Arene Cation Research Articles

Preparation and Identification of Peptides with α-Glucosidase Inhibitory Activity from Shiitake Mushroom (Lentinus edodes) Protein

The shiitake mushroom is the most commonly cultivated edible mushroom in the world, and is rich in protein. This study aims to obtain the peptides with α-glucosidase inhibition activity from shiitake mushroom protein hydrolysate. The conditions of enzymatic hydrolysis of shiitake mushroom protein were optimized by response surface test. The results showed that the optimal conditions were as follows: the E/S was 3390 U/g, the solid–liquid ratio was 1:20, the hydrolysis temperature and time were 46 °C and 3.4 h, respectively, and the pH was 7. The active peptides were separated by gel filtration and identified by LC-MS/MS analysis and virtual screening. The results indicated that fourteen peptides were identified by LC-MS/MS. Among them, four new peptides (EGEPKLP, KDDLRSP, TPELKL, and LDYGKL) with the higher docking score were selected and chemically synthesized to verify their inhibition activity. The IC50 values of EGEPKLP, KDDLRSP, TPELKL, and LDYGKL for α-glucosidase inhibition activity ranged from 452 ± 36 μmol/L to 696 ± 39 μmol/L. The molecular docking results showed that the hydrogen bond and arene–cation bond were the two major interactions between four peptides and 2QMJ. The hydrogen bonds were crucial to the inhibition activity of α-glucosidase. The results indicate the potential of using the peptides from shiitake mushroom protein as functional food with α-glucosidase inhibition activity.

Mechanistic Investigations into Amination of Unactivated Arenes via Cation Radical Accelerated Nucleophilic Aromatic Substitution.

A mechanistic investigation into the amination of electron-neutral and electron-rich arenes using organic photoredox catalysis is presented. Kinetic and computational data support rate-limiting nucleophilic addition into an arene cation radical using both azole and primary amine nucleophiles. This finding is consistent with both fluoride and alkoxide nucleofuges, supporting a unified mechanistic picture using cation radical accelerated nucleophilic aromatic substitution (CRA-SNAr). Electrochemistry and time-resolved fluorescence spectroscopy confirm the key role solvents play in enabling selective arene oxidation in the presence of amines. The synthetic limitations of xanthylium salts are elucidated via photophysical studies. An alternative catalyst scaffold with improved turnover numbers is presented.

Synthesis, characterization, and in vitro antibacterial activity of some new pyridinone and pyrazole derivatives with some in silico ADME and molecular modeling study

A new series of pyridine-2-one and pyrazole derivatives were designed and synthesized based on cyanoacrylamide derivatives containing 2,4-dichlro aniline and 6-methyl 2-amino pyridine as an aryl group. Condensation of cyanoacrylamide derivatives 3a–d with different active methylene (malononitrile, ethyl cyanoacetate cyanoacetamide, and ethyl acetoacetate) in the presence of piperidine as basic catalyst afforded the corresponding pyridinone derivatives 4a–c, 5, 9, and 13. Furthermore, the reaction of cyanoacrylamide derivatives 3a–d with bi-nucleophile as hydrazine hydrate and thiosemicarbazide afforded the corresponding pyrazole derivatives 14a,b and 16. The newly designed derivatives were confirmed and established based on the elemental analysis and spectra data (IR, 1H NMR, 13C NMR, and mass). The in vitro antibacterial activity was evaluated against four bacterial strains with weak to good antibacterial activity. Moreover, the results indicated that the most active derivatives 3a, 4a, 4b, 9, and 16 might lead to antibacterial agents, especially against B. subtilis and P. vulgaris. The DFT calculations were performed to estimate its geometric structure and electronic properties. In addition, the most active pyridinone and pyrazole derivatives were further evaluated for in silico physicochemical, drug-likeness, and toxicity prediction. These derivatives obeyed all Lipinski’s and Veber’s rules without any violation and displayed non-immunotoxin, non-mutagenic, and non-cytotoxic. Molecular docking simulation was performed inside the active site of Topoisomerase IV (PDB:3FV5). It displayed binding energy ranging from -14.97 kcal/mol to -18.86 kcal/mol with hydrogen bonding and arene–cation interaction. Therefore, these derivatives were suggested to be good antibacterial agents via topoisomerase IV inhibitor.Graphical abstract

Investigating the exceptional adducts of alkoxides with Ru(II)-arene cations in alkyl alcohol solution using electrospray ionization mass spectrometry.

