Recent Advances in the Chemical Biology of N-Glycans

Asparagine-linked N-glycans on proteins have diverse structures, and their functions vary according to their structures. In recent years, it has become possible to obtain high quantities of N-glycans via isolation and chemical/enzymatic/chemoenzymatic synthesis. This has allowed for progress in the elucidation of N-glycan functions at the molecular level. Interaction analyses with lectins by glycan arrays or nuclear magnetic resonance (NMR) using various N-glycans have revealed the molecular basis for the recognition of complex structures of N-glycans. Preparation of proteins modified with homogeneous N-glycans revealed the influence of N-glycan modifications on protein functions. Furthermore, N-glycans have potential applications in drug development. This review discusses recent advances in the chemical biology of N-glycans.     

Cata-Annulated Azaacene Bisimides

Ultra-electron-deficient azaacenes were synthesized via Buchwald-Hartwig coupling of ortho-diaminoarenes with chlorinated mellophanic diimide followed by oxidation of the intermediate N,N’-dihydro compounds with MnO₂ or PbO₂. The resulting cata-annulated bisimide azaacenes have ultrahigh electron affinities with first reduction potentials as low as −0.35 V recorded for a tetraazapentacene. Attempts to prepare a tetrakis(dicarboximide)tetraazaheptacene resulted in the formation of a symmetric butterfly dimer.     

1,7-Dinitroperylene bisimides: facile synthesis and characterization as n-type organic semiconductors

1,7-Dinitroperylene bisimides (1a-1b) and 1-nitroperylene bisimides (2a-2b) were synthesized under mild condition in high yields, and were characterized by FT-IR, ¹H NMR, UV-vis, HRMS spectra, cyclic voltammetry, and thermogravimetric analyses. These compounds are stable up to 260 °C according to thermogravimetric analyses. They undergo two quasi-reversible one-electron reductions in THF at modest potentials. The nitro functionalities provide stability of n-type charge carriers by lowering the LUMO to resist ambient oxidation.     

Synthesis and characterization of polystyrene-b-tetraaniline stars from polystyrene stars with surface reactive groups prepared by RAFT polymerization

Functionalized star polymers with tetraaniline on their surface have been successfully prepared by substitution reaction of N-succinimidyl-terminated star polymers with tetraaniline. A novel functional RAFT agent bearing N-succinimidyl group was used in the RAFT polymerization of styrene, and N-succinimidyl groups-terminated polystyrenes with narrow molecular weight distribution were obtained. The star polymers with reactive N-succinimidyl groups on their surface were synthesized via RAFT polymerization of DVB. Polymerization mechanism study by gel permeation chromatography displayed that complete disappearance of linear polymers in the products is difficult. The N-succinimidyl-terminated PSt, polymer stars with surface N-succinimidyl groups and the PSt-b-tetraaniline stars were characterized by ¹H NMR spectroscopy, FT-IR and GPC.     

Effect of the Ortho Alkylation of Perylene Bisimides on the Alignment and Self-Assembly Properties

The effect of the ortho alkylation of perylene bisimides on the alignment and self-assembly properties has been studied. It was found that the dichroic properties of perylene bisimides in a liquid crystal host can be reversed with a single synthetic step by ortho alkylation. Furthermore, a solvent-induced growth of ultralong organic n-type semiconducting fibrils from non-ortho-alkylated perylene bisimide was observed. Ortho substitution of the perylene bisimide core alters the mode of fibrillar growth, leading to isotropic crystallization.     

Photoacid generators (PAGs) based on N-acyl-N-phenylhydroxylamines for carboxylic and sulfonic acids

Simple and efficient photoacid generators (PAGs) for carboxylic and sulfonic acids based on N-acyl-N-phenylhydroxylamines have been demonstrated. Irradiation of o-carboxylates and thermally rearranged o-arenesulfonates of N-acyl-N-phenylhydroxylamines using UV light (≥254 nm) in aqueous methanolic solution resulted in efficient generation of carboxylic and sulfonic acids, respectively. The carboxylic acid generation ability of N-acyl-N-phenylhydroxylamines was found to be dependent on their N-acyl substituents. Further, polymer bearing o-arenesulfonates of N-acyl-N-phenylhydroxylamine was synthesized and demonstrated as PAG for sulfonic acids.     

