acetogenins and squamocin

Annonaceous acetogenins (AAGs) are neurotoxins possibly responsible for atypical Parkinsonism/dementia clusters, via the consumption of edible Annonaceae fruits. Their presence was investigated in fruit pulps of Annona squamosa from different locations. Qualitative analysis of other AAGs was performed. We here report the identification of squamocin in batches from Asia, the Caribbean Basin and the Indian Ocean. This molecule was quantified by HPLC-UV, evidencing a content of 13.5-36.4mg/fruit. HPLC-ESI-Q-TOF allowed the detection of 25 different raw formulas matching with AAGs. LC-MS/MS methodological development was performed using 4 representative standards. The main AAGs could be annotated, including bullatacin (rolliniastatin-2) and annonacin. This study evidences a remarkable homogeneity for the main AAGs within the species, and discrepancies for minor compounds. These findings indicate that A. squamosa should be considered a risk factor for neurodegenerative disorders.

Topics: Acetogenins; Annona; Asia; Caribbean Region; Chromatography, High Pressure Liquid; Fruit; Furans; Lactones; Neurotoxins; Tandem Mass Spectrometry

Four new annonaceous acetogenins (ACGs), squamocin-I (1), II (2) and III (3) and squamoxinone-D (4), together with seven known ACGs (5-11), were isolated from the seeds of Annona squamosa. The structures of all isolates were elucidated and characterised by spectral and chemical methods. Compounds 1-4 were evaluated for their cytotoxicities against Hep G2, SMMC 7721, BEL 7402, BGC 803 and H460 human cancer cell lines. Compound 1 exhibited better potent activity than the positive compound and compound 3 shows selectively cytotoxical activity against H460 with IC50 values of 0.0492 μg/ml.

Topics: Acetogenins; Annona; Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Furans; Humans; Inhibitory Concentration 50; Lactones; Molecular Structure; Plant Extracts; Seeds; Spectrum Analysis

Nineteen biotinylated squamocin/bullatacin derivatives have been synthesized for targeted delivery to biotin receptor overexpressed tumor cells. Most biotinylated squamocin and bullatacin derivatives show similar in vitro cytotoxicity against the biotin receptor non-overexpressed L1210 cells as squamocin and bullatacin, respectively, while against biotin receptor overexpressed 4T1 and P815 tumor cells, several derivatives show significantly higher potency and better selectivity. Among all the synthesized compounds, 15,28-di-O-(6-biotinylamidohexanoyl)squamocin (16) is the most potent, which is 10 and 26 times more active than squamocin against 4T1 and P815 cells, respectively. Compound 16 also appears to be six and fifteen times more selective than squamocin towards 4T1 and P815 cells, respectively, against L1210 cells. The structure activity relationship analysis has revealed that the preferred site for biotinylation is different for squamocin and bullatacin, and it also depends on whether a linking spacer is present.

Topics: Acetogenins; Antineoplastic Agents, Phytogenic; Biotinylation; Cell Line, Tumor; Cell Proliferation; Furans; Humans; Lactones; Neoplasms; Receptors, Growth Factor

Acetogenins of the Annonaceae are strong inhibitors of mitochondrial complex I but discrepancies in the structure/activity relationships pled the search for other targets within the whole cell proteome. Combining hemisynthetic work, Cu-catalyzed Huisgen cycloaddition and proteomic techniques we have identified new putative protein targets of squamocin ruling out the previously accepted 'complex I dogma'. These results give new insights into the mechanism of action of these potent neurotoxic molecules.

Topics: Acetogenins; Annonaceae; Electrophoresis, Polyacrylamide Gel; Furans; Kinetics; Lactones; Microscopy, Confocal; Mitochondria; Neurons; Proteins; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization

In the course of reactivity studies on squamocin (1), a highly cytotoxic acetogenin from the plant family Annonaceae, two diastereomers, 3 and 4, of chamuvarinin (2) were synthesized. Based on this, a plausible relative configuration was proposed for 2, demonstrating the absence of any biogenetic link between 1 and 2. The new analogues 3, 4, and 7 were also tested for their ability to induce apoptosis.

Topics: Acetogenins; Annonaceae; Antineoplastic Agents, Phytogenic; Apoptosis; Fatty Alcohols; Furans; Lactones; Molecular Structure; Plants, Medicinal; Pyrans

Heterocyclic analogues of squamocin have been semisynthesized by condensation reactions between squamocin-derived alpha-keto esters and heterodinucleophiles. The strong complex I inhibitory potency of squamocin-benzimidazole, a hybrid derivative, illustrates for the first time the functional analogy existing between the terminal butenolide of annonaceous acetogenins and heteroaromatic substructures of classic inhibitors of the enzyme. This finding supports the categorization of this atypical group of inhibitors as antagonists of the ubiquinone substrates. In addition, competition experiments of squamocin-benzimidazole versus squamocin and rolliniastatin-2 suggest that the binding of this hybrid inhibitor is responsible for a negative allosteric effect at the level of the first ubiquinone-binding site (A site) of mitochondrial complex I. This result supports the existence of a large cooperatively regulated inhibitor/ubiquinone-binding pocket located within the catalytic core of the enzyme, consisting of the association of the previously defined affinity sites A and B.

Topics: Acetogenins; Annona; Electron Transport Complex I; Enzyme Inhibitors; Esters; Fatty Alcohols; Furans; Lactones; Mitochondria, Heart; NADH, NADPH Oxidoreductases; Oxidation-Reduction; Ruthenium; Seeds; Substrate Specificity

Topics: Acetogenins; Annonaceae; Antineoplastic Agents, Phytogenic; Azo Compounds; Enzyme Inhibitors; Fatty Alcohols; Fluorescence; Furans; Hydroxyl Radical; Lactones; Mitochondria; Spectrometry, Fluorescence

To study the inhibition of oxygen consumption by annonaceous acetogenins (ACG) and their structure-activity relationship (SAR).. The inhibition of oxygen consumption in chicken liver cell respiration by different structural ACG was studied by using oxygen electrode technique.. Six ACG showed potent inhibitory effects like rotenone which was a classical inhibitor of mitochondrial complex I, and was more potent than complex IV inhibitor KCN. The IC50 values of six ACG for inhibiting oxygen consumption suggested that bistetrahydrofuran (THF) ACG was 7-11 times more active than non-THF ACG, and A1-type ACG was more potent than A2-type ACG.. The terminal gamma-lactone was crucial for the inhibition of oxygen consumption. The distance between THF and gamma-lactone, the hydroxyl groups in the alkyl chain, were the important factors of SAR, but the 4-OH group possibly played some negative role in the exhibit of potent activity.

Topics: Acetogenins; Animals; Annona; Cell Separation; Chickens; Fatty Alcohols; Furans; Lactones; Liver; Mitochondria, Liver; Oxygen Consumption; Plants, Medicinal; Seeds; Structure-Activity Relationship