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J Nat Prod. 2019 Mar 20. doi: 10.1021/acs.jnatprod.8b01039. [Epub ahead of print]

Potentially Cardiotoxic Diterpenoid Alkaloids from the Roots of Aconitum carmichaelii.

Author information

1
State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health , Macau University of Science and Technology , Avenida Wai Long , Taipa , Macao 999078 , Special Administrative Region of the People's Republic of China.
2
International Institute for Translational Chinese Medicine , Guangzhou University of Chinese Medicine , Guangzhou 510006 , People's Republic of China.

Abstract

Aconitum carmichaelii is a traditional Chinese herbal medicine used for the treatment of pain and inflammation in the joints. However, the strong cardiotoxicity hinders its use. Although diester- and monoester-type diterpenoids, e.g., aconitine, mesaconitine, and hypacaonitine, are commonly considered as the toxic components, the toxicity of A. carmichaelii cannot be completely explained by the compounds reported. To investigate further the cardiotoxic compounds and their potential mechanism, the chemical constituents were first isolated by column chromatography and identified using mass spectrometry and NMR spectroscopy. Two new hetisine-type (1 and 2) and four new aconitine-type alkaloids (3-6) were assigned. The cardiac cytotoxicity assessed on H9c2 cells indicated that the new compound 4 as well as six known alkaloids (7 and 9-13) exhibited significant toxicities. A preliminary structure-toxicity relationship study suggested that substitution at C-8 and C-10 both have a significant influence on cardiotoxicity, and such toxicity decreased in the order OBz-8, OBu-8, and OMe-8. The presence of an OH-10 group abolished the toxicity. Finally, it was found that ion channel disorder and induction of mitochondrial-mediated cell apoptosis are the possible mechanisms of cardiotoxicity among the compounds studied.

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