Navigating α-Synuclein Aggregation Inhibition: Methods,Mechanisms, and Molecular Targets

Parkinson's disease is a yet incurable, age-related neurodegenerative disorder characterized by the aggregation of small neuronal protein α-synuclein into amyloid fibrils. Inhibition of this process is a prospective strategy for developing a disease-modifying treatment. We overview here small molecule, peptide, and protein inhibitors of α-synuclein fibrillization reported to date. Special attention was paid to the specificity of inhibitors and critical analysis of their action mechanisms. Namely, the importance of oxidation of polyphenols and cross-linking of α-synuclein into inhibitory dimers was highlighted. We also compared strategies of targeting monomeric, oligomeric, and fibrillar α-synuclein species, thoroughly discussed the strong and weak sides of different approaches to testing the inhibitors.     

New α-Functionalized Phosphorus Acid Surfactants: Synthesis,Dissociation Constants and Molecular Aggregation

Abstract

Pursuing our investigation into h e reactivity of red phosphorus. its hydrolysis derivatives (PH₃, and H₃,PO₂).^1,2 and P-H labile compounds? we report here a convenient method for the direct synthesis of free a-hydroxyalkyl phosphinic acid surfactants from aqueous hypophosphorous acid and the long-chain aldehydes or imincs under sonication.     

Determination of 5-Hydroxytryptamine, Norepinephrine, Dopamine and Their Metabolites in Rat Brain Tissue by LC–ESI–MS–MS

A liquid chromatography–electrospray ionization tandem mass spectrometry method has been developed to perform the determination of 5-hydroxytryptamine (5-HT), norepinephrine (NE), dopamine (DA) and their metabolites, i.e., 5-hydroxyindole-3-acetic acid (5-HIAA), 4-hydroxy-3-methoxyphenylglycol (MHPG) sulfate, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in rat brain tissue. Analytes were separated on a Thermo C₁₈ column (4.6 mm × 250 mm, 5 μm, SN: 1245575T, Thermo electron corporation, USA) with a mobile phase of 0.05% formic acid/acetonitrile (92:8 for ESI⁺, 82:18 for ESI^?, v/v) at the flow-rate of 0.8 mL min^?1. The LC system was coupled to a Waters Micromass Quattro Premier XE tandem quadruple mass spectrometer. MS acquisition of 5-HT, NE and DA was performed in positive electrospray ionization multiple reaction monitoring (MRM) mode, while negative electrospray ionization MRM mode was used to monitor their metabolites. The calibration curves were linear within the concentration range of 4–4,450 ng mL^?1 for 5-HT, 4–4,110 ng mL^?1 for NE and 4–4,100 ng mL^?1 for DA (r ≥ 0.999). The limit of quantitation was 4 ng mL^?1. 5-HIAA, MHPG, DOPAC and HVA have good linearity within the range of 12–1,000 ng mL^?1(r ≥ 0.998) and the limit of quantitation was 12 ng mL^?1. The intra- and inter-day RSD were lower than 8.45%. The method is sensitive, fast, accurate and usable for quantity determination of monoamine neurotransmitters and their metabolites in neuropsychiatric diseases.     

Hydrothermal Synthesis,Crystal Structure,and Catalytic Performance of Four Organic–Inorganic Hybrids Based on Polyoxometalates and O/N-Containing Groups

Four new network organic–inorganic hybrid supramolecular compounds [PW₁₂O₄₀](C₂H₄N₃)₃·6H₂O (1), [PMo₁₂O₄₀](C₂H₄N₃)₃·6H₂O (2), [H₄SiW₁₂O₄₀]₈[C₆NO₂H₄]₄[C₆NO₂H₅]₁₆[C₅NH₆]₄·39H₂O (3) and [H₃VW₁₂O₄₀] (C₆H₆NO₂)₂(CHO₂)₂·4H₂O (4) composed by keggin type heteropolyanion and O/N-containing organic groups of 1H-1,2,4-Triazole or 2,3-Pyridinedicarboxylic acid have been successfully synthesized by hydrothermally method, and characterized by infrared spectrum (IR), thermogravimetric–differentialthermal analysis (TG–DTA), cyclic voltammetry (CV) and single crystal X-ray diffraction (XRD). Compounds 1–4 exhibit three dimensional supramolecular network via hydrogen bonds and/or π–π stacking interactions. These compounds exhibit good thermal stability and catalytic ability. They are active for catalytic oxidation of methanol in a continuous-flow fixed-bed micro-reactor, when the initial concentration of methanol is 2.5 g m^?3 in air and flow rate is 10 mL min^?1, the corresponding elimination rates of methanol are 65% (125 °C), 85% (125 °C), 94% (150 °C), and 80% (125 °C), respectively.     