Exploring the formation mechanism of the exceptional adducts of alkoxides with Ru(II)-arene cations in alkyl alcohol solution using electrospray ionization mass spectrometry (ESI-MS) is crucial for further understanding the physicochemical properties of Ru(II)-arene complexes in solution. All mass spectra were collected with an AB SCIEX TripleTOF 5600+ mass spectrometer in positive mode. Theoretical calculations were carried out using the density functional theory method at the B3LYP level with a hybrid basis set consisting of 6-31G(d,p) and LanL2DZ in the Gaussian 03 program. When ruthenated [15 ]paracyclophanes (Ru-[15 ]PCPs) and Ru(II)-arene dimers were dissolved in alkyl alcohol solvents, the adducts of alkoxides with Ru(II)-arene cations were observed under positive ion mode ESI-MS, which resulted from the coordination of alkyl alcohol molecules with the Ru(II)-arene cations followed by the deprotonation of O-H bonds of the coordinated alcohols. Furthermore, the number of alkoxides binding to Ru-[15 ]PCPs was regulated by the number of ruthenium atoms. Attributed to good solubility and small steric hindrance, the signal intensity of the adducts of methoxides with Ru(II)-arene cations was the strongest among the three alkyl alcohols used in this study. The characteristic adducts of alkoxides with Ru(II)-arene cations were pervasively present in positive ion mode ESI-MS of nine Ru(II)-arene complexes dissolved in alkyl alcohol solvents. Taking into consideration the solubility and signal response, methanol is the most suitable solvent for the ESI-MS experiments with Ru(II)-arene complexes among the solvents studied, where almost only the diagnostic adducts of methoxides with Ru(II)-arene cations are present.

Regioselective Arene C-H Alkylation Enabled by Organic Photoredox Catalysis.

Expanding the toolbox of C-H functionalization reactions applicable to the late-stage modification of complex molecules is of interest in medicinal chemistry, wherein the preparation of structural variants of known pharmacophores is a key strategy for drug development. One manifold for the functionalization of aromatic molecules utilizes diazo compounds and a transition-metal catalyst to generate a metallocarbene species, which is capable of direct insertion into an aromatic C-H bond. However, these high-energy intermediates can often require directing groups or a large excess of substrate to achieve efficient and selective reactivity. Herein, we report that arene cation radicals generated by organic photoredox catalysis engage in formal C-H functionalization reactions with diazoacetate derivatives, furnishing sp2 -sp3 coupled products with moderate-to-good regioselectivity. In contrast to previous methods utilizing metallocarbene intermediates, this transformation does not proceed via a carbene intermediate, nor does it require the presence of a transition-metal catalyst.

Regioselective Arene C−H Alkylation Enabled by Organic Photoredox Catalysis

AbstractExpanding the toolbox of C−H functionalization reactions applicable to the late‐stage modification of complex molecules is of interest in medicinal chemistry, wherein the preparation of structural variants of known pharmacophores is a key strategy for drug development. One manifold for the functionalization of aromatic molecules utilizes diazo compounds and a transition‐metal catalyst to generate a metallocarbene species, which is capable of direct insertion into an aromatic C−H bond. However, these high‐energy intermediates can often require directing groups or a large excess of substrate to achieve efficient and selective reactivity. Herein, we report that arene cation radicals generated by organic photoredox catalysis engage in formal C−H functionalization reactions with diazoacetate derivatives, furnishing sp2–sp3 coupled products with moderate‐to‐good regioselectivity. In contrast to previous methods utilizing metallocarbene intermediates, this transformation does not proceed via a carbene intermediate, nor does it require the presence of a transition‐metal catalyst.

