Planta Med 2021; 87(01/02): 177-186
DOI: 10.1055/a-1264-4302
Biological and Pharmacological Activities
Original Papers

Erythroxylum pungens Tropane Alkaloids: GC-MS Analysis and the Bioactive Potential of 3-(2-methylbutyryloxy)tropan-6,7-diol in Zebrafish (Danio rerio)

Letícia Gondim Lambert Moreira
1   Department of Pharmacy, Federal University of Rio Grande do Norte, Natal, RN, Brazil
,
Maria Elisa Leite Ferreira
2   Department of Physiology and Behavior, Federal University of Rio Grande do Norte, Natal, RN, Brazil
,
Fernanda Priscila Santos Reginaldo
1   Department of Pharmacy, Federal University of Rio Grande do Norte, Natal, RN, Brazil
,
Estela Mariana Guimarães Lourenço
3   Faculty of Pharmaceutical Sciences, Food and Nutrition, Federal University of Mato Grosso do Sul, Campo Grande, MS, Brazil
,
José Angelo Silveira Zuanazzi
4   Faculty of Pharmacy, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil
,
Euzébio Guimarães Barbosa
1   Department of Pharmacy, Federal University of Rio Grande do Norte, Natal, RN, Brazil
,
1   Department of Pharmacy, Federal University of Rio Grande do Norte, Natal, RN, Brazil
,
Arthur Germano Fett-Neto
5   Center for Biotechnology and Department of Botany, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil
,
Alberto José Cavalheiro
6   Chemistry Institute, São Paulo State University, Araraquara, SP, Brazil
,
Ana Carolina Luchiari
2   Department of Physiology and Behavior, Federal University of Rio Grande do Norte, Natal, RN, Brazil
,
1   Department of Pharmacy, Federal University of Rio Grande do Norte, Natal, RN, Brazil
› Institutsangaben
Gefördert durch: Fundação de Amparo à Pesquisa do Estado de São Paulo FAPESP/INCTBioNat 2014/50926-0
Gefördert durch: Coordenação de Aperfeiçoamento de Pessoal de Nível Superior Finance code 001
Gefördert durch: Conselho Nacional de Desenvolvimento Científico e Tecnológico 445149/2014-0
Gefördert durch: Conselho Nacional de Desenvolvimento Científico e Tecnológico INCT BioNat 465637/2014

Abstract

Tropane alkaloids are specialized plant metabolites mostly found in the Erythroxylaceae and Solanaceae families. Although tropane alkaloids have a high degree of structural similarity because of the tropane ring, their pharmacological actions are quite distinct. Brazil is one of the main hotspots of Erythroxylum spp. diversity with 123 species (almost 66% of the species catalogued in tropical America). Erythroxylum pungens occurs in the Caatinga, a promising biome that provides bioactive compounds, including tropane alkaloids. As part of our efforts to investigate this species, 15 alkaloids in specimens harvested under different environmental conditions are presented herein. The occurrence of 3-(2-methylbutyryloxy)tropan-6,7-diol in the stem bark of plants growing in their natural habitat, greenhouse controlled conditions, and after a period of water restriction, suggests that it is a potential chemical marker for the species. This alkaloid was evaluated for several parameters in zebrafish (Danio rerio) as a model organism. Regarding toxicity, teratogenic effects were observed at 19.5 µM and the lethal dose for embryos was 18.4 µM. No mortality was observed in adults, but a behavioral screen showed psychostimulatory action at 116.7 µM. Overall, the alkaloid was able to cause zebrafish behavioral changes, prompting further investigation of its potential as a new molecule in the treatment of depression-like symptoms. In silico, targets involved in antidepressant pathways were identified by docking.

Supporting Information



Publikationsverlauf

Eingereicht: 28. März 2020

Angenommen nach Revision: 16. September 2020

Artikel online veröffentlicht:
11. November 2020

© 2020. Thieme. All rights reserved.

