Attenuation and Structural Transformation of Crassicauline A During Sand Frying Process and Antiarrhythmic Effects of its Transformed Products

Abstract

To ensure safety and efficacy, most Aconitum herbs should be processed before clinical application. The processing methods include boiling, steaming, and sand frying. Among these methods, the transformation pathways of diterpenoid alkaloids in the process of sand frying are more complicated. Therefore, crassicauline A, a natural product with two ester bonds, was chosen as the experimental object. Consequently, a known alkaloid, together with three new alkaloids, was derived from crassicauline A. Meanwhile, the cardiotoxicity of converted products was reduced compared with their parent compound. Interestingly, some diterpenoid alkaloids have similar structures but opposite effects, such as arrhythmia and antiarrhythmic. Considering the converted products are structural analogues of crassicauline A, herein, the antiarrhythmic activity of the transformed products was further investigated. In a rat aconitine-induced arrhythmia assay, the three transformed products, which could dose-dependently delay the ventricular premature beat (VPB) incubation period, reduce the incidence of ventricular tachycardia (VT), combined with the increasing arrhythmia inhibition rate, exhibited prominent antiarrhythmic activities. Our experiments speculated that there might be at least two transformation pathways of crassicauline A during sand frying. The structure-activity data established in this paper constructs the critical pharmacophore of diterpenoid alkaloids as antiarrhythmic agents, which could be helpful in searching for the potential drugs that are equal or more active and with lower toxicity, than currently clinical used antiarrhythmic drugs.

Exploring the Biomedical Potential of Terpenoid Alkaloids: Sources, Structures, and Activities

“…Incarvine G (12), a novel monoterpene alkaloid isolated from Incarvillea sinensis Lam., is an ester composed of a monoterpene alkaloid with a cyclopentane[c]piperidine skeleton and glucose [19].…”

“…Incarvine G (12) showed cytotoxicity with the IC 50 value of 60.29 µM against MDA-MB-231 cells and inhibited the migration and invasion of breast cancer cells. Further mechanistic studies showed that Incarvine G inhibited the migration and invasion of MDA-MB-231 cells by inhibiting actin cytoskeleton formation [19].…”

“…Modern pharmacological studies have shown that diterpene alkaloids have significant anti-inflammation, analgesia, anticancer, and anti-arrhythmia effects [8]. Moreover, as a diterpenoid alkaloid, Crassicauline A has been clinically utilized as an anti-arrhythmic drug [12]. Similarly, cyclovirobuxine-D, a triterpene alkaloid, is also used clinically as an antiarrhythmic drug [13] and has been recognized as a lead compound for innovative analgesics [14].…”