Host–guest interactions between niobocene dichloride and α-, β-, and γ-cyclodextrins: preparation and characterization

The possible inclusion complexes of Cp₂NbCl₂ into α-, β-, and γ-CD hosts have been investigated. The existence of a true inclusion complex in the solid state was confirmed by a combination of thermogravimetric analysis, FTIR, PXRD, and ¹³C CP-MAS NMR spectroscopies. The solid-state results demonstrated that α-cyclodextrin does not form inclusion complexes with Cp₂NbCl₂ whereas β- and γ-cyclodextrins do form such complexes. PXRD, NMR, and thermal analysis showed that the organometallic molecules of Cp₂NbCl₂OH are included in the cavities of β- and γ-cyclodextrins, possibly adopting a symmetrical conformation in the complex, with each glucose unit in a similar environment. In solution, ¹H NMR experiments suggest that niobocene has a shallow penetration on the β-CD leading to upfield shift on H-3 signal with a minor perturbation on the H-5 proton while for γ-CD, both H-3 and H-5 are shifted upfield substantially. This suggests that niobocene penetrates deeper into the γ-CD cavity than in the β-CD cavity, as a result of the cavity size. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Natural α-Amino Acid L-Lysine–Catalyzed Knoevenagel Condensations of α,β-Unsaturated Aldehydes and 1,3-Dicarbonyl Compounds

Knoevenagel condensations of α,β-unsaturated aldehydes and 1,3-dicarbonyl compounds were catalyzed by primary natural amino acid L-lysine. The reactions were carried out at room temperature in dimethylsulfoxide. It provides a facile entry to a wide variety of α,β,γ,δ-unsaturated dicarbonyl compounds.

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Aggregation and Tunable Color Emission Behaviors of l-Glutamine-Derived Platinum(II) Bipyridine Complexes by Hydrogen-Bonding, π–π Stacking and Metal–Metal Interactions

A n l -glutamine-derived functional group was introduced to the bis(arylalkynyl)platinum(II) bipyridine complexes 1 – 4 . The emission could be switched between the ³MLCT excited state and the triplet excimeric state through solvent or temperature changes, which is attributed to the formation and disruption of hydrogen-bonding, π–π stacking, and metal–metal interactions. Different architectures with various morphologies, such as honeycomb nanostructures and nanospheres, were formed upon solvent variations, and these changes were accompanied by ¹H NMR and distinct emission changes. Additionally, yellow and red emissive metallogels were formed at room temperature due to the different aggregation behaviors introduced by the substituent groups on bipyridine. The thermoresponsive metallogel showed emission behavior with tunable colors by controlling the temperature. The negative Gibbs free-energy change (ΔG) and the large association constant for excimer formation have suggested that the molecules undergo aggregation through hydrogen-bonding, π–π, and metal–metal interactions, resulting in triplet excimeric emission.     

Aggregation Stability of SiO2, FeOOH, ZrO2, CeO2, and Natural Diamond Sols and Their Binary Mixtures: 2. The Photometric Study of Heterocoagulation of SiO2–FeOOH, SiO2–ZrO2, SiO2–CeO2, and CeO2–Natural Diamond Binary Systems in KCl Solutions

The aggregation stability of 1 : 1 and 3 : 1 (by volume) binary mixtures of two hydrophobic (SiO₂–FeOOH), one hydrophobic and one hydrophilic (SiO₂–ZrO₂, SiO₂–CeO₂), and two hydrophilic (CeO₂–natural diamond) sols was studied by photometry over a wide range of KCl concentrations at pH 6 and 3. The stability of the mixed binary sols was determined by the stability of the sol with a predominant particle number concentration. In the SiO₂–FeOOH system, the phenomenon of heteroadagulation stabilization was caused by the electrostatic factor of the stability of adsorbed SiO₂ particles and, in the SiO₂–ZrO₂ system, by the structural factor of the stability of adsorbed hydrophilic ZrO₂ particles. The stability of binary mixtures containing one or two hydrophobic components is qualitatively explained in terms of the Derjaguin theory of heterocoagulation of hydrophobic colloids. The stability of the binary system of two hydrophilic components (CeO₂–natural diamond) is determined by the structural component of the interaction energy of particles.     

Facile one-pot synthesis,butyrylcholinesterase and α-glucosidase inhibitory activities,structure–activity relationship,molecular docking and DNA–drug binding analysis of Meldrum’s acid derivatives

Research on Chemical Intermediates - Meldrum’s acid derivatives were facile synthesized by one-pot condensation process and characterized by NMR (1H, 13C, DEPT-90 and DEPT-135) and EI-MS. The...     

Catalyst,additive and counterion effects on the efficiency and enantioselectivity of copper-catalysed C–H insertion reactions of α-diazosulfones

Asymmetric copper-catalysed intramolecular C–H insertion reactions of α-diazosulfones in the presence of various group I salts are reported leading to substantial variation in reaction efficiencies and enantioselectivities. The borate additives NaBARF and KBARF were found to be the most effective additives for permitting highly enantioselective syntheses with short reactions times and high efficiency. Significantly, direct evidence of the critical role of the additive in enantioselective carbenoid reactions has been secured.     