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  • References

  • 1 Costa-Lima JL, Loiola MIB, Jardim JG. Erythroxylaceae no Rio Grande do Norte, Brasil. Rodriguésia 2014; 65: 659-671
  • 2 Restrepo DA, Saenz E, Jara-Muñoz OA, Calixto-Botía IF, Rodríguez-Suárez S, Zuleta P, Chavez BG, Sanchez JA, DʼAuria JC. Erythroxylum in focus: an interdisciplinary review of an overlooked genus. Molecules 2019; 24: 1-27
  • 3 Grynkiewicz G, Gadzikowska M. Tropane alkaloids as medicinally useful natural products and their synthetic derivatives as new drugs. Pharmacol Rep 2008; 60: 439-463
  • 4 Loiola MIBB, Agra MDF, Sidney GS, Queiroz RT. Flora da Paraíba, Brasil: Erythroxylaceae Kunth. Acta Bot Bras 2007; 21: 473-487
  • 5 Macedo Pereira G, Moreira LGL, Neto TDSN, Moreira de Almeida WA, Almeida-Lima J, Rocha HAO, Barbosa EG, Zuanazzi JAS, de Almeida MV, Grazul RM, Navarro-Vázquez A, Hallwass F, Ferreira LS, Fernandes-Pedrosa MF, Giordani RB. Isolation, spectral characterization, molecular docking, and cytotoxic activity of alkaloids from Erythroxylum pungens O. E. Shulz. Phytochemistry 2018; 155: 12-18
  • 6 Thomford NE, Senthebane DA, Rowe A, Munro D, Seele P, Maroyi A, Dzobo K. Natural products for drug discovery in the 21st Century: innovations for novel drug discovery. Int J Mol Sci 2018; 19: 1-29
  • 7 Pitchai A, Rajaretinam RK, Freeman JL. Zebrafish as an emerging model for bioassay-guided natural product drug discovery for neurological disorders. Medicines 2019; 6: 61
  • 8 Howe K, Clark MD, Torroja CF, Torrance J, Berthelot C, Muffato M, Collins JE, Humphray S, McLaren K, Matthews L, McLaren S, Sealy I, Caccamo M, Churcher C, Scott C, Barrett JC, Koch R, Rauch GJ, White S, Chow W, Kilian B, Quintais LT, Guerra-Assunção JA, Zhou Y, Gu Y, Yen J, Vogel JH, Eyre T, Redmond S, Banerjee R, Chi J, Fu B, Langley E, Maguire SF, Laird GK, Lloyd D, Kenyon E, Donaldson S, Sehra H, Almeida-King J, Loveland J, Trevanion S, Jones M, Quail M, Willey D, Hunt A, Burton J, Sims S, McLay K, Plumb B, Davis J, Clee C, Oliver K, Clark R, Riddle C, Elliot D, Threadgold G, Harden G, Ware D, Begum S, Mortimore B, Kerry G, Heath P, Phillimore B, Tracey A, Corby N, Dunn M, Johnson C, Wood J, Clark S, Pelan S, Griffiths G, Smith M, Glithero R, Howden P, Barker N, Lloyd C, Stevens C, Harley J, Holt K, Panagiotidis G, Lovell J, Beasley H, Henderson C, Gordon D, Auger K, Wright D, Collins J, Raisen C, Dyer L, Leung K, Robertson L, Ambridge K, Leongamornlert D, McGuire S, Gilderthorp R, Griffiths C, Manthravadi D, Nichol S, Barker G, Whitehead S, Kay M, Brown J, Murnane C, Gray E, Humphries M, Sycamore N, Barker D, Saunders D, Wallis J, Babbage A, Hammond S, Mashreghi-Mohammadi M, Barr L, Martin S, Wray P, Ellington A, Matthews N, Ellwood M, Woodmansey R, Clark G, Cooper J, Tromans A, Grafham D, Skuce C, Pandian R, Andrews R, Harrison E, Kimberley A, Garnett J, Fosker N, Hall R, Garner P, Kelly D, Bird C, Palmer S, Gehring I, Berger A, Dooley CM, Ersan-Ürün Z, Eser C, Geiger H, Geisler M, Karotki L, Kirn A, Konantz J, Konantz M, Oberländer M, Rudolph-Geiger S, Teucke M, Lanz C, Raddatz G, Osoegawa K, Zhu B, Rapp A, Widaa S, Langford C, Yang F, Schuster SC, Carter NP, Harrow J, Ning Z, Herrero J, Searle SM, Enright A, Geisler R, Plasterk RH, Lee C, Westerfield M, de Jong PJ, Zon LI, Postlethwait JH, Nüsslein-Volhard C, Hubbard TJ, Roest Crollius H, Rogers J, Stemple DL. The zebrafish reference genome sequence and its relationship to the human genome. Nature 2013; 496: 498-503
  • 9 Rinkwitz S, Mourrain P, Becker TS. Zebrafish: an integrative system for neurogenomics and neurosciences. Prog Neurobiol 2011; 93: 231-243
