Five annonaceous acetogenins, rolliniastatin-1 (1), rolliniastatin-2 (2), laherradurin (3), squamocin (4), annonacin (5), and rotenone as a reference, differing in their NADH oxidase inhibition activity, have been evaluated for antifeedant, insecticidal, trypanocidal and cytotoxic effects on insect, mammalian and tumor cells. All the test compounds were toxic to Leptinotarsa decemlineata, demonstrated selective cytotoxicity to insect Sf9 cells and a panel of tumor cell lines with the multidrug-resistant SW480 (P-glycoprotein+, Pgp+) being the most sensitive one. Compounds 1, 2, 4, and rotenone had post-ingestive effects against Spodoptera littoralis larvae while 1, 4, 5, and rotenone were active against Trypanosoma cruzi. Based on their biochemical properties (inhibition of the mitochondrial NADH oxidase activity), the in vivo effects of these compounds on S. littoralis and their cytotoxic effects on Sf9 and tumor cells were more predictable than their effect on T. cruzi and mammalian cells.
The insect antifeedant and toxic activity of the Delphinium diterpene alkaloids 15-acetylcardiopetamine, cardiopetamine along with its amino alcohol, the beta,gamma unsaturated ketone, and the acetylated ketone derivatives were studied in Spodoptera littoralis and Leptinotarsadecemlineata. Cardiopetamine and 15-acetylcardiopetamine strongly inhibited the feeding activity of S. littoralis and L. decemlineata, respectively. Structure-activity studies with S. littoralis showed that the C13 and C15 hydroxy substituents are essential features of the active molecule, while a C13 hydroxy and/or a C15 acetate determined their effect on L.decemlineata. The C11 benzoate group enhanced the biological effect on both insect species. These alkaloids were not toxic to S. littoralis, while their toxicity on L. decemlineata was inversely correlated with their antifeedant effects, the beta,gamma unsaturated ketone derivative being the most toxic. Cardiopetamine showed little antifungal action against several species of plant pathogens and did not have any mutagenic effects on Salmonella typhimurium by means of the Ames test.
We have tested the insect antifeedant and toxic activity of 43 norditerpenoid alkaloids on Spodoptera littoralis and Leptinotarsa decemlineata including eserine (physostigmine), anabasine, and atropine. Antifeedant effects of the test compounds were structure- and species-dependent. The most active antifeedants to L. decemlineata were 1,14-diacetylcardiopetaline (9) and 18-hydroxy- 14-O-methylgadesine (33), followed by 8-O-methylconsolarine (12), 14-O-acetyldelectinine (27), karakoline (7), cardiopetaline (8), 18-O-demethylpubescenine (13), 14-O-acetyldeltatsine (18), takaosamine (21), ajadine (24), and 8-O-methylcolumbianine (6) (EC50 < 1 microg/cm2). This insect showed a moderate response to atropine. S. littoralis had the strongest antifeedant response to 24, 18, 14-O-acetyldelcosine (19), and delphatine (29) (EC50 < 3 microg/cm2). None of the model substances affected the feeding behavior of this insect. The most toxic compound to L. decemlineata was aconitine (1), followed by cardiopetalidine (10) (% mortality > 60), 14-deacetylpubescenine (14), 18-O-benzoyl-18-O-demethyl-14-O-deacetylpubescenine (17), 14-O-acetyldelcosine (19), 14-deacetylajadine (25) and methyllycaconitine (30) (% mortality > 45). Orally injected S. littoralis larvae were negatively affected by 1, cardiopetaline (8), 10, 1,14-O-acetylcardiopetalidina (11), 12, 14, 1,18-O-diacetyl-19-oxo-gigactonine (41), olivimine (43), and eserine in varying degrees. Their antifeedant or insecticidal potencies did not parallel their reported nAChR binding activity, but did correlate with the agonist/antagonist insecticidal/antifeedant model proposed for nicotininc insecticides. A few compounds [14, tuguaconitine (38), 14-demethyldelboxine (40), 19, dehydrodelsoline (36), 18-O-demethylpubescenine (13), 41, 9, and delcosine (23)] had selective cytotoxic effects to ward insect-derived Sf9 cells. None were cytotoxic to mammalian CHO cells and none increased Trypanosoma cruzi mortality. The selective cytotoxic effects of some structures indicate that they can act on biological targets other than neuroreceptors.
Annonaceous acetogenins represent a new class of bioactive compounds whose primary mode of action is the inhibition of NADH-ubiquinone oxidoreductase. Given the potential pesticidal use of such a class of compounds, we have further evaluated the antifeedant and insecticidal effects of squamocin and annonacin, two annonaceous acetogenins, on Spodoptera littoralis, Leptinotarsa decemlineata, and Myzus persicae. Additionally, to partially assess their environmental risk, we have also tested their mutagenicity in Salmonella typhimurium strains TA98, TA100, and TA102 in the presence and absence of a metabolic activation system. Among the test compounds, annonacin showed antifeedant effects on L. decemlineata, while squamocin was toxic to L. decemlineata and M. persicae. Neither acetogenin was mutagenic, although both were toxic in the absence of a metabolic activation system. We compared these results with those obtained with rotenone, a well-known respiratory inhibitor that was highly toxic to L. decemlineata and M. persicae and showed no mutagenicity/toxicity in the S. typhimurium strains tested up to a concentration of 1000 microg per plate.
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