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Authors personal copy      PART 2      Effects of Specific Nuts and Seeds                          INTRODUCTION            ...
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Authors personal copy      PART 2      Effects of Specific Nuts and Seeds                          FIGURE 51.3             ...
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Authors personal copy      PART 2      Effects of Specific Nuts and Seeds                           TABLE 51.1 Complex I In...
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ACG-008-Risk-Seeds of annona squamosa-FR-2011

  1. 1. Authors personal copy Provided for non-commercial research and educational use only. Not for reproduction, distribution or commercial use. This chapter was originally published in the book Nuts and Seeds in Health and Disease Prevention. The copy attached is provided by Elsevier for the authors benefit and for the benefit of the authors institution, for non-commercial research, and educational use. This includes without limitation use in instruction at your institution, distribution to specific colleagues, and providing a copy to your institutions administrator.All other uses, reproduction and distribution, including without limitation commercial reprints, selling or licensing copies or access, or posting on open internet sites, your personal or institution’s website or repository, are prohibited. For exceptions, permission may be sought for such use through Elsevier’s permissions site at: From Champy, P. (2011). Acetogenins from the seeds of the Custard Apple (Annona squamosa L.) and their health outcomes. In V. R. Preedy, R. R. Watson, V. B. Patel (Editors), Nuts & Seeds in Health and Disease Prevention (1st ed.) (pp 429-437). London, Burlington, San Diego: Academic Press is an imprint of Elsevier. ISBN: 9780123756886 Copyright © 2011 Elsevier Inc. All rights reserved Academic Press
  2. 2. Authors personal copy CHAPTER 51Acetogenins from theSeeds of the Custard Apple(Annona squamosa L.) andtheir Health OutcomesPierre Champy ´Laboratoire de Pharmacognosie, UMR CNRS 8076 BioCIS, Faculte de Pharmacie, ´Universite Paris-Sud 11, France CHAPTER OUTLINE Introduction 430 Applications to Health Promotion 429 Botanical Description 430 and Disease Prevention 431 Historical Cultivation and Adverse Effects and Reactions Usage 430 (Allergies and Toxicity) 434 Present-Day Cultivation and Summary Points 435 Usage 430 References 435LIST OF ABBREVIATIONS ACG, annonaceous acetogenins ATP, adenosine tri-phosphate EC, effective concentration FDA, Food and Drug Administration HPLCeDAD, high performance liquid chromatographyediode array detection IC, inhibitory concentration NADH, nicotinamide adenine dinucleotide, reduced form PSP, progressive supranuclear palsy ROS, reactive oxygen species SARs, structure activity relationships THF, tetrahydrofuran UQ, ubiquinoneNuts & Seeds in Health and Disease Prevention. DOI: 10.1016/B978-0-12-375688-6.10051-9Copyright Ó 2011 Elsevier Inc. All rights reserved.
  3. 3. Authors personal copy PART 2 Effects of Specific Nuts and Seeds INTRODUCTION Annona squamosa L., a small tropical tree, is a famous cultivated Annonaceae. Its fruit is known as the custard apple, sugar apple, or fruta do conde. Its seeds are poisonous, and have multiple, mainly traditional, uses. They contain high amounts of annonaceous acetogenins (ACGs), for which a phytochemical update is proposed. This group of polyketides comprises the most potent inhibitors of mitochondrial complex I (Bermejo et al., 2005). Recent biological outcomes are presented, in regard to antitumoral and pesticidal potential. ACGs are being proposed as environmental neurotoxins, toxicological data are summarized, along with concerns about seed uses. BOTANICAL DESCRIPTION The pseudosyncarpic fruits of A. squamosa are green, and display marked carpel protuberances. They are heart-shaped, measure approximately 7.5 cm in length, and weigh 100e400 g, depending on the cultivar and cultivation conditions. Their whitish, custard-like sweet pulp contains 35 to 50 black seeds of 1e1.5 cm in length and 0.5e0.8 cm in width, with a glossy cuticle (Figure 51.1). HISTORICAL CULTIVATION AND USAGE Originating from Central America, like most Annona species, the tree is believed to have spread to Mexico, South America, and the Caribbean in the 16th to 17th centuries, and is now commonly found in domestic gardens in tropical America. It was brought to India by the Portuguese during the same period, then to South-east Asia, and was also introduced into Africa and Oceania (Pinto et al., 2005). Alimentary use of the fruit appears mostly to be a South-American and Asian habit. In tropical areas, various and convergent medicinal uses, mainly of bark and leaves, are reported.430 PRESENT-DAY CULTIVATION AND USAGE Custard apple grows at low altitudes (0e1500 m), and is widely cultivated in tropical to semi- arid regions, in orchards or on commercial farms. Considered to be a minor crop by the FAO, it is the third most commercially cultivated Annonaceae in South and Central America (behind A. cherimolia and A. muricata), Brazil being one of the main producers (cultivation > 1200 ha, and production > 11,000 tonnes, in 2000). The tree is also cultivated in India (44,000 ha in the 1980s), Sri Lanka, Malaysia, Viet Nam, the Philippines, and Taiwan (2500 tonnes per year). FIGURE 51.1 A. squamosa fruits and seeds.
