A modular autonomous flow reactor combining monitoring technologies with a feedback algorithm is presented for the synthesis of the natural product carpanone. The autonomous self-optimizing system, controlled via MATLAB, was designed as a flexible platform enabling an adaptation of the experimental setup to the specificity of the chemical transformation to be optimized. The reaction monitoring uses either online high pressure liquid chromatography (HPLC) or in-line benchtop nuclear magnetic resonance (NMR) spectroscopy. The custom-made optimization algorithm derived from the Nelder-Mead and golden section search methods performs constrained optimizations of black-box functions in a multidimensional search domain, thereby assuming no a priori knowledge of the chemical reactions. This autonomous self-optimizing system allowed fast and efficient optimizations of the chemical steps leading to carpanone. This contribution is the first example of a multistep synthesis where all discrete steps were optimized with an autonomous flow reactor.
Allosteric potentiation of acetylcholine nicotinic receptors is considered to be one of the most promising approaches for the treatment of Alzheimer's disease. However, the exact localization of the allosteric binding site and the potentiation mechanism at the molecular level are presently unknown. We have performed the "blind docking" of three known allosteric modulators (galanthamine, codeine and eserine) with the Acetylcholine Binding Protein and models of human alpha7, alpha3beta4 and alpha4beta2 nicotinic receptors, created by homology modeling. Three putative binding sites were identified in the channel pore, each one showing different affinities for the ligands. One of these sites is localized opposite to the agonist binding site and is probably implicated in the potentiation process. On the basis of these results, a possible mechanism for nicotinic acetylcholine receptor (nAChRs) activation is proposed. The present findings may represent an important advance for understanding the allosteric modulation mechanism of nAChRs. [Figure: see text].
The influence of sucrose (30, 60, 90 and 120 g/L), activated charcoal (5 and 10 g/L), and various levels of several plant growth regulators (6-benzyladenine, naphthalene-1-acetic acid, 2,4-dichlorophenoxyacetic acid, and picloram) on organogenesis (bulb and root development) and the accumulation of alkaloid and galanthamine in shoot cultures of three Amaryllidaceae species (Narcissus pseudonarcissus, Galanthus elwesii, and Leucojum aestivum) was investigated in a full-factorial experiment. Alkaloid extracts were analyzed by gas chromatographymass spectrometry, leading to the quantification of galanthamine and to the identification of other alkaloids. The different extracts were then subjected to an Ellman test to evaluate the inhibitory activity of acetylcholinesterase. The highest contents of galanthamine [0.02-0.1% dry weight (DW) depending on the plant species] were always accompanied with a high level of acetylcholinesterase inhibition ([30%). However, some samples containing low amounts of galanthamine (0.005% DW) showed high inhibitory activities (40-80%). These findings demonstrate the presence of Amaryllidaceae alkaloids that have not yet been identified as having anti-acetylcholinesterase activity.
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