Diterpenoid alkaloid lappaconitine

Fig. 7 Structures of the tyrosinase inhibitory diterpenoid alkaloids lappaconitine hydrobromide (44), methyllycaconitine perchlorate (45), and aconine (46) [49]...

In another report Sultankhodzhaev et al. discussed the tyrosinase inhibitory potentials and structure-activity relationships of 15 diterpenoid alkaloids with the lycoctonine skeleton, and their semisynthetic derivatives [49]. At least three of them, lappaconitine hydrobromide (44, IC50 =... 

Lappaconitine represents the first example of a Ci9-diterpenoid alkaloid with one of the carbon atoms, which is usually attached to C-4, replaced by an oxygen atom. The presence of the C-8-C-9 vicinal diol system in lappaconitine is also unusual. 

The Cig-diterpenoid alkaloids are a member of small groups within the diterpenoid alkaloids. The first Cig-diterpenoid alkaloid named lappaconitine was isolated from the plant Aconitum septentrionale [55], and its structure was confirmed after several years by extensive chemical studies [56], In the beginning of the 1970s, three more Cig-diterpenoid alkaloids named lappaconidine [57], aconosine [58], and excelsine [59] were isolated and characterized which advanced this class of diterpenoid alkaloids. Until today, over 100 compounds of this class have been isolated from around 40 plant species mainly from Aconitum followed by Delphinium. 

The lappaconitine-type Cig-diterpenoid alkaloids are structurally classified by lack of an oxygen functionality and presence of a methine unit at C-7 [6]. This is a fairly... 

Allapinine (lappaconitine hydrobromide) has passed clinical trials and was commercially available as a drug since 1987. Cardiologists believe that allapinine is the first-line drug for the treatment of certain types of cardiac arrhythmia [74]. The investigation of the structure-activity relationship of more than 200 diterpenoid alkaloids and their derivatives revealed that the structural elements are responsible for the arrhythmogenic and antiarrhythmic properties [75]. It is also noted that diterpenoid alkaloids containing the same skeletal and similar functionalities exhibited both arrhythmogenic and antiarrhythmic properties. 

The Cig-diterpenoid alkaloid group is represented by lappaconitine 9 or ranaconitine, which are derivatives of Cig-alkaloids devoid of the benzoyl moiety at position 14 [21]. 

Evaluation of anesthetic versus toxic properties of diester diterpenoid alkaloids revealed that they possess good anesthetic potential and high therapeutic indices, with LD50/ED50 ratios of 510 for 3-acetylaconitine, 479 for iV-deacetyllappaconitine, 303 for bulleyaconitine, 292 for lappaconitine, and 274 for iV-deacetylranaconitine. 

The most toxic alkaloids of aconite, such as aconitine, mesaconitine, hypaconitine, etc., are known to possess arrhythmogenic effect. Aconitine itself has long been used to induce arrhythmia in experimental models [38, 39]. Aconitine and its structural analogues induce ventricular ectopics, ventricular tachycardia, torsades de pointes, and ventricular fibrillation in a dose-dependent manner. Aconitine has a positive inotropic effect on the heart. It has hypotensive and bradycardic actions [40]. Another group of diterpenoid alkaloids possessing C18 and C19 skeleton, such as lappaconitine, A -deacetyllappac(Miitine, heteratisine, and 6-benzoylheteratisine, are... 

The second group of diterpenoid alkaloids comprises moderately toxic Cig-alkaloids having a benzoyl moiety on the C-6, C-4, or C-14 positions, and without an acetyl moiety on the C-8 position. The representatives of alkaloids with a C-6 or a C-4 benzoyl moiety are 6-benzoylheteratisine, lappaconitine, and ranaconitine. Even if the LD50 values of lappaconitine and 6-benzoylheteratisine found in the literature are not identical [32, 33, 35], these compounds remain about 20-50 times less toxic than diester alkaloids. However, they are more toxic than the de-esterified derivatives of aconitine-like alkaloids having a benzoyl group at C-14, such as benzoylaconine, benzoylmesaconine, and benzoylhypaconine, which indicates the importance of the position of the benzoyl moiety for toxicity. 

Heubach JF, Schule A (1998) Cardiac effects of lappaconitine and N-deacetyllappaconitine, two diterpenoid alkaloids from plants of the Aconitum and Delphinium species. Planta Med... 

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