Recent progress in (hetero)arene cation radical-based heteroarene modification.

The transformation of (hetero)arene cation radicals has become a powerful tool for the construction of highly functionalized (hetero)arenes. These (hetero)arene cation radicals could be generated under electrochemical, photochemical or chemical oxidation systems. The in situ generated (hetero)arene cation radicals can be attacked by various nucleophiles, such as (hetero)aromatics and anions, yielding structurally diverse molecules. Recently, a large number of impressive heteroarene modifications have been designed by this strategy. This review summarizes the advances in heteroarene modification via reactions of in situ formed (hetero)arene cation radicals, ranging from 2010 to 2020.

Electrochemical C−H/N−H Oxidative Cross Coupling of Imidazopyridines with Diarylamines to Synthesize Triarylamine Derivatives

AbstractAn electrochemical dehydrogenative C−H/N−H cross coupling of imidazopyridines with diarylamines has been developed. A variety of triarylamine derivatives could be obtained in high regioselectivities and moderate‐to‐good yields. In this transformation, the reaction is conducted in a simple undivided cell without using a metal catalyst or a stoichiometric amount of external chemical oxidants. Mechanistic studies indicate that the C−N bond is likely to be formed through the cross coupling between an arene cation radical and a nitrogen radical.

Novel nalidixic acid derivatives targeting topoisomerase II enzyme; Design, synthesis, anticancer activity and effect on cell cycle profile

AimDesign and synthesis of novel nalidixic acid derivatives of potent anticancer and topoisomerase II inhibitory activities were our major aim. Materials & methodsAll the newly synthesized nalidixic acid derivatives were submitted to the National Cancer Institute (NCI), Bethesda, USA and were accepted for single dose screening. Further investigation via IC50 determination of the most potent compound 6a against K-562 and SR leukemia cell lines. Finally, the topoisomerase II inhibitory activity, the cell cycle analysis and molecular docking of 6a were performed in order to identify the possible mechanism of the anticancer activity. ResultsCompound 6a showed interesting selectivity against leukemia especially K-562 and SR subpanels with IC50 35.29 µM and 13.85 µM respectively. Moreover, compound 6a revealed potent topoisomerase IIα and topoisomerase IIβ inhibitory activity compared with known topoisomerase inhibitors such as doxorubicin and topotecan with IC50 1.30 µM and 0.017 µM respectively. Cell cycle analysis indicated that compound 6a induced cell cycle arrest at G2-M phase leading to inhibition of cell proliferation and apoptosis. Molecular modeling demonstrated that the potent topoisomerase inhibitory activity of 6a was due to the interaction with the topoisomerase II enzyme through coordinate bonding with the magnesium ion Mg2+, hydrogen bonding with Asp 545 and arene cation interaction with His 759.

Ru-η6-Arene Cations [{(Ph2PC6H4)2B(η6-Ph)}RuX]+(X=Cl, H) as Lewis Acids

Invited for the cover of this issue is the group of Doug Stephan at the University of Toronto. The image depicts the sites of reaction for Lewis bases at the Lewis acidic site of the η6-arene ring and the adjacent boron atom of the cationic complexes [{(Ph2PC6H4)2B(η6-Ph)}RuX]+. Read the full text of the article at 10.1002/chem.201304289.

Discovery of highly potent and selective D4 ligands by interactive SAR study

A series of thienylmethylphenylpiperazins was synthesized and tested for affinity towards the five subtypes of dopaminergic receptors. Compound 5f showed more than 1000 folds selectivity to D4 receptors; analogue 5e showed the highest affinity to D4 receptors with Ki 3.9nM. An interactive SAR approach was adopted and lead to compound 14a with Ki (D4) as low as 0.03nM. Molecular docking studies showed a potential, first to report arene cation interaction between the D4 unique residue Arg-186 and the ligands’ arene moiety, explaining the importance of having a strong negative electrostatic potential at this area of the compound structure.

