Yufen Zhao

TiO2 nanoparticles promote beta-amyloid fibrillation in vitro

Alzheimers disease (AD) is the most common neurodegenerative disease in the world. The pathogenesis of AD is associated with beta-amyloid (Abeta) fibrillation. Nanoparticles have large surface area and can access the brain. But no investigation has been made to study the relationship between nanoparticles and AD. In our study, we observed Abeta fibril formation in the presence of six kinds of nanoparticles and found that TiO2 nanoparticles can promote Abeta fibrillation by shortening nucleation process, which is the key rate-determining step of fibrillation. Hereby the interaction between Abeta and nanoparticles may contribute to AD etiology.

Copper-catalyzed synthesis of benzimidazoles via cascade reactions of o-haloacetanilide derivatives with amidine hydrochlorides

We have developed an efficient method for the synthesis of benzimidazoles via cascade reactions of o-haloacetoanilide derivatives with amidine hydrochlorides. The protocol uses 10 mol % CuBr as the catalyst, Cs2CO3 as the base, and DMSO as the solvent, and no ligand is required. The procedure proceeds via the sequential coupling of o-haloacetoanilide derivatives with amidines, hydrolysis of the intermediates (amides), and intramolecular cyclization with the loss of NH3 to give 2-substituted 1H-benzimidazoles.

An Efficient One-Pot Copper-Catalyzed Approach to Isoquinolin-1(2H)-one Derivatives

A simple and efficient copper-catalyzed method for synthesis of 3,4-disubstituted isoquinolin-1(2H)-one derivatives via cascade reactions of substituted 2-halobenzamides with beta-keto esters under mild conditions has been developed, and the method has economical and practical advantages.

Sequestration of Copper from β-Amyloid Promotes Selective Lysis by Cyclen-Hybrid Cleavage Agents

Decelerated degradation of β-amyloid (Aβ) and its interaction with synaptic copper may be pathogenic in Alzheimer disease. Recently, Co(III)-cyclen tagged to an aromatic recognition motif was shown to degrade Aβ in vitro. Here, we report that apocyclen attached to selective Aβ recognition motifs (KLVFF or curcumin) can capture copper bound to Aβ and use the Cu(II) in place of Co(III) to become proteolytically active. The resultant complexes interfere with Aβ aggregation, degrade Aβ into fragments, preventing H2O2 formation and toxicity in neuronal cell culture. Because Aβ binds Cu in amyloid plaques, apocyclen-tagged targeting molecules may be a promising approach to the selective degradation of Aβ in Alzheimer disease. The principle of copper capture could generalize to other amyloidoses where copper is implicated.

General and efficient copper-catalyzed amidation of saturated C-H bonds using N-halosuccinimides as the oxidants

We have developed a general and efficient method for copper-catalyzed amidation of saturated C-H bonds under mild conditions, and the used substrates include benzylic reagents, the N, N-dimethylaniline derivatives, the free carboxamides, and sulfonamides. The protocol uses inexpensive and readily available CuBr/ N-halosuccinimide (NBS or NCS) as the catalyst/oxidant, so it provides practical applications for synthesis of various amides via C-H activation.

Copper-Catalyzed Aerobic Oxidative Intramolecular C-H Amination Leading to Imidazobenzimidazole Derivatives

A highly efficient copper-catalyzed aerobic oxidative intramolecular C-H amination has been developed using substituted 2-(1H-imidazol-1-yl)-N-alkylbenzenamines as the starting materials, and the corresponding imidazobenzimidazole derivatives were obtained in excellent yields. This is an economical and practical method for the construction of N-heterocycles.

Highly efficient copper-catalyzed amidation of aldehydes by C-H activation.

We have developed a highly efficient method for the copper-catalyzed amidation of aldehydes in the presence of N-bromosuccinimide (NBS). This method is simple, economical, and has practical advantages for synthesis of imides.

Copper binding properties of a tau peptide associated with Alzheimer's disease studied by CD, NMR, and MALDI-TOF MS

