Potentially Cardiotoxic Diterpenoid Alkaloids from the Roots of Aconitum carmichaelii

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.

Diterpenoid Alkaloids from the Aerial Parts of Aconitum flavum Hand.-Mazz

“…The MeOH extract was subjected to repeated column chromatography to yield four new ones (flavumolines A − D, 1-4), one new natural compound (5), together with 11 known analogues 13-hydroxylfranchetine (6) [9], vilmorisine (7) [10], franchetine (8) [11], 3-acetylaconitine (9) [12], 15-dehydroxyldecludine A (10) [13], pubescensine (11) [14], 3-O-acetyl-20-deethyl-20-formylaconitine (12) [15], 14α-benzoyloxy-N-ethyl-3α,13β,15α-trihydroxy-1α,6α,8β,16β,18-pentamethoxyaconitane (13) [16], 15-acetylsongoramine (14) [17], dehydrolucidusculine (15) [18], and veatchine azomethine ( 16) [19].…”

“…Flavumoline Moreover, the benzoyl group was placed at C-14 according to the HMBC correlation from H-14 (δ H 5.07, s) to carbonyl (δ C 166.7, s). Three methoxy units were located at C-1, C- 16 Biogenetically, the configurations of H-5, 9, 10, could be ascribed to β-orientation whereas H-17 to α-orientation, which could be confirmed by ROESY correlations of H-5/9/10/12β and H-17/12α, respectively [21]. Then, the α-orientation of the benzoyl group at C-14 was determined on the ROESY correlations between H-14 and H-9.…”

“…In this study, sixteen DAs including four new 7,17-seco-aconitine-type DAs (flavumolines A − D, 1 − 4), one new natural compound (5), together with 11 known analogues (6 − 16) were identified. These compounds could be divided into four different types: six aconitines (5 and 9 − 13), seven 7,17-seco-aconitines (1 − 4 and 6 − 8), two napellines (14 and 15) as well as one veatchine-type alkaloid (16). All of these isolated compounds were evaluated for their inhibitory effects on Ca v 3.1 low voltage-gated Ca 2+ channel, NO production in LPS-activated RAW264.7 cells, five human tumor cell lines, and acetylcholinesterase (AChE).…”

Development of an ic-ELISA and an immunochromatographic strip assay for the detection of aconitine

“…On the other hand, aconitine is also a lethal toxin (Lou et al, 2018), which can cause arrhythmia, dizziness, numbness, hypotension and even death (Gao et al, 2017;Yang et al, 2019;Zhang, Cai, Zhang, Qi, & Lu, 2018), and the treatment for aconitine poisoning is still limited to supportive treatments such as gastric lavage, charcoal perfusion, injection of magnesium sulfate, etc. (Clara, Rauch, Überbacher, Felgenhauer, & Drüge, 2015;Zong et al, 2019). If a new treatment based on aconitine-containing Chinese medicine is developed (Xiaodong Li et al, 2017;Xiumei Li et al, 2018), the content of aconitine in Chinese medicine must be strictly tested to avoid patient poisoning.…”

Discrimination of the Geographical Origin of the Lateral Roots of Aconitum carmichaelii Using the Fingerprint, Multicomponent Quantification, and Chemometric Methods

“…The first three alkaloids are representative diester-type diterpenoid alkaloids. According to modern pharmacological studies, they are the main toxic components of Fuzi, and they have a strong cardiotoxicity and neurotoxicity [9,10,11,12]. Their contents are also strictly limited to less than 0.020% in the Chinese Pharmacopoeia [1].…”