This paper examines annona muricata (graviola): toxic or therapeutic

Gray, A.I.

Hollinshead, J.

Jones, L.

Jones, P.W.

Mohanty, S.

Thomas, D.

Watson, A.A.

Watson, D.G.

English

Name not available

Annona muricata (graviola): toxic or therapeutic

University of Strathclyde Institutional Repository

Strathprints Institutional RepositoryMohanty, S. and Hollinshead, J. and Jones, L. and Jones, P.W. and Thomas, D. and Watson, A.A.and Watson, D.G. and Gray, A.I. (2008) Annona muricata (graviola): toxic or therapeutic. NaturalProduct Communications, 3 (1). pp. 31-33.Strathprints is designed to allow users to access the research output of the University of Strathclyde.Copyright c© and Moral Rights for the papers on this site are retained by the individual authorsand/or other copyright owners. You may not engage in further distribution of the material for anyprofitmaking activities or any commercial gain. You may freely distribute both the url (http://strathprints.strath.ac.uk/) and the content of this paper for research or study, educational, ornot-for-profit purposes without prior permission or charge.Any correspondence concerning this service should be sent to Strathprints administrator:mailto:strathprints@strath.ac.ukhttp://strathprints.strath.ac.uk/Volume 3. Issue 1. Pages 1-112. 2008 ISSN 1934-578X (printed); ISSN 1555-9475 (online) www.naturalproduct.us  This Issue is Dedicated to Professor Peter G. Waterman    Annona muricata (Graviola): Toxic or Therapeutic  Sambeet Mohantya, Jackie Hollinsheadb, Laurence Jonesb, Paul Wyn Jonesb, David Thomasb, Alison A. Watsonb, David G. Watsona, Alexander I. Graya, Russell J. Molyneuxc  and Robert J. Nashb*  aStrathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde,  27 Taylor Street, Glasgow G4 0NR, UK  bSummit (Wales) Limited, Plas Gogerddan, Aberystwyth, Ceredigion, SY23 3EB, UK  cUSDA-ARS, Western Regional Research Center, Albany, CA, USA  robert.nash@summitplc.com   Received: October 31st, 2007; Accepted: November 1st , 2007   Dedicated to Professor Peter G Waterman, one of the pioneers of phytochemical research.     The medicinal plant Annona muricata (Annonaceae), also known as Graviola or Soursop, is reported here to contain imino sugar alkaloids. This is the first report of imino sugars in the Annonaceae. Graviola has very broad medicinal claims and is also widely consumed as a food and in drinks in the tropics. The plant produces a wide range of secondary chemicals, some already known to be toxic, but the discovery here of the imino sugars as a new group of chemicals, including the neurotoxin swainsonine, raises questions about the safety of consumption of this plant.   Keywords:  Annona muricata, soursop, graviola, imino sugar, swainsonine, toxicity, immune modulator, glycosidase inhibitors.    Of the 60 or more species of the genus Annona, family Annonaceae, the soursop or graviola, A. muricata L., is the most tropical, the largest-fruited, and the only one lending itself well to preserving and processing. The leaves and bark contain cytotoxic acetogenins and the plant also produces isoquinoline and phenanthrene alkaloids [1]. The bark is high in hydrocyanic acid. The seeds contain 45% of a yellow non-drying oil, which is an irritant poison, causing severe eye inflammation. There are many medicinal claims for A. muricata. The juice of the ripe fruit is said to be diuretic and a remedy for haematuria and urethritis. Taken when fasting, it is believed to relieve liver ailments and leprosy. Pulverized immature fruits, which are very astringent, are decocted as a dysentery remedy. To speed wound healing the flesh of the unripe fruit is applied as a poultice and left unchanged for 3 days. Consumption of the plant is also thought to be related to an abnormally high frequency of levodopa-resistant Parkinsonism or progressive supranuclear palsy in the French West Indies [2]. Studies with neurons in culture have indicated that alkaloids from A. muricata vegetative tissues can modulate the function and the survival of dopaminergic nerve cells in vitro.   