  4. 4. Authors personal copy CHAPTER 51 Acetogenins of Annona Squamosa SeedsSmaller production areas are encountered in southern Florida, Australia (2 tonnes in 2003),tropical Africa, and Egypt (170 tonnes in 1997). Exportation to northern market is, however,limited. The ripe fruit was being sold at US$ 0.56/kg in 2004, for direct consumption or forindustrial processing as juices or ice creams. For this use, prior peeling and removal of seeds isperformed (Pinto et al., 2005).APPLICATIONS TO HEALTH PROMOTION ANDDISEASE PREVENTIONScarcity of traditional internal use of seeds, and convergence in topical treatment againstexternal parasites with crushed seeds or oil, are remarkable. Seeds are also often reported astraditional pesticides, and, less frequently, as fish poison. Among various other bioactivesecondary metabolites (i.e., isoquinolines, ent-kauranes, cyclopeptides), ACGs appear tosupport these uses. These white, waxy polyketides, specific to the Annonaceae family, havebeen encountered in all Annona species studied so far. Derived from long chain fatty acids, theyconstitute 35 or 37 carbon atoms, with an alkyl chain bearing a central oxygenated system(tetrahydrofuranic (THF) rings) and a terminal butyrolactone. Inner classification is based onthe structure of these moieties (Figure 51.2).Extensive chemical studies of the seeds of A. squamosa led to isolation of 74 ACGs, mostbearing two adjacent THF rings (e.g., rolliniastatin-2 (1), squamocin (2)) or a single THFring (e.g., annonacin (3); Figure 51.3). ACGs are also reported in the bark (Bermejo et al.,2005) and fruit pulp (Champy et al., 2008). Yang and colleagues, in a simultaneous HPLCeDAD determination of eight ACGs from a supercritical CO2 extract of seeds from China,evidenced 1 and 2 as major representatives (0.58 and 0.37 mg/g; total ACGs, 2.29 mg/g) 431 FIGURE 51.2 Structural features of ACGs from A. squamosa seeds. Structural characteristics that are the most favorable for complex I inhibition are underlined (compare with structure of (1), Figure 51.3). Types and sub-types are classified according to Cave ´ et al., 1997, and Bermejo et al., 2005 (in italics). Percentages are calculated with respect to the total number of ACGs isolated from seeds (Bermejo et al., 2005; Souza et al., 2008, and references cited in Figure 51.4). Length of 13 carbon atoms for alkyl spacer between lactone and hydroxylated THF system: ~50% of type A and type B ACGs. Note that a type D (three adjacent THF groups), a type E bearing three epoxides, a C-18, and a bis-lactonic C-22 representative were also obtained.
