ABSTRACT
Herein, we report the diastereoselective synthesis of a 3-amino-1,2,4-oxadiazine (AOXD) scaffold. The presence of a N-O bond in the ring prevents the planar geometry of the aromatic system and induces a strong decrease in the basicity of the guanidine moiety. While DIBAL-H appeared to be the most efficient reducing agent because it exhibited high diastereoselectivity, we observed various behaviors of the Mitsunobu reaction on the resulting ß-aminoalcohol, leading to either inversion or retention of the configuration depending on the steric hindrance in the vicinity of the hydroxy group. The physicochemical properties (pKa and log D) and hepatic stability of several AOXD derivatives were experimentally determined and found that the AOXD scaffold possesses promising properties for drug development. Moreover, we synthesized alchornedine, the only natural product with the AOXD scaffold. Based on a comparison of the analytical data, we found that the reported structure of alchornedine was incorrect and hypothesized a new one.
ABSTRACT
An efficient and user-friendly palladium(II) precatalyst, POxAP (post-oxidative-addition precatalyst), was identified for use in Fukuyama cross-coupling reactions. Suitable for storage under air, the POxAP precatalyst allowed reaction between thioesters and organozinc reagents with turnover numbers of â¼90000. A series of 23 ketones were obtained with yields ranging from 53 to 99%. As proof of efficacy, an alternative approach was developed for the synthesis of a key precursor of the natural product isoprekinamycin.
ABSTRACT
Recently, anandamide (AEA) analogues have been well recognized for its potent neuroprotective effects in counteracting the deterioration of Alzheimer's disease (AD) brains through multiple pathological processes. In our previous studies, dipotassium N-stearoyltyrosinate (NSTK), an AEA analogue synthesized by our laboratory was reported to exert significant efficacy through multiple interventions. Within this study, the amyloid precursor protein (APP)SWE/presenilin-1 (PS1)M146V/TauP301L mouse (3×Tg-AD) model was used to explore further the neuroprotective effects of NSTK and its underlying mechanisms. NSTK could increase spontaneous locomotor activity in the open field and low anxiety-like behavior in the elevated plus maze, and improve the spatial memory deficits in the Morris water maze. The biochemical analysis suggested that NSTK could decrease Aß42 deposition, abnormal tau aggregation, and the expressions of p-APP Thr668, PS1 and p-tau Ser202/Thr205 in the hippocampus of 3×Tg-AD mice. Consistently, NSTK could reduce the level of malondialdehyde, increase the activity of superoxide dismutase and catalase. Up-regulation of Bcl-2, and down-regulation of BAX, caspase-3 and inflammatory cytokines also occurred in the hippocampus of 3×Tg-AD mice after treatment with NSTK. Thus, NSTK could intervene in multiple pathological processes of AD and would be a drug candidate against AD.
Subject(s)
Alzheimer Disease/drug therapy , Neuroprotective Agents/therapeutic use , Tyrosine/analogs & derivatives , Alzheimer Disease/metabolism , Amyloid beta-Peptides/metabolism , Amyloid beta-Protein Precursor/genetics , Animals , Brain/drug effects , Brain/metabolism , Caspase 3/metabolism , Cytokines/metabolism , Disease Models, Animal , Male , Maze Learning/drug effects , Mice, Inbred C57BL , Mice, Transgenic , Neuroprotective Agents/pharmacology , Presenilin-1/genetics , Proto-Oncogene Proteins c-bcl-2/metabolism , Tyrosine/pharmacology , Tyrosine/therapeutic use , bcl-2-Associated X Protein/metabolism , tau Proteins/genetics , tau Proteins/metabolismABSTRACT
N-stearoyltyrosine dipotassium (NST-2K) as a neuroprotective candidate is currently in preclinical studies in China. This study investigated the anti-obese effect of NST-2K in high-fat diet-induced obese (DIO) mice. The DIO mice were induced from male C57BL/6 mice by feeding high-fat diet for 11-weeks and treated orally with NST-2K for other 4 weeks. The treatments of DIO mice with NST-2K at 60 or 100 mg/kg/day suppressed the body weight gain, decreased both visceral fat weight and adipocyte size without influence on food intake. To evaluate the effect of NST-2K on lipid metabolism, lipid parameters and several key molecules in the plasma, liver, duodenum mucosa and adipose tissue were analyzed. NST-2K ameliorated the low-grade inflammation in liver, inhibited pancreatic lipase activity in duodenum mucosa, activated ß-oxidation system and reduced lipogenesis, thus suppressed lipid accumulation in the liver, reduced adipocyte size and improved lipid and carbohydrate metabolism. Overall, without influence on food intake, NST-2K ameliorated high-fat diet-induced obesity via suppressing liver inflammation, inhibiting dietary fat absorption, promoting lipolysis and reducing lipogenesis.