We here report, for the first time, the presence of imino sugars, including the neurotoxic alkaloid swainsonine (1) in A. muricata. Swainsonine is a potent mannosidase inhibitor that causes neurotoxicity through inhibition of lysosomal acidic  α-mannosidase [3]. Although the concentration of swainsonine was low in the commercial herbal medicine sample we purchased (0.0004% dry weight), it has been estimated that as little as 0.001% in the diet may cause neurological disorders in livestock [3]. The toxic dose for humans and symptoms are not known. It may well be that the concentrations of swainsonine will vary in A. muricata products due to, for example, variety, growth conditions, harvesting time and processing method.  Imino sugars are always distributed NPC Natural Product Communications 2008 Vol. 3 No. 1 31 - 33  32  Natural Product Communications Vol. 3 (1) 2008 Mohanty et al. throughout plant organs, but are usually concentrated in fruits and seeds [4].   Glycosidase-inhibiting imino sugar alkaloids arouse a lot of interest for potential therapeutic applications including diabetes, viral infections and anti-cancer uses [4]. In view of the range of medicinal claims for A. muricata it is interesting, therefore, to note also the immuno-modulatory and anti-cancer activity      of swainsonine and of pyrrolizidine imino sugars, such as casuarine (2) [5], which was also found        in A. muricata. The plant material analyzed           also contained the glucosidase-inhibiting imino        sugars calystegine B2 (3), deoxynojirmycin (DNJ) (4) and 2R, 3R, 4R, 5R-2,5-dihydroxymethyl-3,4,-dihydroxypyrrolidine (DMDP) (5). Another imino sugar was tentatively identified as deoxymannojirimycin (DMJ) (6). DMDP (5) was the most major imino sugar, being present at 0.01% dry weight. The specificity of glycosidase inhibition is very important for its potential therapeutic activity with DNJ (4), for example, having anti-viral activity through inhibition of glycoprotein processing glucosidases [4].  DMJ (6) and swainsonine (1) inhibit mannosidases very specifically and can have anti-viral activity through inhibition of glycoprotein processing mannosidases. Swainsonine has also   been shown to have potent anti-cancer activity       [4].  Calystegine B2 is a strong competitive inhibitor of human liver α-galactosidase and rat liver             β-glucosidase [6].  A. muricata highlights the complexity                       of   understanding    whether    medicinal   plants   are  therapeutically useful. In many cases it is not certain that they have any therapeutically-active components other than perhaps important nutrients. In the case of A. muricata, there are many very biologically-active components, including acetogenins and alkaloids. We now add to the known complexity of this plant by reporting glycosidase-inhibiting imino sugars, some of which are known to have direct anti-viral activity (e.g. DNJ, DMJ) and others that stimulate immune responses (e.g. swainsonine and casuarines). However, swainsonine and calystegines have been implicated as neurotoxins in livestock [7] and their presence in A. muricata raises the possibility that they might be involved in neurological disorders in man associated with consumption of the plant [2].  The polyhydroxylated alkaloids, as tms derivatives, have good resolution and give characteristic mass spectral fragmentation patterns, as shown for swainsonine (1) at 7.9 min (Figure 1). The other imino sugars were identified by comparison with authentic standards and were DMDP (5) [retention time 7.6 min and main fragments 217 (50%), 258 (30%), 348 (100%)], DNJ (4) [retention time 9.8 min and main fragments 217 (100%), 258 (80%) and 348 (80%)], calystegine B2 (3) [(retention time 10 min with main fragments 217 (100%), 244 (10%), 284 (10%)], and casuarine [(retention time 10.5 min and main fragments 217 (40%), 258 (40%) and 462 (100%)]. In addition there was an unknown imino sugar at 7.8 min, thought to be deoxymannojirimycin (DMJ) (6) [(main fragments at 217 (100%), 258 (30%) and 348 (30%)].    