Redox reactions of natural alkaloid lappaconitine

Abstract

A review on redox reactions of natural alkaloid lappaconitine, a known sodium channel blocker, is presented. The NMR and CIDNP data on the mechanism of phototransformation of lappaconitine, in particular, of its paramagnetic species formed by both the direct photolysis and photoinitiated interaction with electron donors and acceptors, are analyzed. Special atten tion is given to the interaction of lappaconitine with amino acids, which are present in the active site of the sodium channel. Hypotheses about a relationship between this process and the mechanism of therapeutic activity of lappaconitine are discussed.

A photochemical approach for evaluating the reactivity of substituted lappaconitines

“…7. The stages 1-4 and 6-7 have been established earlier by the analysis of spin effects, 10,[13][14][15][16] while steps 5.1-5.3 are proposed based on the analysis of the NMR spectra of photolysis products in this work. The photolysis of N-acetyl-AA is considered to involve a cleavage and photo-Fries rearrangement.…”

“…We attribute this to the fact that the rate constant of ET has to be substantially high (10 8 -10 9 s −1 ), as follows from the manifestation of the initial LC CIDNP effect. 10,[13][14][15][16] It allows us to observe only a little effective yield of the triplet state.…”

“…Therefore, to trace the contribution of singlet and triplet excited states to LC photodegradation one can only compare fluorescence and photodecomposition quantum yields, taking into account the decomposition considered to occur through the triplet-excited state. 10,[13][14][15][16] According to the modern point of view, intersystem crossing between singlet and triplet excited states in compounds, involving closely located amine and carbonyl groups, might be caused by the vibrational interaction between close-lying S 1 (π,π*) and S 2 (n,π*) states. 28 This interaction leads to a large increase in the non-radiative decay rate of the lowest excited singlet state.…”

“…In addition, the shortening of the LC fluorescence lifetime (2.15 ns), in comparison with N-acetyl-AA (4 ns), is most likely to reveal the process of the fluorescence quenching of the anthranilic fragment through the previously described ET from the amine group of the alkaloid to the anthranilic fragment. 10,[13][14][15][16] In this connection, the difference between LC and MA fluorescence quantum yields and lifetimes is caused by two factors: the influence of the acetyl group leading to the loss of the molecular planarity and a decrease of the electron-donating character of the amine group towards the aromatic moiety and the process of intramolecular ET. Table 2 summarizes the fluorescence data obtained for all derivatives of LC.…”

“…1, a detailed mechanism of photolysis has been established by CIDNP and EPR analysis in previous studies. 10,[13][14][15][16] According to these studies, a photoreaction begins from the partially reversible intramolecular electron transfer (ET) between nitrogen located in the diterpenoid skeleton and the AA fragment with a subsequent cleavage of the ether bond. Since the anthranilic fragment is a chromophore in these molecules as well as a potential electron acceptor in redox processes, substituents have a significant impact on the efficiency of ET and subsequent photodegradation, respectively.…”