Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 16, Issue 6, Pages 3025-3031Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2007.12.037
Keywords
alkaloid; conformation; NMR; hydrogen bonding; structure fluctuation; veratridine; sodium channel
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The lipid-soluble veratrum alkaloids, veratridine and cevadine, are plant neurotoxins that are agonists of voltage-gated sodium channel. Their conformations in a hydrophobic environment were analyzed by NMR spectroscopy in solution phase chloroform at low temperatures. The conformations around the 3-carboxylic esters which is essential for their neurotoxicity, was completely different from the previously reported X-ray crystallographic structure. The carbonyl oxygen atom (028) of the carboxylic ester forms a weak intramolecular hydrogen bond with the OH proton at C4 (4-OH) that loosely restricts the conformation of the 3-veratroyl ester in veratridine and the 3-angeloyl ester in cevadine. Methylation at C4 hydroxyl group of veratridine had much reduced its neurotoxic activity relating to voltage-gated sodium channel. The results suggested that the loose conformational restrictions of the carboxylic esters are important for neurotoxicity of the veratrum alkaloids. (C) 2007 Elsevier Ltd. All rights reserved.
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