NHOHOHOH,  13-Jul-2007 + 11:11:49SWAINSONINE STD86 106 126 146 166 186 206 226 246 266 286 306 326 346 366 386 406m/z0100%vast190604 1162 (7.879) Scan EI+ 1.53e9185143120115101129 142170157147158184172260186210204 217 244230258261299273 286 374316 346 389      Figure 1: Structure and mass spectrum of swainsonine (1) as the O-trimethylsilylderivative  NOHOHHCH2OHHOOH  HNHOOHOHOH  N CH2OHOHOHHOH   N CH2OHHO OHHOH2CH   N CH2OHOHOHHOH             (2)         (3)   (4)   (5)    (6)  Figure 2: Structure of casuarine (2), calystegine B2 (3), deoxynojirmycin (4), DMDP (5) and deoxymannonojirmycin (6). Imino sugars from. Annona muricata Natural Product Communications Vol. 3 (1) 2008 33  Experimental Plant material: Annona muricata material (leaves/stems) from Brazil was purchased from Raintree Nutrition, Inc, Carson City, NV 89701, USA (July 2007 batch 0 12345 10011 6).   Extraction and GC-MS analysis: The plant material powder was extracted at room temperature in 50% aqueous ethanol for 15 h. The extract was filtered and run through strongly acidic cation exchange resin (IR120, Merck, H+ form) and the alkaloids displaced by 2M ammonia solution, after washing the resin with water.  The alkaloid fractions were dried and weighed. GC-MS was conducted on 1 mg samples of each cation exchange bound sample using 200 µL of Sigma Sil A reagent to produce O-trimethylsily-derivatives (tms). Samples were heated at 60°C for 15 minutes and then left at room temperature for at least 60 min.  Insoluble reaction products were sedimented by centrifugation, and the supernatant was transferred to fresh vials, using a syringe. The GC column was a high polarity, fused-silica column (Varian ‘Factor Four’ VF-5ms column, 25 m x 0.25 mm i.d., 0.25 μm phase thickness).  The carrier gas (helium) flow rate was 1 mL min-1.  TMS derivatives were separated using a temperature program that started at 160°C for 5 min, followed by a linear increase to 300°C at a rate of 10°C min-1. The temperature was held at 300°C for an additional      10 min; the total analysis time was 29 min.  EI MS of the column eluant was carried out using a Perkin Elmer TurboMass Gold mass spectrometer, with a quadrupole ion filter system, which was run at 250°C constantly during analysis.  The detector mass range was set to 100 to 650 amu. The temperature of the transfer line (GC to MS) was held at 250°C.  Samples were injected onto the column via a split vent      (split ratio 50:1) through a fused silica narrow bore injection liner packed with deactivated quartz wool; the injection port temperature was maintained at 200°C.  The injection volume was 1 μL. System control, data collection and mass spectral analysis was carried out using Perkin Elmer TurboMass software (TurboMass v. 4.4). All compounds were identified by GC-MS through comparison with authentic standards. The swainsonine concentration was calculated by comparison with an internal standard of the related alkaloid castanospermine, which was added at a concentration range of 0.0001-0.1mg into 10g of the original plant material prior to extraction. A dose response curve of the two alkaloids together was also used to determine the comparative response factors for the alkaloids. The quantity of DMDP (5) was determined by isolation and the structure confirmed by proton NMR spectroscopy. References [1]  Dictionary of Natural Products on DVD (2007) Chapman and Hall/CRC Press, London. [2]  Lannuzel A, Michel PP, Caparros-Lefebvre D, Abaul J, Hocquemiller R, Ruberg M. (2002) Toxicity of Annonaceae for dopaminergic neurons: potential role in atypical parkinsonism in Guadeloupe. Movement Disorders, 17, 84-90. [3]  Molyneux RJ, James LF, Ralphs MH, Pfister JA, Panter KP, Nash RJ. (1994)  Polyhydroxyalkaloid glycosidase inhibitors from poisonous plants of global distribution: analysis and identification.  In: Plant-Associated Toxins - Agricultural, Phytochemical and Ecological Aspects.  (Eds, Colgate SM, Dorling PR), CAB International, Wallingford, U.K., pp 107-112.  [4]  Watson AA, Fleet GWJ, Asano N, Molyneux RJ, Nash RJ. (2001) Polyhydroxylated alkaloids - Natural occurrence and therapeutic applications.  Phytochemistry, 56, 265-295. [5] Patent PCT/GB2004/000198. [6] Asano N, Kato A, Miyauchi M, Kizu H, Tomimori T, Matsui K, Nash RJ, Molyneux RJ. (1997) Specific alpha-galactosidase inhibitors, N-methylcalystegines - structure/activity relationships of calystegines from Lycium chinense.  