corynoxine-b and corynoxine

Kratom,

Topics: Alkaloids; Animals; Indole Alkaloids; Indoles; Male; Mitragyna; Molecular Structure; Oxindoles; Plant Preparations; Rats; Rats, Sprague-Dawley; Secologanin Tryptamine Alkaloids; Spiro Compounds

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Electrophoresis, Capillary; Hydrogen-Ion Concentration; Indoles; Ionic Liquids; Limit of Detection; Linear Models; Reproducibility of Results; Spiro Compounds; Stereoisomerism

Recent studies have demonstrated that dysregulation of macroautophagy/autophagy may play a central role in the pathogenesis of neurodegenerative disorders, and the induction of autophagy protects against the toxic insults of aggregate-prone proteins by enhancing their clearance. Thus, autophagy has become a promising therapeutic target against neurodegenerative diseases. In this study, quantitative phosphoproteomic profiling together with a computational analysis was performed to delineate the phosphorylation signaling networks regulated by 2 natural neuroprotective autophagy enhancers, corynoxine (Cory) and corynoxine B (Cory B). To identify key regulators, namely, protein kinases, we developed a novel network-based algorithm of in silico Kinome Activity Profiling (iKAP) to computationally infer potentially important protein kinases from phosphorylation networks. Using this algorithm, we observed that Cory or Cory B potentially regulated several kinases. We predicted and validated that Cory, but not Cory B, downregulated a well-documented autophagy kinase, RPS6KB1/p70S6K (ribosomal protein S6 kinase, polypeptide 1). We also discovered 2 kinases, MAP2K2/MEK2 (mitogen-activated protein kinase kinase 2) and PLK1 (polo-like kinase 1), to be potentially upregulated by Cory, whereas the siRNA-mediated knockdown of Map2k2 and Plk1 significantly inhibited Cory-induced autophagy. Furthermore, Cory promoted the clearance of Alzheimer disease-associated APP (amyloid β [A4] precursor protein) and Parkinson disease-associated SNCA/α-synuclein (synuclein, α) by enhancing autophagy, and these effects were dramatically diminished by the inhibition of the kinase activities of MAP2K2 and PLK1. As a whole, our study not only developed a powerful method for the identification of important regulators from the phosphoproteomic data but also identified the important role of MAP2K2 and PLK1 in neuronal autophagy.

Topics: alpha-Synuclein; Amyloid beta-Peptides; Animals; Autophagy; Cell Cycle Proteins; Computer Simulation; Indoles; MAP Kinase Kinase 2; Mice; Neurodegenerative Diseases; Neurons; PC12 Cells; Phosphoproteins; Phosphorylation; Polo-Like Kinase 1; Protein Serine-Threonine Kinases; Proteome; Proto-Oncogene Proteins; Rats; Ribosomal Protein S6 Kinases, 70-kDa; Spiro Compounds

A facile and straightforward method was developed to construct the fused tetracyclic 3-spirooxindole skeleton, which exists widely in natural products. The formation of the tetracyclic 3-spirooxindole structure was achieved through a transition-metal-free intramolecular cross-dehydrogenative coupling of pyridinium, which were formed in situ by the condensation of 3-(2-bromoethyl)indolin-2-one derivatives with 3-substituted pyridines. As examples of the application of this new methodology, two potentially medicinal natural products, (±)-corynoxine and (±)-corynoxine B, were efficiently synthesized in five scalable steps.

Topics: Biological Products; Chemistry Techniques, Synthetic; Hydrogen; Indoles; Oxindoles; Pyridines; Spiro Compounds