Azacalix[4]arene cation radicals: spin-delocalised doublet- and triplet-ground states observed in the macrocyclic m-phenylene system connected with nitrogen atoms

Electron paramagnetic resonance spectroscopy has unmasked for the first time the spin-delocalised doublet- and triplet-ground states of azacalix[4]arene cation radicals.

Synthesis of Bimetallic Iron-Chromium and Iron-Manganese Complexes with Conjugated Benzodithiophene-Based Spacers

Palladium-catalyzed Sonogashira coupling reactions of an ethynylferrocene complex, [η 6 -phenylethynyl]tricarbonyl chromium and [η 5 (1-5)-1-ethynyl-4-methoxycyclohexa-2,4-dienyl]tricarbonyl manganese with a 2-iodobenzodithiophene derivative lead to the formation of mononuclear complexes. Similarly, condensation of the iodo derivative of one of these complexes with the [η 6 -phenylethynyl]tricarbonyl chromium and [η 5 (1-5)-1-ethynyl-4-methoxycyclohexa-2,4-dienyl]tricarbonyl manganese complexes affords bimetallic iron-chromium and iron-manganese complexes. Upon hydride abstraction, the manganese derivatives give the corresponding (η 6 -arene) cations. The structure of the neutral bimetallic iron-manganese complex has been investigated by X-ray diffraction study.

The Question of Aromaticity in Open-Shell Cations and Anions as Ion-Radical Offsprings of Polycyclic Aromatic and Antiaromatic Hydrocarbons

Arene cation-radicals and anion-radicals result directly from the one-electron oxidation and reduction of many aromatic hydrocarbons, yet virtually nothing is known of their intrinsic (thermodynamic) stability and hence "aromatic character". Since such paramagnetic ion radicals lie intermediate between aromatic (Hückel) hydrocarbons with 4n + 2-electrons and antiaromatic analogues with 4n-electrons, we can now address the question of pi-delocalization in these odd-electron counterparts. Application of the structure-based "harmonic oscillator model of aromaticity" or the HOMA method leads to the surprising conclusion that the aromaticity of these rather reactive, kinetically unstable arene cation and anion radicals (as measured by the HOMA index) is actually higher than that of their (diamagnetic) parent-contrary to conventional expectations.

Substituent constants for predicting aromatic molecular quadrupole moments

Work in our group has shown a direct relationship between arene–cation binding enthalpies and the aromatic quadrupole moment ( Θ zz ); the more negative the Θ zz value, the greater the arene–cation binding enthalpy. The ability to predict aromatic Θ zz values from the aromatic substitution pattern would therefore allow for the simultaneous prediction of the arene–cation binding enthalpy. Substituent constants were developed for the accurate prediction of Θ zz values for mono-, di-, tri- and tetra-substituted aromatics. The Θ zz values predicted from the developed substituent constants perform very well in determining relative arene–cation binding enthalpies.

A theoretical study of the cis-dihydroxylation mechanism in naphthalene 1,2-dioxygenase

The catalytic mechanism of naphthalene 1,2-dioxygenase has been investigated by means of hybrid density functional theory. This Rieske-type enzyme, which contains an active site hosting a mononuclear non-heme iron(II) complex, uses dioxygen and two electrons provided by NADH to carry out the cis-dihydroxylation of naphthalene. Since a (hydro)peroxo-iron(III) moiety has been proposed to be involved in the catalytic cycle, it was probed whether and how this species is capable of cis-dihydroxylation of the aromatic substrate. Different oxidation and protonation states of the Fe-O2 complex were studied on the basis of the crystal structure of the enzyme with oxygen bound side-on to iron. It was found that feasible reaction pathways require a protonated peroxo ligand, FeIII-OOH; the deprotonated species, the peroxo-iron(III) complex, was found to be inert toward naphthalene. Among the different chemical patterns which have been explored, the most accessible one involves an epoxide intermediate, which may subsequently evolve toward an arene cation, and finally to the cis-diol. The possibility that an iron(V)-oxo species is formed prior to substrate hydroxylation was also examined, but found to implicate a rather high energy barrier. In contrast, a reasonably low barrier might lead to a high-valent iron-oxo species [i.e. iron(IV)-oxo] if a second external electron is supplied to the mononuclear iron center before dioxygenation.