Synthesis, transport and ionophore properties of α,ω-biphosphorylated azapodands: V. Acid-base properties of new phosphorylated azapodands and α,ω-diamines and their participation in the membrane transport of I–III groups metal ions

Acid-base properties of newly and previously synthesized phosphorylated azapodands and ??,??-diamines and their amine precursors were studied. We found that they differ in the same range as has been found previously for the other aminophosphoryl compounds. The investigation of the processes of passive membrane ion transport of a series of metals of I?CIII groups by these reactants showed with all diphosphoryl diamines higher values of the transfer flow of the ions Sc(III), Nd(III), and Sm(III), than the ions of alkali and alkaline earth metals. Under the conditions of active membrane transport the azapodand IV exhibits high efficiency in the ion transport of Sr(II) and Ba(II), while diphosphoryldiamine III exhibits effective transport of Nd(III) ions. The factors that determine the efficiency and selectivity of the membrane extraction of the I?CIII groups metal ions by these diphosphoryl diamines are discussed.     

Triflic Acid–Catalyzed Michael Reactions of Indole and Pyrrole Compounds with α,β‐Unsaturated Ketones in Water

The Michael reactions of indole and pyrrole compounds to α,β‐unsaturated ketones catalyzed by triflic acid (HOTf, 0.1–1 mol%) were performed in water to give alkylated indoles (3a–m) and dialkylsubstituted pyrroles (6a–b) in good to excellent yields.     

Chiral,non-racemic diols,and α-amino acid-derived β-amino alcohols as templates for chiral catalysts in the Tsuji–Trost reaction

A commercially available collection of β-amino alcohols have been converted to their corresponding β-(o-diphenylphosphino) benzoyloxy(o-diphenylphosphino) benzamides and have been employed in the Tsuji–Trost asymmetric alkylation reaction with 1,3-diphenylpropenyl acetate. The best ligand was derived from l-tert-leucinol and when applied to the asymmetric allylic alkylation reaction, yielded the product in an enantiomeric ratio of 99.5:0.5 favoring the (S)-enantiomer.     

Syntheses,crystal structures,and magnetic properties of RE(III)–Cu(II) heteronuclear complexes with α-methylacrylic acid

A series of carboxylate-bridged heteronuclear 3d–4f complexes have been prepared by reaction of REL₃ (HL = CH₂ = C(CH₃)COOH) with Cu(NO₃)₂. A family of air-stable 2-D complexes [RECuL₄(H₂O)₄] _n L _n (RE = La (1), Ce (2), Eu (3), and Gd (4)) have the same crystal system (monoclinic) and space group (P2₁/c). The chains which are made by the carboxylate-bridged alternating Cu(II)–RE(III) fragments spreading along the c-axis are linked through hydrogen bonds by uncoordinated carboxylates to form a 2-D network structure along the bc planes. Magnetic measurements showed that 1 and 2 have antiferromagnetic interaction between RE and Cu, but 4 exhibits ferromagnetic interaction. Eu ions show van Vleck behavior in 3.     

Micellar Mediated Halodecarboxylation of α,β‐Unsaturated Aliphatic and Aromatic Carboxylic Acids—A Novel Green Hunsdiecker–Borodin Reaction

A Novel Hunsdiecker‐Borodin reaction (HBR) has been carried out efficiently with α,β‐unsaturated aliphatic and aromatic carboxylic acids by using N‐halo succinimides such as N‐chloro succinimide (NCS), N‐bromo succinimide (NBS), and N‐iodo succinimide (NIS) under micellar media. The reaction with α,β‐unsaturated aromatic carboxylic acids afforded β‐halo styrenes in excellent yield while α,β‐unsaturated aliphatic carboxylic acids underwent decarboxylation and to give corresponding halo derivatives. The reactions are dramatically accelerated in micellar media. This procedure works efficiently in CTAB (cetyl trimethyl ammonium bromide), SDS (sodium dodecyl sulfate), and TX (Triton‐X‐100) media under stirred conditions at room temperature. At reflux temperatures the yield of reaction products were further enhanced from good to excellent.     

Diastereo- and enantioselective synthesis of anti-1,3-mercapto alcohols from α,β-unsaturated ketones via tandem Michael addition–MPV reduction

A new and effective asymmetric synthesis of anti-1,3-mercapto alcohols 3 from α,β-unsaturated ketones 1 utilizing tandem Michael addition–Meerwein–Ponndorf–Verley (MPV) reduction is described. Transformation of the MPV products anti-4 via the Wagner–Meerwein rearrangement was optimized under acidic or basic conditions to afford 1,3-mercapto alcohols anti-3, depending on the substituent R² of 4.