European Journal of Biochemistry, 248, 296-303. [7] Haraguchi M, Gorniak SL, Ikeda K, Minami Y, Kato A, Watson AA, Nash RJ, Molyneux RJ, Asano N. (2003) Alkaloidal components in the poisonous plant, Ipomoea carnea (Convolvulaceae). Journal of Agricultural and Food Chemistry, 51,         4995-5000. Natural Product Communications Vol. 3 (1) 2008 Published online (www.naturalproduct.us)    A Method of Selecting Plants with Anti-inflammatory Potential for Pharmacological Study G. David Lin, Rachel W. Li, Stephen P. Myers and David N. Leach      71   Review /Account  Recent Advances of Biologically Active Substances from the Marchantiophyta Yoshinori Asakawa           77  Non-Protein Amino Acids: A Review of the Biosynthesis and Taxonomic Significance E. Arthur Bell (the late), Alison A. Watson and Robert J. Nash       93 Natural Product Communications 2008 Volume 3, Number 1   Contents  Original paper           Page  A Novel Sesquiterpene from Pulicaria crispa (Forssk.) Oliv. Michael Stavri, Koyippally T. Mathew and Simon Gibbons       1  Cassane diterpenoids from Lonchocarpus laxiflorus John O. Igoli, Samuel O. Onyiriuka, Matthias C. Letzel,  Martin N. Nwaji and Alexander I. Gray    5  COX-2 Inhibitory Activity of Cafestol and Analogs from Coffee Beans Ilias Muhammad, Satoshi Takamatsu, Jamal Mustafa, Shabana I. Khan, Ikhlas A. Khan,  Volodymyr Samoylenko, Jaber S. Mossa, Farouk S. El-Feraly and D. Chuck Dunbar    11  Antibacterial Diterpenes from the Roots of Ceriops tagal Musa Chacha, Renameditswe Mapitse, Anthony J. Afolayan and Runner R. T. Majinda    17  Boswellic Acids with Acetylcholinesterase Inhibitory Properties from Frankincense Masahiro Ota and Peter J. Houghton         21  Synthesis of Pregnenolone and Methyl Lithocholate Oxalate Derivatives  Lutfun Nahar, Satyajit D. Sarker and Alan B. Turner        27  Annona muricata (Graviola): Toxic or Therapeutic Sambeet Mohanty, Jackie Hollinshead, Laurence Jones, Paul Wyn Jones, David Thomas,  Alison A. Watson, David G. Watson, Alexander I. Gray, Russell J. Molyneux  and Robert J. Nash   31  Two New Alkylated Piperidine Alkaloids from Western Honey Mesquite:  Prosopis glandulosa Torr. var. torreyana Volodymyr Samoylenko, D. Chuck Dunbar, Melissa R. Jacob, Vaishali C. Joshi,  Mohammad K. Ashfaq and Ilias Muhammad        35  Selective Metabolism of Glycosidase Inhibitors by a Specialized Moth Feeding on  Hyacinthoides non-scripta Flowers Alison A. Watson, Ana L. Winters, Sarah A. Corbet, Catherine Tiley and Robert J. Nash    41  Antimicrobial Activities of Alkaloids and Lignans from Zanthoxylum budrunga M. Mukhlesur Rahman, Alexander I. Gray, Proma Khondkar and M. Anwarul Islam    45  A Pyranochalcone and Prenylflavanones from Tephrosia pulcherrima (Baker) Drumm Seru Ganapaty, GuttulaV.K. Srilakshmi, Steve T. Pannakal and Hartmut Laatsch    49  Phenolic Glycosides from Phlomis lanceolata (Lamiaceae) Hossein Nazemiyeh, Abbas Delazar, Mohammed-Ali Ghahramani, Amir-Hossein Talebpour,  Lutfun Nahar and Satyajit D. Sarker         53  Bisresorcinols and Arbutin Derivatives from Grevillea banksii R. Br.  Hao Wang, David Leach, Michael C. Thomas, Stephen J. Blanksby, Paul I. Forster and          Peter G. Waterman           57   Antioxidant and Membrane Stabilizing Properties of the Flowering Tops of  Anthocephalus cadamba M. Ashraful Alam, Abdul Ghani, Nusrat Subhan, M. Mostafizur Rahman,  M. Shamsul Haque, Muntasir M. Majumder, M. Ehsanul H. Majumder, Raushan A. Akter,  Lutfun Nahar and Satyajit D. Sarker         65   Continued inside back cover 

[1] Dictionary of Natural Products on DVD (2007) Chapman and

Alkaloidal components in the poisonous plant, Ipomoea carnea (Convolvulaceae).

Polyhydroxyalkaloid glycosidase inhibitors from poisonous plants of global distribution: analysis and identification. In:

Polyhydroxylated alkaloids - Natural occurrence and therapeutic applications.

Published online (www.naturalproduct.us) A Method of Selecting Plants with Anti-inflammatory Potential for Pharmacological

Specific alpha-galactosidase inhibitors, N-methylcalystegines - structure/activity relationships of calystegines from Lycium chinense.

http://strathprints.strath.ac.uk/19802/1/npc3_1_31_2008_2_.pdf

Annona muricata (graviola): toxic or therapeutic

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