Medicinal Attributes of Lignans Extracted from Piper Cubeba
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DOI:10.1002/open.201700182 Medicinal Attributes of Lignans Extracted from Piper Cubeba:Current Developments Regiane Godoy de Lima,[a, b] Maria Teresa Barros,*[a] and Rosangela da Silva Laurentiz[b, c] ChemistryOpen 2018, 7,180 –191 180 2018 The Authors. PublishedbyWiley-VCH Verlag GmbH &Co. KGaA, Weinheim Lignans are alarge class of natural products that have been The cubebins have been identified asalactol monomer and isolated from many plants.They revealdiverse biological activi- dimers as amixture of diastereoisomers. Recently,their struc- ties, especially antiviral and antitumorproperties. From Piper tural characterization and the synthesis of the possible struc- cubeba,lignans of several classes can be isolatedfrom the tures have led to the correction of some earlier structural pro- roots, rhizomes, stems,leaves,seeds, and fruits.Among its vari- posals. This review describes the more recent developmentsin ous chemical constituents, ( )-cubebin and ( )-hinokinin are the study of the medicinalattributesofcubebin and hinokinin À À found in significant quantities.Although they have been extracted from Piper cubeba and the synthesis and biological known for some time, during the last few decades their biolog- testingofsome analogues. ical properties have been studied by severalresearch groups. 1. Introduction group of dimericphenylpropanoidsand, therefore, originated from awide variety of lignans. There are eight subclasses of li- Piper cubeba is an important plant belonging to the Piperaceae gnans, including dibenzylbutane, dibenzylbutyrolactol, diben- family,commonly known as cubeb or Java pepper,and it is zylbutyrolactone, furan, furofuran, aryltetralin, arylnaphthalene, cultivated for its fruit andessential oils. It is grown in Indone- and dibenzocyclooctadiene (Figure 1).[10–12] sia, mainly in the Java and Sumatra islands, andinsouthern India.[1] Piper cubeba is used as aspice in many countries and is economically important.[1,2] The bioactive compoundsfrom Piper cubeba have been of great value in the discovery of new therapeutic agents to treat ailments associated with inflammatory problems, renal disor- ders, gonorrhea, syphilis, abdominal pain, enteritis, and asthma.[3,4] 2. Lignans in General Analysis of the literatureindicates that 24 lignans have so far been reported from extracts of P. cubeba.[1,3, 5–7] Lignans are sec- ondary metabolites produced by plants that have awide range of biological properties which are intrinsically related to their stereochemistry.[5,6,8,9] This variety is relatedtothe diversi- ty of carbon skeletons that these classes of natural products present in plants.[10] The denomination of the lignan class of compounds was created in 1936 by Haworth to describe a Figure 1. General classesoflignans.[10] [a] R. Godoy de Lima, Prof. M. T. Barros LAQV,REQUIMTE Departamento de Química, Faculdade de CiÞncias eTecnologia Universidade Nova de Lisboa Lignans are present mainly in plants but can also be found 2829-516 Caparica (Portugal) in mammals and are produced by the action of intestinal bac- Tel. (+351) 212948361 teria from food lignans (matairesinol, secoisolariciresinol, pinor- E-mail:[email protected] esinol, sesamin, lariciresinol, syringaresinol, 7-hydroxytatairesi- [b] R. Godoy de Lima, Prof. R. da Silva Laurentiz Department of Physicsand Chemistry nol, and artigenina) found in flax seeds, fruits, and vegeta- [13–18] S¼oPaulo State University bles. In Linum, Anthriscus,and Podophyllum plants, matair- Av.Brasil 56, 15380-000, Ilha Solteira-SP (Brasil) esinol is also converted into hinokinin, yatein, or podophyllo- [c] Prof. R. da Silva Laurentiz toxin throughmultiple biosynthetic pathways, even though all Department of Physicsand Chemistry relevant enzymes have not yet been identified.[19] S¼oPaulo State University Av.Brasil 56, 15380-000, Ilha Solteira-SP (Brasil) Enterolactone and enterodiol have been cited as providing The ORCID identification number(s) for the author(s) of this article can protection against cardiovascular disease, diabetes, and be found under https://doi.org/10.1002/open.201700182. cancer.[18] These and other lignans also have antioxidant activi- 2018 The Authors. Published by Wiley-VCH Verlag GmbH &Co. KGaA. ty[20] and reduce oxidative stress. Lignans with anticancer activ- This is an openaccessarticleunder the termsofthe Creative Commons ity behaveinmetabolic pathways, however,through the in- Attribution-NonCommercial-NoDerivs License, which permits useand ductionofcell death by apoptosis.