  5. 5. Authors personal copy PART 2 Effects of Specific Nuts and Seeds FIGURE 51.3 Prototypical ACGs from A. squamosa seeds. (Yang et al., 2009a). In our experience, with several batches from Brazil, 2 was the main ACG (~60% of total ACGs), with a similar yield. Since the last review on ACGs (Bermejo et al., 2005), eight articles have been published, describing isolation of 46 of these compounds from the seeds, of which 19 were obtained for the first time in the species (annotemoyins-1 and -2, bullatencin, cis-bullatencin, corepox- ylone, diepomuricanins A and B, dieporeticenin, glabranin, glabrencin B, probably narumicin- II (“Compound 1” in Sousa et al., 2008), reticulatains-1 and -2, solamin, erythro-solamin,432 tripoxyrollin, and uvariamicins I, II, and III; “isosquamocin” is also mentioned (Grover et al., 2009)); 17 display original structures (note that homonymies exist for squamostatin-C and for squamocenin) (Figure 51.4). ACGs are very strong inhibitors of mitochondrial complex I (NADH ubiquinone oxido- reductase). Most act as uncompetitive semiquinone antagonists, with the lactonic ring as a probable inhibitory pharmacophore, and THF system allowing positioning in mitochondrial ´ internal membrane (Bermejo et al., 2005; Barrachina et al., 2007; see also Derbre et al., 2005 and references cited in Kojima and Tanaka, 2009). Rolliniastatin-2 (1) is the most active representative, squamocin (2) displaying close potency (Table 51.1; see also structureeactivity relationships (SARs) depicted in Figure 51.1). ACGs show tremendous cytotoxicity, with IC50 values ranging from 10 mM to 10À4 nM. However, striking discrepancies in SARs versus that for complex I appear in the literature. Differential intracellular distribution of these amphiphilic, apolar compounds might be implicated (Hollerhage et al., 2009). Fluorescent analogs of 2 showed mitochondrial tropism ¨ ´ in Jurkat cells (Derbre et al., 2005). Alternative targets are also proposed but their relevance is ´ unknown (Derbre et al., 2008; Liaw et al., 2008; Takahashi et al., 2008). In vitro studies in various mammal cell lines or primary cultures reported death to be triggered by ROS production or ATP deprivation, depending on the in vitro paradigm. Apoptotic mechanisms consistent with a mitochondrial pathway were observed, notably with 2 as a pharmacological tool. The perspective of ACGs being anticancer agents has thus motivated most research on these metabolites during the past three decades, with promising milestones being achieved. Selectivity for cancerous cells in regard to normal ones was proposed, on the basis of discrepancies in ATP requirements, but this issue remains under discussion (Garcia-Aguirre et al., 2008). ACGs also proved cytotoxic in multi-drug resistant cell lines expressing the ATP- dependent MDR efflux transporter (McLaughlin, 2008). Numerous semisynthesic analogs designed for activity enhancement or mechanistic studies were obtained, 2 being a lead
  6. 6. Authors personal copy CHAPTER 51 Acetogenins of Annona Squamosa Seeds 433FIGURE 51.4Original ACGs isolated from A. squamosa seeds between 2005 and 2009. Relative configurations: er, erythro; th, threo; c,cis; t, trans. *Undetermined absolute configurations. References: Compounds (8), Yu et al. (2005); (6,7, 11e16), Liaw et al.(2008); (4,5,9,10), Bajin ba Ndob et al. (2009); (17, 18), Yang et al. (2009b); (19, 20), Yang et al. (2009c).compound (Kojima & Tanaka, 2009). Among other ACGs, 1 underwent promising antitumorassays, and was reported as being well tolerated in several animal species (McLaughlin, 2008;see also Cuendet et al., 2008). However, to our knowledge, no ACG passed preclinical eval-uation, and no clinical studies were published. According to McLaughlin (2008), dietarysupplements containing ACGs gave satisfactory results as oral adjuncts to chemotherapy incancer patients. Indeed, poorly evaluated Annonaceae dietary supplements are sold for cancertreatment and prevention, on the Internet and in health stores. None contain A. squamosaseeds or seed extracts, but between 2007 and 2010 five patents related to the use of A. squamosaseeds ACGs in cancer were deposited in China.ACGs also proved molluscidal and anthelmintic (antibacterial, antifungal, immunosuppres-sive, and antiparasitic activities have also been reported, Bermejo et al., 2005). They displayimpressive acaricidal and insecticidal potency (McLaughlin, 2008): Among extracts containingACGs, those of A. squamosa seeds were extensively studied (Grover et al., 2009). Promising