Ferrocene derivatives as receptors to explore ammonium cation–π interactions

The potential importance in biology of ammonium–arene cation–π interactions has fostered the development of a model system that uses ferrocene as a scaffold that can rotate groups with respect to each other while maintaining them at a fixed distance. The preparation of 1-benzyl-1′-N,N-dimethylaminomethylferrocene methiodide is reported along with the solid state structure of it and its precursor. Clear evidence is presented for an intermolecular ammonium–arene interaction. The results are analyzed in the context of existing arene–ammonium ion contacts.

Direct Observation of the Wheland Intermediate in Electrophilic Aromatic Substitution. Reversible Formation of Nitrosoarenium Cations

The Wheland intermediate in electrophilic aromatic nitrosation, viz. the nitrosoarenium σ-complex, is directly observed by transient absorption spectroscopy. Femtosecond time-resolved laser experiments based on charge-transfer photoexcitation of electron donor/acceptor (EDA) complexes of nitrosonium cation with various arenes reveal the ultrafast formation of nitrosobenzenium to occur in less than 10 ps via the radical/radical coupling of arene cation radicals and nitric oxide. The lifetimes of the σ-complexes in dichloromethane solution are strongly temperature dependentvarying from nanoseconds (T = 298 K) to microseconds (T = 195 K). Steady-state photolysis of arene/NO+ complexes in n-BuCl glasses at T = 77 K leads to nitrosoarenium σ-complexes which persist for several hours. Based on a reaction scheme that includes an ultrafast equilibrium between the [ArH+•,NO•] radical pair and the nitrosoarenium σ-complex, energy diagrams are constructed which establish the highly endergonic reaction profile of electrophilic aromatic nitrosations with the arene/nitrosonium π-complex as the thermodynamic sink.

Ultraviolet Laser Desorption of Chromium Tricarbonyl Arene Complexes: A Route to Extended Sandwich Complexes

The positive-ion ultraviolet laser desorption/ionization mass spectra of the benzene complex Cr(CO)3(C6H6) and the [2.2]cyclophane complexes Cr(CO)3(C16H16-1,4), Cr(CO)3(C16H16-1,3), and {Cr(CO)3}2(C24H24) are reported. In each spectrum intense ion signals are obtained which correspond to the decarbonylated chromium arene cation [Cr(arene)]+ and the bis(arene) sandwich cation [Cr(arene)2]+. The cyclophane complexes also generate ion signals at higher masses which can be attributed to extended polynuclear sandwich complexes. In addition, the ultraviolet laser desorption mass spectrum of a mixture of Cr(CO)6 and [2.2]paracyclophane is shown to comprise ions containing new metal−ligand bonds, viz. the sandwich species [Cr(C16H16-1,4)2]+.

Ultrafast electron transfer in arene - Br atom charge transfer complexes

Ultrafast pump-probe transient absorption spectroscopy was applied to study, return electron transfer in the areneBr atom charge transfer (CT) complexes. Ultrafast optical excitation of the charge transfer band, of the complex, yields an excited Franck-Condon state of the CT complex, which relaxes to form an ion pair. The rate of charge recombination between the bromide and arene cation strongly depends on arene concentration, indicating on efficient quenching of the ion pair by another donor molecule. The return electron transfer has been studied in various solvents. In general, the observed kinetics is nonexponential, with distribution of relaxation times from 1 ps to ∼1000 ps. The slowest component in the relaxation is attributed to charge recombination of the ion pair in an equilibrium configuration. The rate of charge recombination of the excited areneBr complex does not depend significantly on the donor strength.