The vapour pressure behaviour and the association of N-methylethylamine,diethylamine and their N-deuterioanalogues in mixtures with n-hexane

The vapour pressure isotherms of mixtures of N-methylethylamine and N-methyl(N-²H)ethylamine with n-hexane have been measured between 273 and 323 K. The vapour pressure isotherms of mixtures of diethylamine and (N-²H)diethylamine with nhexane between 293 and 353 K have also been measured. In addition, the vapour pressures of the pure amines have been determined down to 228 or 243 K. As evidenced by the small values for the Wilson coefficients, the activity coefficients, the Gibbs free energies and the data derived from the theory of ideal associated solutions, the association of diethlamine is very weak; that of N-methylethylamine is not much larger. The observations on the vapour pressure isotope effect of the two amines and their N-deuterioanalogues are compatible with this interpretation. The normal effect is smaller for diethylamine, with ratios P_D/P_H of 0.972–0.997 between 243 and 323 K, than for N-methylethylamine with values of 0.965–0.991, and the partial pressure quotients calculated for mixtures of the two compounds with n-hexane show the transition from the normal to the inverse effect on low dilution. The data for the N-deuterioanalogues and their mixtures with n-hexane suggest a somewhat greater energy of the deuterium bonds.     

Synthesis and free-radical polymerization of water-soluble acrylamide monomers

Water-soluble acrylamide monomers N-(hydroxymethyl)acrylamide, N-(hydroxymethyl)methacrylamide, N,N-diethanolacrylamide, N,N-diethanolmethacrylamide, N,N-methylethanolacrylamide, and N,N-methylethanolmethacrylamide have been synthesized and characterized. The kinetics and thermodynamics of the free-radical polymerization of these monomers and of the model compounds N-isopropylacrylamide and acrylamide have been studied by the methods of isothermal and scanning calorimetry. The structure and the solubility of the said polymers in water and organic solvents have been investigated and their molecular-mass characteristics and temperatures of glass transition (T _g) and melting (T _m) have been examined by DSC, liquid chromatography, ¹H NMR and IR spectroscopy, and chemical analysis of functional groups. Hydrogels and amphiphilic network polymers based on acrylamide monomers have been prepared and characterized.     

Visual chiral recognition of mandelic acid and α-amino acid derivatives by enantioselective gel formation and precipitation

Novel chiral receptors based on l-phenylalanine and l-valine have been synthesized and their chiral recognition properties toward mandelic acid and N-tosyl α-amino acids are studied. The phenylalanine-based receptor undergoes enantioselective gel formation with R-mandelic acid and N-tosyl-d-valine, whereas the valine-linked receptor in their presence results in the formation of precipitates.     

Thiocyanation of N-aryl,N-acetyl,and N-[arylsulfonylimino(methyl)methyl] derivatives of 1,4-benzoquinone monoimine

N-[arylsulfonylimino(methyl)methyl] derivatives of 1,4-benzoquinone monoimine with alkyl substituents in the quinoid ring have been synthesized and their spectral characteristics were determined. The thiocyanation of N-aryl, N-acetyl, and N-[arylsulfonylimino(methyl)methyl] derivatives of 1,4-benzoquinone monoimine depending on the LUMO energy of the initial quinone monoamine affords derivatives of benzo[d][1,3]oxathiol-2-ones and benzo[d]oxazole-2(3H)-thiones.     

Enantioselectivity switch controlled by N,N′-di- or N,N,N′,N′-tetra-substituted chiral thiophosphorodiamide ligands,structural relatives of thioureas,in catalytic additions of diethylzinc to aldehydes

We have developed a series of new chiral thiophosphorodiamide ligands derived from (1R,2R)-(+)-1,2-diphenylethylenediamine, which are the structural relatives of thioureas. An investigation into their catalytic properties in asymmetric additions of diethylzinc to aldehydes has shown that N,N,N′,N′-tetra-substituted chiral thiophosphorodiamides can give (R)-secondary alcohols with up to 98% yield and 98% ee, while N,N′-di-substituted chiral thiophosphorodiamides give (S)-secondary alcohols with up to 99% yield and 97% ee values. The enantioselectivity switch is highly efficient with a broad substrate scope. We have also proposed hypothetical reaction pathways, which result in an enantioselectivity switch.     