  7. 7. Authors personal copy PART 2 Effects of Specific Nuts and Seeds TABLE 51.1 Complex I Inhibition Potential ACGs from A. squamosa Seeds NADH Oxidase NADH/DB Oxidoreductase Ki (nM) IC50 (nM) IC50 (nM) Rolliniastatin-2 (1) 0.85e1.2a 0.6e Squamocin (2) 0.8b; 1.3c 2.0 b 0.4e Annonacin (3) 2.3 Æ 0.3d 26.1 Æ 3.2d Rotenone 30c; 5.1 Æ 0.9d 28.8 Æ 1.5d 4.0e IC50-Complex I, half-maximal concentration inhibiting NADH oxidase activity in the absence and presence of an exogenous ubiquinone analog (decyl-UQ; NADH-DB oxido-reductase activity), in bovine heart sub-mitochondrial particles; data from: a Miyoshi et al.1998 and Fujita et al., 2005; cited in Kojima & Tanaka (2009); b Duval et al. (2005); cited in Kojima & Tanaka (2009); c ´ Derbre et al., 2006, cited in Kojima & Tanaka (2009); d Tormo et al. (2003); cited in Bermejo et al. (2005); e Degli-Espoti et al. (1994), cited in Bermejo et al. (2005). semisynthesic ACGs were also obtained, including b-amino-(2), a dual complex I/complex III inhibitor designed by Duval and colleagues (Kojima & Tanaka, 2009). A patent for an anti- head-lice shampoo containing a standardized extract of seeds of A. squamosa has been regis- tered, alike Asimina triloba products containing similar ACGs (McLaughlin, 2008). Agro- chemical valorization of A. squamosa seeds appears to be a potentially important outcome, with five publications in 2009 and three Indian patents on standardized apolar extracts since 2006. This is reminiscent of rotenoid-containing Fabaceae and of rotenone, a reference lipo- philic complex I inhibitor sharing the enzyme binding domain of ACGs, with potency close to that of 3 (Table 51.1). ADVERSE EFFECTS AND REACTIONS (ALLERGIES AND TOXICITY)434 Seeds of A. squamosa are of notorious toxicity, and are thus barely used orally in traditional medicine (except as an abortive in India, where aqueous extracts are used). They are reported to cause irritation to the eye and mucosa. Oral ingestion provokes vomiting, related to the ACG content (McLaughlin, 2008). The plant is mentioned in the poisonous plants database of the FDA (American Food and Drug Administration), and the AFSSA (Agence ´ ´ Francaise de Securite Sanitaire des Aliments: Saisine 2007-SA-0231, 2007/12/21; pp 3, 5; ¸ Saisine 2008-SA-0171, 2010/04/28, 7 p.) has expressed safety concerns regarding its use in dietary supplements. In relation to pesticide use, safety evaluation of a defatted seed extract (MeOH/CH2Cl2 1:1) in female Wistar Rats was proposed by Grover et al. (2009). Mortality was observed at 2 g/kg p.o. At doses of 150 and 300 mg/kg, genotoxicity was evidenced in leukocytes and bone marrow, from 4 to 72 h after ingestion, possibly due to ACGs (Garcia-Aguirre et al., 2008). Consistent with complex I inhibition, involvement of ROS was suggested by significantly enhanced lipid peroxidation, and decreased glutathione and glutathione S-transferase levels. However, an MeOH extract likely to contain ACGs did not increase oxidative markers in the livers of female Swiss mice (dosage 200 mg/kg, p.o., 10 days; Panda & Khar, 2007; see also Damasceno et al., 2002; Pardhasaradhi et al., 2005). Histological examination of liver and kidney revealed no lesions. Authors have expressed concern about the use of A. squamosa seed extract as a pesticide until more tests are carried out (Grover et al., 2009). Nevertheless, complex I dysfunction has been reported in Parkinson’s disease (a movement disorder with progressive degeneration of dopaminergic neurons in substantia nigra), as well as in the tauopathy progressive supernuclear palsy (PSP), an atypical form of parkinsonism. Complex I inhibitors such as 1-methyl-4-phenylpyridinum, paraquat or rotenone are used to establish animal models of neurodegeneration, and are linked to the occurrence of parkin- sonism (Gibson et al., 2010). PSP-like syndromes were observed in genetically heterogeneous populations regularly consuming alimentary and medicinal Annonaceae products. Thus, in
