudomerohedral twinning complicated the phasing of one structure. AetF is structurally related to flavin-dependent monooxygenases. It contains two dinucleotide-binding domains for binding the ADP moiety with unusual sequences that deviate from the consensus sequences GXGXXG and GXGXXA. A large domain tightly binds the cofactor flavin adenine dinucleotide (FAD), while the small domain responsible for binding the nicotinamide adenine dinucleotide (NADP) is unoccupied. About half of the protein forms additional structural elements containing the tryptophan binding site. FAD and tryptophan are about 16 Å apart. A tunnel between them presumably allows diffusion of the active halogenating agent hypohalous acid from FAD to the substrate. Tryptophan and 5-bromotryptophan bind to the same site but with a different binding pose. A flip of the indole moiety identically positions C5 of tryptophan and C7 of 5-bromotryptophan next to the tunnel and to catalytic residues, providing a simple explanation for the regioselectivity of the two successive halogenations. AetF can also bind 7-bromotryptophan in the same orientation as tryptophan. This opens the way for the biocatalytic production of differentially dihalogenated tryptophan derivatives. The structural conservation of a catalytic lysine suggests a way to identify novel single-component FDHs.