  • 10 Kalueff AV, Stewart AM, Gerlai R. Zebrafish as an emerging model for studying complex brain disorders. Trends Pharmacol Sci 2014; 35: 63-75
  • 11 Waller GR, Nowacki EK. Metabolic (catabolic) Modifications of Alkaloids by Plants. In: Waller GR, Nowacki EK. eds. Alkaloid Biology and Metabolism in Plants. Boston: Springer US; 1978: 183-249
  • 12 Magedans YMS, Rodrigues-Corrêa K, Costa C, Matsuura H, Fett-Neto AG. Sustainable production of bioactive alkaloids in Psychotria L. of southern Brazil: propagation and elicitation strategies. Acta Bot Bras 2019; 33: 607-617
  • 13 Christen P, Roberts MF, Phillipson JD, Evans WC. Alkaloids of Erythroxylum zambesiacum stem-bark. Phytochemistry 1993; 34: 1147-1151
  • 14 Christen P, Roberts MF, Phillipson JD, Evans WC. Alkaloids of Erythroxylum monogynum root-bark. Phytochemistry 1995; 38: 1053-1056
  • 15 Al-Said MS, Evans WC, Grout RJ. Alkaloids of Erythroxylum hipericifolium stem bark. Phytochemistry 1989; 28: 671-673
  • 16 Zanolari B, Guilet D, Marston A, Queiroz EF, Paulo MQ, Hostettmann K. Methylpyrrole tropane alkaloids from the bark of Erythroxylum vacciniifolium . J Nat Prod 2005; 68: 1153-1158
  • 17 Oliveira SL, Da Silva MS, Tavares JF, Sena-Filho JG, Lucena HFS, Romero MAV, Barbosa-Filho JM. Tropane alkaloids from Erythroxylum genus: distribution and compilation of 13C-NMR spectral data. Chem Biodivers 2010; 7: 302-326
  • 18 Berkov S, Pavlov A, Kovatcheva P, Stanimirova P, Philipov S. Alkaloid spectrum in diploid and tetraploid hairy root cultures of Datura stramonium . Z Naturforsch C Biosci 2003; 58: 42-46
  • 19 Kan-Fan C, Lounasmaa M. Sur les alcaloïdes de Knightia deplanchei Vieill. ex Brongn. et Gris (Protéacées). Acta Chem Scand 1973; 27: 1039-1052
  • 20 Witte L, Muller K, Arfmann HA. Investigation of the alkaloid pattern of Datura innoxia plants by capillary gas-liquid-chromatography-mass spectrometry. Planta Med 1987; 53: 192-197
  • 21 Blossey EC, Budzikiewicz H, Ohashi M, Fodor G, Djerassi C. Mass spectrometry in structural and stereochemical problems – XXXIX: Tropane alkaloids. Tetrahedron 1964; 20: 585-595
  • 22 Dohmeier-Fischer S, Krämer N, Grützmacher HF. Rearrangement by intermediate ion/neutral complexes during the McLafferty fragmentation of unsaturated ketones. Eur J Mass Spectrom 1995; 1: 310
  • 23 MacLeod JK, Djerassi C. Mass spectrometry in structural and stereochemical problems. CXXXVI. Primary hydrogen isotope effects in the McLafferty rearrangement. J Am Chem Soc 1967; 89: 5182-5190
  • 24 Kingston DGI, Bursey JT, Bursey MM. Intramolecular Hydrogen transfer in mass spectra. II. The McLafferty rearrangement and related reactions. Chem Rev 1974; 74: 215-242
  • 25 Bursey JT, Bursey MM, Kingston DGI. Intramolecular hydrogen transfer in mass spectra. I. Rearrangements in aliphatic hydrocarbons and aromatic compounds. Chem Rev 1973; 73: 191-234
  • 26 Basas-Jaumandreu J, de las Heras FXC. Allelochemicals and esters from leaves and inflorescences of Sambucus nigra L. Phytochem Lett 2019; 30: 107-115
  • 27 Nicolescu TO. Interpretation of Mass Spectra. In: Aliofkhazraei M. ed. Mass Spectrometry. London: Intech Open Limited; 2017: 24-72
  • 28 Heringa MF, Slowik JG, Goldmann M, Signorell R, Hemberger P, Bodi A. The distant double bond determines the fate of the carboxylic group in the dissociative photoionization of oleic acid. Chemphyschem 2006; 18: 12-19
  • 29 Philipov S, Berkov S. GC-MS Investigation of tropane alkaloids in Datura stramonium . Z Naturforsch C 2002; 57: 559-561