  8. 8. Authors personal copy CHAPTER 51 Acetogenins of Annona Squamosa Seeds TABLE 51.2 In vitro Neurotoxicity of ACGs (Striatal Primary Cultures) IC50-Cpx I (nM) EC50-ATP (nM) EC50-ND (nM) EC5-Tau (nM) * * Rolliniastatin-2 (1) 0.9 3.6 1.1 0.6* Squamocin (2) 1.4 2.9 1.1 0.6 Annonacin (3) 54.8 134.0 60.8 44.1 Rotenone 6.8 7.3 8.1 7.2 IC50-Cpx I, half-maximal concentration inhibiting complex I activity (brain homogenates); EC50-ATP, half-maximal effective concentration inducing a decrease in ATP levels (cultures, 6 h); EC50-ND, half-maximal effective concentration inducing neuronal cell death (cultures, 48 h); EC5-Tau, concentration at which tau was redistributed in 5% of the neurons as a measure of minimum ¨ concentration inducing tauopathy (cultures, 48 h); see Escobar-Khondiker et al. (2007) and Hollerhage et al. (2009).Guadeloupe (French West Indies), such patients account for two-thirds of all cases ofparkinsonism, compared to approximately 30% of atypical forms in European countries. Theydisplay a combination of movement disorders and dementia, the disease being thoroughlycharacterized. Autopsies performed in three patients revealed accumulation of neuronal Tau-fibrils (see references cited in Camuzat et al., 2008; Champy et al., 2009). ACGs were identifiedas candidate toxins using PC12 cells (unpublished data), as confirmed for annonacin (3) inmesencephalic primary cultures. In striatal primary cultures, ACGs induced ATP loss, Tauhyperphosphorylation and redistribution, microtubular disruption, and cell death at lownanomolar concentrations (Table 51.2; Hollerhage et al., 2009). ¨Subchronic systemic intoxication of Lewis rats with 3 (continuous i.v., 3.8; 7.6 mg/kg per day,28 days) did not cause locomotor dysfunction or signs of illness. However, 3 crossed thebloodebrain barrier, reduced cerebral ATP levels, and caused neuronal cell loss and gliosis inthe brain stem and basal ganglia. These features are similar to those obtained with rotenone(Hoglinger et al., 2006), and are reminiscent of the human disease. ACGs are therefore proposed ¨as etiological agents for cases of sporadic atypical parkinsonism and tauopathies worldwide, 435upon chronic exposure. However, pharmacokinetic parameters remain to be determined, andfurther epidemiological studies are needed before drawing firm conclusions. It is noteworthythat rotenone, widely used as an organic pesticide with low environmental reminiscence, wasbanned in 2008 in the European Union. In the absence of a defined benefiterisk balance, thesefacts challenge the various alternatives proposed for valorization of A. squamosa seeds.SUMMARY POINTSl Annona squamosa is a cultivated pantropical fruit tree, and its seeds are by-products.l Annona squamosa seeds constitute a major source of Annonaceous acetogenins (ACGs), which are potent lipophilic complex I inhibitors.l Sources of ACGs are proposed as antitumoral dietary supplements.l The seeds have major potential as an organic pesticide, with patents applied.l An extract of A. squamosa seeds was shown to be mildly genotoxic.l An epidemiological link between Annonaceae and atypical parkinsonian syndromes was evidenced.l ACGs are neurotoxic in vitro and in vivo.l The benefiterisk balance of use of A. squamosa seeds remains undefined, and caution should therefore prevail.References ´Bajin ba Ndob, I., Champy, P., Gleye, C., Lewin, G., & Akendengue, B. (2009). Annonaceous acetogenins: Precursors from the seeds of Annona squamosa. Phytochemistry Letters, 2, 72e76.Barrachina, I., Royo, I., Baldoni, H. A., Chahboune, N., Suvire, F., DePedro, N., et al. (2007). New antitumoral acetogenin “guanacone type” derivatives: Isolation and bioactivity. Molecular dynamics simulation of diacetyl- guanacone. Bioorganic & Medicinal Chemistry, 15, 4369e4381.
