Lycopsamine

1 Amsinckia sp. 2 Anchusa sp. 3 Borago sp. 4 Cryptantha sp. 5 Eupatorium sp. 6 Heliotropium sp. 7 Messerschmidia sp. 8 Symphytum sp.

Semi-automated separation of the epimeric dehydropyrrolizidine alkaloids lycopsamine and intermedine: preparation of their N-oxides and NMR comparison with diastereoisomeric rinderine and echinatine.[Pubmed:24816769]

Phytochem Anal. 2014 Sep-Oct;25(5):429-38.

INTRODUCTION: The diversity of structure and, particularly, stereochemical variation of the dehydropyrrolizidine alkaloids can present challenges for analysis and the isolation of pure compounds for the preparation of analytical standards and for toxicology studies. OBJECTIVE: To investigate methods for the separation of gram-scale quantities of the epimeric dehydropyrrolizidine alkaloids Lycopsamine and intermedine and to compare their NMR spectroscopic data with those of their heliotridine-based analogues echinatine and rinderine. METHODS: Lycopsamine and intermedine were extracted, predominantly as their N-oxides and along with their acetylated derivatives, from commercial samples of comfrey (Symphytum officinale) root. Alkaloid enrichment involved liquid-liquid partitioning of the crude methanol extract between dilute aqueous acid and n-butanol, reduction of N-oxides and subsequent continuous liquid-liquid extraction of free base alkaloids into CHCl3 . The alkaloid-rich fraction was further subjected to semi-automated flash chromatography using boronated soda glass beads or boronated quartz sand. RESULTS: Boronated soda glass beads (or quartz sand) chromatography adapted to a Biotage Isolera Flash Chromatography System enabled large-scale separation (at least up to 1-2 g quantities) of Lycopsamine and intermedine. The structures were confirmed using one- and two-dimensional (1) H- and (13) C-NMR spectroscopy. Examination of the NMR data for Lycopsamine, intermedine and their heliotridine-based analogues echinatine and rinderine allowed for some amendments of literature data and provided useful comparisons for determining relative configurations in monoester dehydropyrrolizidine alkaloids. A similar NMR comparison of Lycopsamine and intermedine with their N-oxides showed the effects of N-oxidation on some key chemical shifts. A levorotatory shift in specific rotation from +3.29 degrees to -1.5 degrees was observed for Lycopsamine when dissolved in ethanol or methanol respectively. CONCLUSION: A semi-automated flash chromatographic process using boronated soda glass beads was standardised and confirmed as a useful, larger scale preparative approach for separating the epimers Lycopsamine and intermedine. The useful NMR correlations to stereochemical arrangements within this specific class of dehydropyrrolizidine alkaloid cannot be confidently extrapolated to other similar dehydropyrrolizidine alkaloids. Published 2014. This article is a U.S. Government work and is in the public domain in the USA.

TLC densitometric method for screening of lycopsamine in comfrey root (Symphytum officinale L.) extracts using retrorsine as a reference compound.[Pubmed:25531790]

Acta Pharm. 2014 Dec;64(4):503-8.

Due to severe toxicity of pyrrolizidine alkaloids, their quantification in medicinal products is very important. The idea of this research was to use retrorsine as a surrogate reference compound instead of Lycopsamine reference or Lycopsamine isolated from comfrey. A method for the analysis of Lycopsamine in extracts of comfrey roots was developed and validated, employing thin layer chromatography, derivatisation with Dann-Mattocks reagent followed by densitometric analysis. The new method showed linearity within 0.70 to 7.0 mug of Lycopsamine per application of 10 muL of a solution. It has also been proven to be specific and precise (repeatability RSD 2-4 % within the plate). The method was successfully employed for quantification of Lycopsamine in comfrey root and comfrey root medicinal products such as ointments.

The comparative toxicity of a reduced, crude comfrey (Symphytum officinale) alkaloid extract and the pure, comfrey-derived pyrrolizidine alkaloids, lycopsamine and intermedine in chicks (Gallus gallus domesticus).[Pubmed:26177929]

J Appl Toxicol. 2016 May;36(5):716-25.

Comfrey (Symphytum officinale), a commonly used herb, contains dehydropyrrolizidine alkaloids that, as a group of bioactive metabolites, are potentially hepatotoxic, pneumotoxic, genotoxic and carcinogenic. Consequently, regulatory agencies and international health organizations have recommended comfrey be used for external use only. However, in many locations comfrey continues to be ingested as a tisane or as a leafy vegetable. The objective of this work was to compare the toxicity of a crude, reduced comfrey alkaloid extract to purified Lycopsamine and intermedine that are major constituents of S. officinale. Male, California White chicks were orally exposed to daily doses of 0.04, 0.13, 0.26, 0.52 and 1.04 mmol Lycopsamine, intermedine or reduced comfrey extract per kg bodyweight (BW) for 10 days. After another 7 days chicks were euthanized. Based on clinical signs of poisoning, serum biochemistry, and histopathological analysis the reduced comfrey extract was more toxic than Lycopsamine and intermedine. This work suggests a greater than additive effect of the individual alkaloids and/or a more potent toxicity of the acetylated derivatives in the reduced comfrey extract. It also suggests that safety recommendations based on purified compounds may underestimate the potential toxicity of comfrey.

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