  • 30 Ionkova I, Witte L, Alfermann HA. Spectrum of tropane alkaloids in transformed roots of Datura innoxia and Hyoscyamus gyorffyi cultivated in vitro . Planta Med 1994; 60: 382-384
  • 31 El Bazaoui AE, Bellimam MA, Soulayman A. Nine new tropane alkaloids from Datura stramonium L. identified by GC/MS. Fitoterapia 2011; 82: 193-197
  • 32 Liu H, Sheng N, Zhang W, Dai J. Toxic effects of perfluorononanoic acid on the development of zebrafish (Danio rerio) embryos. J Environ Sci 2015; 32: 26-34
  • 33 Schmidt R, Strähle U, Scholpp S. Neurogenesis in zebrafish – from embryo to adult. Neural Dev 2013; 8: 1-13
  • 34 Bilotta J, Barnett JA, Hancock L, Saszik S. Ethanol exposure alters zebrafish development: a novel model of fetal alcohol syndrome. Neurotoxicol Teratol 2004; 26: 737-743
  • 35 Bretaud S, Lee S, Guo S. Sensitivity of zebrafish to environmental toxins implicated in Parkinsonʼs disease. Neurotoxicol Teratol 2004; 26: 857-864
  • 36 Hannun YA, Luberto C. Ceramide in the eukaryotic stress response. Trends Cell Biol 2000; 10: 73-80
  • 37 Blaser RE, Chadwick L, McGinnis GC. Behavioral measures of anxiety in zebrafish (Danio rerio). Behav Brain Res 2010; 208: 56-62
  • 38 Karl T, Pabst R, von Hörsten S. Behavioral phenotyping of mice in pharmacological and toxicological research. Exp Toxicol Pathol 2003; 55: 69-83
  • 39 Gould TD, Dao DT, Kovacsics CE. The open Field Test. In: Gould TD. ed. Mood and Anxiety related Phenotypes in Mice. Baltimore: Springer; 2009: 1-20
  • 40 Ferguson SA, Bowman RE. A nonhuman primate version of the open field test for use in behavioral toxicology and teratology. Neurotoxicol Teratol 1990; 12: 477-481
  • 41 Dal-Pan A, Pifferi F, Marchal J, Picq JL, Aujard F, Restrikal C. Cognitive performances are selectively enhanced during chronic caloric restriction or resveratrol supplementation in a primate. PLoS One 2011; 6: 1-9
  • 42 Champagne DL, Hoefnagels CCM, de Kloet RE, Richardson MK. Translating rodent behavioral repertoire to zebrafish (Danio rerio): relevance for stress research. Behav Brain Res 2010; 214: 332-342
  • 43 Rosemberg DB, Rico EP, Mussulini BH, Piato AL, Calcagnotto ME, Bonan CD, Dias RD, Blaser RE, Souza DO, Oliveira DL. Differences in spatio-temporal behavior of zebrafish in the open tank paradigm after a short-period confinement into dark and bright environments. PLoS One 2011; 6: 1-11
  • 44 Stewart AM, Gaikwad S, Kyzar E, Kalueff AV. Understanding spatio-temporal strategies of adult zebrafish exploration in the open field test. Brain Res 2012; 1451: 44-52
  • 45 Egan RJ, Bergner CL, Hart PC, Cachat JM, Canavello PR, Elegante MF, Elkhayat SI, Bartels BK, Tien AK, Tien DH, Mohnot S, Beeson E, Glasgow E, Amri H, Zukowska Z, Kalueff AV. Understanding behavioral and physiological phenotypes of stress and anxiety in zebrafish. Behav Brain Res 2009; 205: 38-44
  • 46 Luscher B, Shen Q, Sahir N. The GABAergic deficit hypothesis of major depressive disorder. Mol Psychiatry 2011; 16: 383-406
  • 47 Stewart JJP. MOPAC2016. Stewart Computational Chemistry. Accessed August 16, 2019 at: http://OpenMOPAC.net
  • 48 Bernstein FC, Koetzle TF, Williams GJ, Meyer EF, Brice MD, Rodgers JR, Kennard O, Shimanouchi TM, Tasumi M. The protein data bank: a computer-based archival file for macromolecular structures. J Mol Biol 1977; 112: 535-542
  • 49 Trott O, Olson AJ. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multi-threading. J Comput Chem 2010; 31: 455-461
  • 50 Korb O, Monecke P, Hessler G, Stützle T, Exner TE. PharmACOphore: multiple flexible ligand alignment based on ant colony optimization. J Chem Inf Model 2010; 50: 1669-1681