  9. 9. Authors personal copy PART 2 Effects of Specific Nuts and Seeds ` Bermejo, A., Figadere, B., Zafra-Polo, M.-C., Barrachina, I., Estornell, E., & Cortes, D. (2005). Acetogenins from Annonceae: Recent progress in isolation, synthesis and mechanisms of action. Natural Product Reports, 22, 269e303. Camuzat, A., Romana, M., Durr, A., Feingold, J., Brice, A., Ruberg, M., et al. (2008). The PSP-associated MAPT H1 ¨ subhaplotype in Guadeloupean atypical parkinsonism. Movement Disorders, 23, 2384e2391. ´ ` Cave, A., Figadere, B., Laurens, A., & Cortes, D. (1997). Acetogenins from Annonaceae. In W. Herz, G. W. Kirby, R. E. Moore, W. Steglich, & Ch. Tamm. (Eds.), In Progress in the chemistry of organic natural products, Vol. 70 (pp. 81e288). Vienna, Austria: Springer-Verlag. ´ Champy, P., Escobar-Khondiker, M., Bajin ba Ndob, I., Yamada, E., Lannuzel, A., Laprevote, O., et al. (2008). Atypical parkinsonism induced by Annonaceae: Where are we yet? Proceedings of the 7th Joint Meeting of the AFERP, ASP, GA, PSE & SIF, Athens, August 2008. Planta Medica, 74, 936e937. ´ ´ Champy, P., Guerineau, V., & Laprevote, O. (2009). MALDI-TOF MS profiling of Annonaceous acetogenins in Annona muricata products of human consumption. Molecules, 14, 5235e5246. Cuendet, M., Oteham, C. P., Moon, R. C., Keller, W. J., Peaden, P. A., & Pezzuto, J. M. (2008). Dietary administration of Asimina triloba (pawpaw) extract increases tumor latency in N-methyl-N-nitrosourea treated rats. Pharma- ceutical Biology, 46, 3e7. Damasceno, D. C., Volpato, G. T., Sartori, T. C. F., Rodrigues, P. F., Perin, E. A., Calderon, I. M. P., et al. (2002). Effects of Annona squamosa extract on early pregnancy in rats. Phytomedicine, 9, 667e672. ´ ´ Derbre, S., Roue, G., Poupon, E., Susin, S.-A., & Hocquemiller, R. (2005). Annonaceous acetogenins: The hydroxyl groups and THF rings are crucial structural elements for targeting the mitochondria, demonstration with the synthesis of fluorescent squamocin analogues. Chemistry and Biochemistry, 6, 979e982. ´ Derbre, S., Gil, S., Taverna, M., Boursier, C., Nicolas, V., Demey-Thomas, E., et al. (2008). Highly cytotoxic and neurotoxic acetogenins of the Annonaceae: New putative biological targets of squamocin detected by activity- based protein profiling. Bioorganic & Medicinal Chemistry Letters, 18, 5741e5744. Escobar-Khondiker, M., Hollerhage, M., Michel, P. P., Muriel, M.-P., Champy, P., Yagi, T., et al. (2007). Annonacin, ¨ a natural mitochondrial complex I inhibitor, causes Tau pathology in cultured neurons. Journal of Neuroscience, 27, 7827e7837. Garcia-Aguirre, K. K., Zepeda-Vallejo, L. G., Ramon-Gallegos, E., Alvarez-Gonzalez, I., & Madrigal-Bujaidar, E. (2008). Genotoxic and cytotoxic effects produced by acetogenins obtained from Annona cherimolia Mill. Biological & Pharmaceutical Bulletin, 31, 2346e2349. Gibson, G. E., Starkov, A., Blass, J. P., Ratan, R. R., & Beal, M. F. (2010). Cause and consequence: Mitochondrial436 dysfunction initiates and propagates neuronal dysfunction, neuronal death and behavioral abnormalities in age-associated neurodegenerative diseases. Biochimica Biophysica Acta, 1802, 122e134. Grover, P., Singh, S. P., Prabhakar, P. V., Reddy, U. A., Balasubramanyam, A., Mahboob, M., et