N-Aryl diketopyrrolopyrrole derivatives towards organic optical and electronic materials

Diketopyrrolopyrrole (DPP) and related derivatives have drawn great attention due to their applications in organic optical /electronic materials. Progress in these materials is associated with developments in the syntheses of the DPP family. Chemical modification of DPP at nitrogen atom, including N-alkylation and N-arylation, is an effective strategy to improve its physical and chemical properties, such as solubility, optical and semiconducting properties. However, N-arylation of DPPs remains challenging compared to the easily accessible N-alkylation. Herein, the synthesis of N-aryl DPP derivatives and correlated π-expanded DPPs are summarized, and their optical/electronic properties are introduced. The future perspectives of N-aryl DPP derivatives are also discussed.     

Metabolic N-Dealkylation and N-Oxidation as Elucidators of the Role of Alkylamino Moieties in Drugs Acting at Various Receptors

Metabolic reactions that occur at alkylamino moieties may provide insight into the roles of these moieties when they are parts of drug molecules that act at different receptors. N-dealkylation of N,N-dialkylamino moieties has been associated with retaining, attenuation or loss of pharmacologic activities of metabolites compared to their parent drugs. Further, N-dealkylation has resulted in clinically used drugs, activation of prodrugs, change of receptor selectivity, and providing potential for developing fully-fledged drugs. While both secondary and tertiary alkylamino moieties (open chain aliphatic or heterocyclic) are metabolized by CYP450 isozymes oxidative N-dealkylation, only tertiary alkylamino moieties are subject to metabolic N-oxidation by Flavin-containing monooxygenase (FMO) to give N-oxide products. In this review, two aspects will be examined after surveying the metabolism of representative alkylamino-moieties-containing drugs that act at various receptors (i) the pharmacologic activities and relevant physicochemical properties (basicity and polarity) of the metabolites with respect to their parent drugs and (ii) the role of alkylamino moieties on the molecular docking of drugs in receptors. Such information is illuminative in structure-based drug design considering that fully-fledged metabolite drugs and metabolite prodrugs have been, respectively, developed from N-desalkyl and N-oxide metabolites.     

3-(α-Nitroalkyl- and α-polynitroalkyl-ONN-azoxy)-4-nitraminofurazans and some their derivatives

Methods for the preparation of 3-(α-nitroalkyl- and α-polynitroalkyl-ONN-azoxy)-4-nitraminofurazans with primary and secondary nitramine groups and their derivatives, including N,N′-bis[(3-(α-polynitromethyl-ONN-azoxy)furazan-4-yl]alkylen-N,N′-dinitramines, have been elaborated.     

Donor-π-acceptor benzothiazole-derived dyes with an extended heteroaryl-containing conjugated system: synthesis, DFT study and antimicrobial activity

A series of novel derivatives containing an electron-donating N,N-dimethylaminophenyl ring connected to an electron-withdrawing benzothiazole or benzothiazolium moiety via a heteroaryl system (furan, thiophene or N-methylpyrrole) and up to two ethenylene groups have been synthesized and characterized. Furthermore, their nonlinear optical (NLO) properties have been investigated at the theoretical level using DFT and time-dependent DFT methods, and their antimicrobial activities were evaluated against a standard set of unicellular organisms. Both benzothiazole and benzothiazolium systems are predicted to exhibit large NLO responses, based on the calculated static molecular quadratic hyperpolarizabilities β₀ as well as intramolecular charge transfer (ICT) transition characteristics. Moreover, the 3-alkyl-benzothiazolium salts were found to display high toxicity against several tested microbes.     

Synthesis,characterization and study of antibacterial activity of enaminone complexes of zinc and iron

Complexes of enaminones; 4-N,N-diethylamine-pent-3-ene-2-one [HL¹], 4-N,N-di n-propylamine-pent-3-ene-2-one [HL²] and 4-N,N-dicyclohexylamine-pent-3-ene-2-one [HL³] with Fe(II) and Zn(II) ions were prepared by reacting the equimolar ethanolic solutions of the ligands (HL¹, HL² and HL³) with ethanolic metal solutions. The complexes formed, were characterized by infrared, ultraviolet and atomic absorption spectroscopy. Ligands and their metal complexes were tested against Escherichia coli and Staphylococcus aureus bacteria to assess their antibacterial action using disc diffusion method. Ligands were completely inactive against bacteria whereas the complex Zn (HL¹) has significant action on both bacteria, indicating that it has a good potential as bactericide. Other complexes have normal antiseptic character.     