We have previously reported the copper binding properties of R3 peptide (residues 318-335: VTSKCGSLGNIHHKPGGG, according to the longest tau protein) derived from the third repeat microtubule-binding domain of water-soluble tau protein. In this work, we have investigated copper binding properties of R2 peptide (residues 287-304: VQSKCGSKDNIKHVPGGG) derived from the second repeat region of tau protein. Similar to R3 peptide, R2 peptide also plays an important role in the formation of neurofibrillary tangles (NFTs) which is one of the two main biological characteristics of Alzheimers disease (AD). Based on the copper binding properties of R2 peptide, the possible influences of the binding on the formation of NFTs were investigated. Results from circular dichroism (CD) spectra, nuclear magnetic resonance (NMR) spectroscopy, and matrix assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS) suggest that the binding is pH-dependent and stoichiometry-determined. In addition, these results also reveal that R2 peptide adopts a monomeric alpha-helical structure in aqueous solutions at physiological pH after the addition of 1 mol equiv. of Cu2+. Since alpha-helix structure is responsible for the formation of paired helical filaments (PHFs) which aggregate into NFTs, it is hypothesized that Cu2+ induces R2 peptide to self-assemble into a PHFs-like structure. Hence, it is postulated that Cu2+ plays an important role in the aggregation of R2 peptide and tau protein and that copper binding to R2 peptide may be another possible involvement in AD.

Copper-Catalyzed P-Arylation via Direct Coupling of Diaryliodonium Salts with Phosphorus Nucleophiles at Room Temperature

A new method for copper-catalyzed P-C bond formation through reaction of phosphorus nucleophiles with diaryliodonium salts at room temperature is described. Most target products are obtained with this method in high yields within a short reaction time of 10 min. It can be easily adapted to large-scale preparations. When unsymmetrical iodonium salts are employed, nucleophilic substitution occurs preferentially on the sterically hindered aromatic ring or the more electron-deficient ring.

Transition‐Metal‐Free Intramolecular Ullmann‐Type O‐Arylation: Synthesis of Chromone Derivatives

Aromatic C O bond-forming reactions are important in organic synthesis because these bonds occur in numerous natural products, biological compounds, pharmaceuticals, fragrances, cosmetics, and polymers. Traditionally, aryl ethers have been prepared by copper-mediated Ullmann coupling reactions of aryl bromides/iodides and phenols, but the drawbacks include harsh reaction conditions, such as: the need for a strong base, long reaction times in high polar solvents, and a stoichiometric amount of copper. Subsequently, some significant achievements in the palladiumcatalyzed O-arylation have been made under mild reaction conditions (Scheme 1a). Recently, copper-catalyzed Ullmann-type O-arylations have been developed under milder reaction conditions (Scheme 1a) using inexpensive copper salts and readily accessible ligands, such as phenanthrolines, N,N-dimethyl glycine, pyridine derivatives, bdiketones, 1,1,1-tris(hydroxymethyl)ethane, and pyrrolidine-2-phosphonic acid phenyl monoester. Palladiumor copper-catalyzed intramolecular O-arylations have attracted much attention, and some oxygen heterocycles were constructed with the Ullmann-type O-arylation strategy, for example copper-catalyzed synthesis of substituted 4H-1benzopyrans (Scheme 1b), 2,3-dihydro-1,4-benzoxazines (Scheme 1c), benzoxazoles (Scheme 1d), and copper[6g,h] and palladium-catalyzed synthesis of five and sixmembered oxygen heterocycles (Scheme 1e). The results above show that transition-metal catalysts (palladium and copper) seem to be necessary in O-arylations. Chromone derivatives are ubiquitous to green-plant cells and are highly diverse; more than 2000 different flavonoids have been identified, and their number is growing rapidly. These derivatives show various biological and pharmaceutical activity, so they are interesting as structural scaffolds and have been assigned as privileged structures in drug development. Although some approaches to the chromone derivatives have been developed, the methods often suffer from harsh reaction conditions, limited substrate scope, poor substituent tolerance, and low yields. Several efficient palladium-catalyzed routes have been developed for the synthesis of chromone derivatives. The excellent results from the copperand palladium-catalyzed O-arylations above prompted us to make chromone derivatives by using a transition-metal-catalyzed strategy. Thus, considering the ready availability and low toxicity of copper catalysts, we first screened copper-catalyzed reaction conditions by using the intramolecular O-arylation of 1-(2-bromophenyl)-3-ptolylpropane-1,3-dione (1a) as the model reaction (Table 1). Surprisingly, a more highly efficient O-arylation was observed in the absence of a copper salt (entry 7, Table 1). Herein, we report the unexpected transition-metal-free intramolecular Ullmann-type O-arylation leading to chromone derivatives (Scheme 1 f). 1-(2-Bromophenyl)-3-p-tolylpropane-1,3-dione (1a) was first used as the model substrate to screen the reaction conditions for the optimization of the catalyst, base, solvent, temperature, and reaction time under air. As shown in Table 1, six copper catalysts were tested at 110 8C in the presence of one equivalent of Cs2CO3 (relative to the amount Scheme 1. a–e) Copperand palladium-catalyzed Ullmann-type O-arylations (previous research). f) Transition-metal-free intramolecular Ullmann-type O-arylation leading to chromones (this work). DMF=N,N’dimethylformamide.