al. (2009). In vivo assessment of genotoxic effects of Annona squamosa seed extract in rats. Food and Chemical Toxicology, 47, 1964e1971. Hoglinger, G. U., Oertel, W. H., & Hirsch, E. C. (2006). The rotenone model of parkinsonism e the five year ¨ inspection. Journal of Neural Transmission Supplementa, 70, 269e272. ` Hollerhage, M., Matusch, A., Champy, P., Lombes, A., Ruberg, M., Oertel, W. H., et al. (2009). Natural lipophilic ¨ inhibitors of mitochondrial complex I are candidate toxins for sporadic tau pathologies. Experimental Neurology, 220, 133e142. Kojima, N., & Tanaka, T. (2009). Medicinal chemistry of Annonaceous acetogenins: Design, synthesis, and bio- logical evaluation of novel analogues. Molecules, 14, 3621e3661. Liaw, C.-C., Yang, Y.-L., Chen, M., Chang, F.-R., Chen, S.-L., Wu, S.-H., et al. (2008). Mono-tetrahydrofuran Annonaceous acetogenins from Annona squamosa as cytotoxic agents and calcium ion chelators. Journal of Natural Products, 71, 764e771. McLaughlin, J. L. (2008). Paw paw and cancer: Annonaceous acetogenins from discovery to commercial products. Journal of Natural Products, 7, 1311e1321. Panda, S., & Khar, A. (2007). Annona squamosa seed extract in the regulation of hyperthyroidism and lipid-peroxidation in mice: Possible involvement of quercetin. Phytomedicine, 14, 799e805. Pardhasaradhi, B. V. V., Reddy, M., Ali, A. M., Kumari, A. L., & Khar, A. (2005). Differential cytotoxic effects of Annona squamosa seed extracts on human tumour cell lines: Role of reactive oxygen species and glutathione. Journal of Bioscience, 30, 237e244. Pinto, A. C., de Q., Cordeiro, M. C. R., de Andrade, S. R. M., Ferreira, F. R., Figueiras, H. A., de, C., et al. (2005). Annona species (pp. 1e268). Southampton, UK: International Center for Underutilised Crops, University of Southampton. Souza, M. M. C., Bevilaqua, C. M. L., Morais, S. M., Costa, C. T. C., Silva, A. R. A., & Braz-Fhilo, R. (2008). Anthelmintic acetogenin from Annona squamosa L. seeds. Anais Academia Brasileira Ciencias, 80, 271e277. Takahashi, S., Yonezawa, Y., Kubota, A., Ogawa, N., Maeda, K., Koshino, H., et al. (2008). Pyranicin, a non-classical annonaceous acetogenin, is a potent inhibitor of DNA polymerase, topoisomerase and human cancer cell growth. International Journal of Oncology, 32, 451e458.
  10. 10. Authors personal copy CHAPTER 51 Acetogenins of Annona Squamosa SeedsYang, H.-J., Li, X., Tang, Y., Zhang, N., Chen, J.-W., & Cai, B.-C. (2009a). Supercritical fluid CO2 extraction and simultaneous determination of eight annonaceous acetogenins in Annona genus plant seeds by HPLC-DAD method. Journal of Pharmaceutical and Biomedical Analysis, 49, 140e144.Yang, H.-J., Li, X., Zhang, N., He, L., Chen, J.-W., & Wang, M.-Y. (2009b). Two new cytotoxic acetogenins from Annona squamosa. Journal of Asian Natural Products Research, 11, 250e256.Yang, H.-J., Zhang, N., Li, X., He, L., & Chen, J.-W. (2009c). New nonadjacent bis-THF ring acetogenins from the seeds of Annona squamosa. Fitoterapia, 80, 177e181.Yu, J.-G., Luo, X.-Z., Sun, L., Li, D.-Y., Huang, W.-H., & Liu, C.-Y. (2005). Chemical constituents from the seeds of Annona squamosa. Yao Xue Xue Bao, 40, 153e158. 437