Synthesis of N-Vinyl Cinnamaldehyde Nitrones through Atropisomeric Quinoxaline-Derived N,N,O-Ligand-Promoted Chan-Lam Reaction.

A type of quinoxaline-derived tridentate N,N,O-ligand was synthesized in good to excellent yields over three steps through iodination of 2-aryl indoles, sequential Kornblum-type oxidation with DMSO, and capture by 1,2-diaminobenzenes. The prepared atropisomeric N,N,O-ligand was successfully applied in the synthesis of N-vinyl cinnamaldehyde nitrones as only Z-isomers in good yields through the Chan-Lam reaction. The method features an easily accessed tunable tridentate N,N,O-ligand, broad substrate scope, good functional group tolerance, and high Z-isomer for N-vinyl nitrones.

Cinchonidine-Catalyzed Synthesis of Oxazabicyclo[4.2.1]nonanones from N-Aryl-α,ß-unsaturated Nitrones and 1-Ethynylnaphthalen-2-ols.

A variety of oxazabicyclo[4.2.1]nonanone derivatives were prepared in good yields through a cinchonidine-catalyzed cascade reaction of N-aryl-α,ß-unsaturated nitrones and 1-ethynylnaphthalen-2-ols. Mechanistic studies show that the reaction undergoes a [4 + 3] cycloaddition of nitrones to vinylidene o-quinone methide generated in situ from 1-ethynylnaphthalen-2-ols in the presence of cinchonidine, 1,3-rearrangement of N-O vinyl moieties, ring-opening, and finally double intramolecular cyclizations to afford oxazabicyclo[4.2.1]nonanones over five steps in a one-pot reaction.

Naturally occurring autoantibodies against Aß oligomers exhibited more beneficial effects in the treatment of mouse model of Alzheimer's disease than intravenous immunoglobulin.

Alzheimer's disease (AD) is characterized by memory loss, intracellular neurofibrillary tangles, and extracellular plaque deposits composed of ß-amyloid (Aß). Previous reports showed that naturally occurring autoantibodies, such as intravenous immunoglobulin (IVIG), benefited patients with moderate-stage AD who carried an APOE-ε4 allele. However, the mechanism underlying the role of IVIG remains unclear. In this study, we identified naturally occurring autoantibodies against Aß oligomers (NAbs-Aßo), which were purified by Aß42 oligomer or Cibacron Blue affinity chromatography from IVIG and termed as Oli-NAbs and Blue-NAbs, respectively. Oli-NAbs and Blue-NAbs recognized Aß42 oligomers or both Aß40 and 42 oligomers, differently. Both antibodies inhibited Aß42 aggregation and attenuated Aß42-induced cytotoxicity. Compared with vehicles, Oli-NAbs, Blue-NAbs and IVIG significantly improved the memory and cognition, and reduced the soluble and oligomeric Aß levels in APPswe/PS1dE9 transgenic mice. Further investigation showed that Blue-NAbs at increased doses effectively decreased plaque burden and insoluble Aß levels, whereas Oli-NAbs significantly declined the microgliosis and astrogliosis, as well as the production of proinflammatory cytokines in vivo. Therefore, high levels of these antibodies against oligomeric Aß40 or Aß42 were required, correspondingly, to achieve the optimal effect. NAbs-Aßo could be condensed to a high concentration by affinity chromatography and its isolation from IVIG may not interfere with the normal function of conventional IVIG as its concentration is very low. Thus, the isolated NAbs-Aßo as an extra product of plasma required low cost and the enriched NAbs-Aßo may be more feasible than IVIG for the treatment of AD.

N-terminal PEGylation of human serum albumin and investigation of its pharmacokinetics and pulmonary microvascular retention.

Human serum albumin (HSA) is used as an important plasma volume expander in clinical practice. In the present study, HSA was N-terminally PEGylated and a PEGylated HAS (PEG-HSA) carrying one chain of PEG (20 kDa) per HSA molecule was obtained. The purity, secondary structure and hydrodynamic radius of the modified protein were characterized using sodium dodecyl sulfate polyacrylamide gel electrophoresis, circular dichroism measurements, and dynamic light scattering, respectively. The pharmacokinetics in normal mice and vascular permeability of the PEG-HSA in a lipopolysaccharide-induced acute lung injury mice model were evaluated. The results showed that the biological half-life of the modified HSA was approximately 2.2 times of that of native HSA, and PEG-HSA had a lower vascular permeability which suggested that PEGylation of HSA could reduce extravasation into interstitial space. It can be inferred that due to the prolonged half-life time and enhanced vascular retention, the molecularly homogeneous PEG-HSA may be a superior candidate as a plasma volume expander in treating capillary permeability increase related illness.

Site-specific chemical modification of human serum albumin with polyethylene glycol prolongs half-life and improves intravascular retention in mice.

Human serum albumin (HSA) is used as an important plasma volume expander in clinical practice. However, the infused HSA may extravasate into the interstitial space and induce peripheral edema in treating the critical illness related to marked increase in capillary permeability. Such poor intravascular retention also demands a frequent administration of HSA. We hypothesize that increasing the molecular weight of HSA by PEGylation may be a potential approach to decrease capillary permeability of HSA. In the present study, HSA was PEGylated in a site-specific manner and the PEGylated HSA carrying one chain of polyethylene glycol (PEG) (20 kDa) per HSA molecule was obtained. The purity, PEGylated site and secondary structure of the modified protein were characterized by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), thiol group blockage method and circular dichroism (CD) measurement, respectively. In addition, the pharmacokinetics in normal mice was investigated, vascular permeability of the PEGylated HSA was evaluated in lipopolysaccharide (LPS)-induced lung injury mouse model and the pharmacodynamics was investigated in LPS-induced sepsis model with systemic capillary leakage. The results showed that the biological half-life of the modified HSA was approximately 2.3 times of that of the native HSA, PEG-HSA had a lower vascular permeability and better recovery in blood pressure and haemodilution was observed in rats treated with PEG-HSA. From the results it can be inferred that the chemically well-defined and molecularly homogeneous PEGylated HSA is superior to HSA in treating capillary permeability increase related illness because of its longer biological half-life and lower vascular permeability.