Molecular mode of action of annonins

Abstract

Extracts of ground seeds from Annona squamosa revealed interesting insecticidal properties. By an activity‐monitored fractionation, different acetogenins, called annonins and annonacin, were determined to be the active components. The investigation of ATP‐levels (at the LT50 value) in Plutella xylostella under treatment with annonin I and antimycin A revealed values of 1.45 and 1.35 μmole g−1 fresh weight respectively, whereas insecticides primarily afecting neurotoxic targets, e.g. cyfluthrin (sodium channels; 2.25 μmole g−1 fresh weight) or parathion (acetylcholinesterase; 2.0 μmole g−1 fresh weight) did not influence the ATP‐levels significantly (control; 1.98 μmole g−1 fresh weight). Further studies on the target site of annonins revealed an inhibitory effect on the NADH‐cytochrome c‐reductase and complex I of insect mitochondria with IC50 values of 4–8 nmole mg−1 protein and 0.8 μM respectively for annonin I. Similar results were observed for the inhibition of complex I from bovine heart muscle (IC50: <0.1 μM) or Neurospora crassa cells (IC50: 0.3 μM), whereas coupling sites II or III were not afected. Furthermore, annonins did not reveal any direct inhibition of oxidative phosphorylation or uncoupling efects.

Two binding sites of inhibitors in NADH:ubiquinone oxidoreductase (complex I)

“…The effect of these compounds on a mammalian, a fungal and a bacterial complex I and a bacterial glucose dehydrogenase was studied in a comparative manner. Annonin VI, aurachin A and B, aureothin, benzimidazole, fenpyroximate, myxalamid PI, phenoxan, phenalamid A, and thiangazole which were known or suspected to inhibit the mammalian complex I (Londershausen et al, 1991;Kunze et al, 1987;Hirata et al, 1961;Kuwano et al, 1982;Motoba et al, 1992;Gerth et al, 1983;Kunze et al, 1992;Trowitzsch-Kienast et al, 1992;Jansen et al, 1991 and were shown to act also on the fungal and bacterial complex I. Furthermore, it was demonstrated that with the exception of the aurachins and myxalamid PI, all inhibitors also act on the isolated N. crassu complex I.…”

“…Benzimidazole and fenpyroximate were synthesized as described (Nakagawa et al, 1985;Motoba et al, 1992). Bayer AG, Leverkusen kindly donated annonin VI from Annona squarnosu (Londershausen et al, 1991). Rotenone from D. elliptica and dihydrocapsaicin were purchased from Sigma.…”

A γ-Lactone Form Nafuredin, Nafuredin-γ, also Inhibits Helminth Complex I

“…Annonins are g-lactone compounds isolated from seeds of Annona squamosa and known as complex I inhibitors [11]. Annonin group compounds are called acetogenins, and their inhibitory activity against complex I, cytotoxicity, and insecticidal activity are well studied [12,13].…”

Historic Perspectives on Annonaceous Acetogenins from the Chemical Bench to Preclinical Trials

“…Two groups in China also started related research on AGEs in China during that period [40,41], one of which -Dr. Yangʼs group in Yun-Nancooperated with us to elucidate the structures of the AGEs from A. muricata [42]. To improve the efficiency of the chromatography, repeated open column chromatography and high-performance liquid chromatography (HPLC) were introduced for the isolation of AGEs [43][44][45][46] such that AGEs with minor structural differences could be isolated more easily and quickly. Based on the isolations of different AGEs, their general structural features can be divided into two classes: 1) the moiety of the γ-lactone rings: the α,β-unsaturated γ-lactone ring (normal form) or the ketolactone (isoform) (see l " Fig.…”

“…Due to the difficulty in crystallising aliphatic AGEs, the determination of the absolute stereochemistry of AGEs became the main challenge of the research work. Hoye et al first used spectroscopic methodologies to determine the absolute configurations of stereogenic carbinol centres in the five adjacent bis-THF AGEs and four mono-THF AGEs with the refined Mosher method in 1992 [43,44]. They also validated the configuration at the C-4 carbinol centre in these bioactive AGEs as the R configuration [49].…”