Stereoselective radical cyclizations of N-(2-halobenzoyl)-cyclic ketene-N,X(X=O, S)-acetals

2-Alkyloxazolines and 2-alkylthiazolines react with 2-halobenzoyl chlorides to form N-(2-halobenzoyl)-cyclic ketene-N,O-acetals and N-(2-halobenzoyl)-cyclic ketene-N,S-acetals in excellent yields, respectively. These ketene acetals readily undergo stereocontrolled aryl radical cyclizations to afford the central six-membered rings of substituted-2,3,10,10α-tetrahydrooxazolo[3,2-b]isoquinolin-5-ones and their 2,3,10,10α-tetrahydrothiazolo[3,2-b]isoquinolin-5-one analogs. The tertiary N,O- and N,S-radicals formed upon aryl radical reaction at the ketene-N,X(X=O, S)-acetal double bond appear to have reasonable stability. The stereoselectivity in hydrogen abstractions by these intermediate radicals from both Bu₃SnH and (Me₃Si)₃SiH was investigated. The N,S-heterocyclic fused ring products may have potential medical value.     

Trialkylammonium salt degradation: implications for methylation and cross-coupling

Trialkylammonium (most notably N,N,N-trimethylanilinium) salts are known to display dual reactivity through both the aryl group and the N-methyl groups. These salts have thus been widely applied in cross-coupling, aryl etherification, fluorine radiolabelling, phase-transfer catalysis, supramolecular recognition, polymer design, and (more recently) methylation. However, their application as electrophilic methylating reagents remains somewhat underexplored, and an understanding of their arylation versus methylation reactivities is lacking. This study presents a mechanistic degradation analysis of N,N,N-trimethylanilinium salts and highlights the implications for synthetic applications of this important class of salts. Kinetic degradation studies, in both solid and solution phases, have delivered insights into the physical and chemical parameters affecting anilinium salt stability. ¹H NMR kinetic analysis of salt degradation has evidenced thermal degradation to methyl iodide and the parent aniline, consistent with a closed-shell S_N2-centred degradative pathway, and methyl iodide being the key reactive species in applied methylation procedures. Furthermore, the effect of halide and non-nucleophilic counterions on salt degradation has been investigated, along with deuterium isotope and solvent effects. New mechanistic insights have enabled the investigation of the use of trimethylanilinium salts in O-methylation and in improved cross-coupling strategies. Finally, detailed computational studies have helped highlight limitations in the current state-of-the-art of solvation modelling of reaction in which the bulk medium undergoes experimentally observable changes over the reaction timecourse.

The dual reactivity of N,N,N-trimethylanilinium salts towards arylation and methylation is decoupled in this mechanistic investigation to enable more strategic application of these salts in either reaction class.     

Ionic liquids as additives in high performance liquid chromatography: Analysis of amines and the interaction mechanism of ionic liquids

As novel solvents, ionic liquids have many applications in synthesis, catalysis and analytical separation, i.e. extraction and chromatography separation. In this paper, some amines including benzidine, benzylamine, N-ethylaniline and N,N′-dimethylaniline are separated using ionic liquids as additives for the mobile phase in high performance liquid chromatography (HPLC). The effects of the length of alkyl chain or counterions on different ionic liquids and their concentrations on the separation of these analytes are performed. The differences between ionic liquids and tetrabutylammonium bromide (TBA) on the separation of o-, m-, p-phthalic acids are compared and the results show that ionic liquids are ion-pair reagents in essence, although their hydrophobicity and hydrogen bonding also play important roles.     

New Trends in Diaziridine Formation and Transformation (a Review)

This review focuses on diaziridine, a high strained three-membered heterocycle with two nitrogen atoms that plays an important role as one of the most important precursors of diazirine photoaffinity probes, as well as their formation and transformation. Recent research trends can be grouped into three categories, based on whether they have examined non-substituted, N-monosubstituted, or N,N-disubstituted diaziridines. The discussion expands on the conventional methods for recent applications, the current spread of studies, and the unconventional synthesis approaches arising over the last decade of publications.