[21–24] distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are Of the Piper cubeba lignans,several classes can be isolated made. from roots, rhizomes, stems,leaves, seeds (Figure 2), and ChemistryOpen 2018, 7,180 –191 www.chemistryopen.org 181 2018 The Authors. PublishedbyWiley-VCH Verlag GmbH &Co. KGaA, Weinheim Regiane Godoy de Lima graduated with adegree in physics from S¼o Paulo State University (Unesp), School of Technology and Sciences,in2010 and received her Master’s degree in materials science from S¼oPaulo State University (Unesp), School of Engineer- ing, Ilha Solteira, in 2013. Currently, she is aPh.D. student at the S¼oPaulo State University (Unesp), School of En- gineering. She has experience in the area of physics, with emphasis on su- Figure 2. Piper cubeba seeds.[29] perconducting. Her present work is in the field of polymeric nano- particles for controlled delivery of drugs and the study of cyto- [1,25] toxicity. fruits. Recent studies aimed at investigating the biological activities of crude fruit extracts[26,27] have been related to bio- logical properties discovered in lignans.[28] Maria Teresa Barros received her Ph.D. Some interesting biological activities of lignans extracted degree in organic chemistry from the from P. cubeba have been reported, and these lignans could University of Paris-Sud (Doctorat potentially be developed as new drugs.[1,6,25,29] Thus, the aim of d’État) in1981. Her doctoral studies in- this review is to describe the medicinal attributes and current volved methodological improvements developments of the structurally similarlignans hinokinin and for the application of pentavalent bis- cubebin, which possess abroad range of biological activities muth derivatives in organic synthesis and are major componentsofthe fruits of P. cubeba.[1] working under the supervision of Pro- fessor Sir Derek Barton. She worked as apostdoctoral researcher at the 3. ( )-Cubebin Chemistry Department, University of À California at Berkeley studying organic An important dibenzylbutyrolactone lignan is ( )-cubebin (1); À bridged uranocenes with Professor Andrew Streitwieser and at the the lactol structure and stereochemistry of cubebin (Figure 3), Lawrence Berkeley Laboratory as avisiting scholar.Currently,she is aconstituent of cubeb fruits (Piper cubeba), waselucidated by Associate Professor with habilitation in the Chemistry Department Batterbee.[30] ( )-Cubebin (1)has been isolated from acrude À of the Faculty of Sciences and Technology of the New University of hexane extract of the leaves of Zanthoxylumnaranjillo.[31] The Lisbon and is aresearcher of REQUIMTE/LAQV at the same institu- Piper nigrum crude ethanolextract presents phytochemical tion. Her research covers abroad range of topics in synthetic bio- compounds,[32] althoughthe crude ethanolextract of P. cubeba organic chemistry,especially the synthesis of large and small mole- has higher antioxidantactivity than the extracts from other cules with potential biological activity.Her research group is also Piper species.[27] ( )-Cubebin is amajor component of Piper À involved in the development of new strategies for drug delivery. cubeba seeds.[33] During the last decades, interesting new bio- logical properties of this compound have been discovered. Rosagela da Silva Laurentiz received her Ph.D. degree in chemistry at the University of S¼oPaulo in 2002. In 2004, she carried out postdoctoral studies at the Faculty of Pharmaceuti- cal Sciences of Ribeir¼oPreto-USP at the Laboratory of Clinical, Toxicologi- cal, and Bromatology Analysis. She started her project as ayoung re- searcher at the University of Franca and is currently an Assistant Professor [33] Figure 3. ( )-Cubebin structure as amixture of epimers at C-9’. in the Department of Physics and À Chemistry,School of Engineering, Ilha Solteira. She teaches post- graduate courses in the materials science program and classes in 3.1. Synthesis biochemistry and organic chemistry for undergraduate courses in animal science, agronomy,and biology.She develops projects in 3.1.1. Biosynthetic Pathways organic synthesis and natural products applied to human and In 2017, Pissurno and Laurentiz proposed biosynthetic path- animal health. ways for lignans containing oxygen atoms at the C-9 and C-9’ ChemistryOpen 2018, 7,180 –191 www.chemistryopen.org 182 2018 The Authors. PublishedbyWiley-VCH Verlag GmbH &Co. KGaA, Weinheim positions (Scheme 1). The biosynthesis of these lignans is initi- ated by enantioselective dimerization of two units of coniferyl alcohol (4)toprovide pinoresinol(5), which is reduced to lari- ciresinol (6)toproduce secoisolariciresinol (7). Compound 7 is then oxidized by secoisolariciresinol dehydrogenase to pro- duce matairesinol (8). Cubebin (9)isobtained through conden- sation of the hydroxy and methoxy groups on the aromatic rings thus to produce the methylenodioxygroup.[11] Scheme2.Semisynthetic derivatives of ( )-cubebin. Reagents and condi- À tions:a)Ac2O,