Abstract
It has long been recognized that many sesquiterpene lactones possess very prominent anti-infective as well as antitumour potential. The structure-activity relationships underlying these as well as many other aspects of their biological activity have been reviewed extensively. Since 2006, a variety of new data have emerged that warrant an update. The activity of sesquiterpene lactones against “protozoan” parasites has been the topic of studies from various laboratories, and the current chapter will attempt a synopsis of the existing biological data related to inhibitory effects on parasites of the genera Trypanosoma, Leishmania and Plasmodium as causative agents of major tropical diseases. Besides some recent new mechanistic evidence to explain the strong anti-trypanosomal activity of certain sesquiterpene lactones, a main focus will be on quantitative structure-activity relationship studies which have recently led to the discovery of certain furanoheliangolide-type compounds as extremely potent agents against Trypanosoma brucei, the pathogen responsible for human African trypanosomiasis or “sleeping sickness”. Investigations on the long-known antitumoural potential of sesquiterpene lactones have recently received new impetus by the finding that certain compounds of this class possess a hitherto unknown mechanism of action that may make them interesting leads, or even therapeutic agents, against certain types of leukaemia and some other tumours known to be characterized by an excessive activity of the transcription factor c-Myb. This factor plays important roles in cell proliferation and differentiation and has been identified as an interesting drug target. Sesquiterpene lactones were discovered as the first type of low-molecular-weight inhibitors of c-Myb and C/EBP transcriptional activity. Besides extensive QSAR studies on this new activity of sesquiterpene lactones, the chapter will also focus on very recent mechanistic studies into the peculiar mode of action of the most active sesquiterpene lactones on the transcriptional activity of c-Myb and C/EBP.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Acevedo CH, Scotti L, Alves MF et al (2017) Computer-aided drug design using sesquiterpene lactones as sources of new structures with potential activity against infectious neglected diseases. Molecules 22:79
Becker JVW, van der Merwe MM, van Brummelen AC et al (2011) In vitro anti-plasmodial activity of Dicoma anomala subsp. gerrardii (Asteraceae): identification of its main active constituent, structure-activity relationship studies and gene expression profiling. Malar J 10:295
Bender TP, Kremer CS, Kraus M et al (2004) Critical functions for c-Myb at three checkpoints during thymocyte development. Nat Immunol 5:721–729
Berge T, Matre V, Brendeford EM et al (2007) Revisiting a selection of target genes for the hematopoietic transcription factor c-Myb using chromatin immunoprecipitation and c-Myb knockdown. Blood Cells Mol Dis 39:278–286
Branquinho RT, Mosqueira VC, de Oliveira-Silva JC et al (2014) Sesquiterpene lactone in nanostructured parenteral dosage form is efficacious in experimental Chagas disease. Antimicrob Agents Chemother 58:2067–2075
Bujnicki T, Wilczek C, Schomburg C et al (2012) Inhibition of Myb-dependent gene expression by the sesquiterpene lactone mexicanin-I. Leukemia 26:615–622
Carpinelli MR, Hilton GJ, Metcalf D et al (2004) Suppressor screen in Mpl/mice: c-Myb mutation causes supraphysiological production of platelets in the absence of thrombopoietin signaling. Proc Natl Acad Sci USA 101:6553–6558
Davydov IV, Krammer PH, Li-Weber M (1995) Nuclear factor-IL6 activates the human IL-4 promoter in T cells. J Immunol 155:5273–5279
Emambokus N, Vegiopoulos A, Harman B et al (2003) Progression through key stages of haemopoiesis is dependent on distinct threshold levels of c-Myb. EMBO J 22:4478–4488
Fabian L, Sülsen V, Frank F et al (2013) In silico study of structural and geometrical requirements of natural sesquiterpene lactones with trypanocidal activity. Mini Rev Med Chem 13:1407–1414
Garcia-Pineres AJ, Castro V, Mora G et al (2001) Sesquiterpene lactones inhibit the transcription factor NF-kappa B by alkylating its p65 subunit. J Biol Chem 276:39713–39720
Gökbulut A, Kaiser M, Brun R et al (2012) 9β-Hydroxyparthenolide esters from Inula montbretiana DC and their antiprotozoal activity. Planta Med 78:225–229
Greenwel P, Tanaka S, Penkov D et al (2000) Tumor necrosis factor alpha inhibits type I collagen synthesis through repressive ccaat/enhancer-binding proteins. Mol Cell Biol 20:912–918
Jakobs A, Uttarkar S, Schomburg C et al (2016a) An isoform-specific C/EBPβ inhibitor targets acute myeloid leukemia cells. Leukemia 30:1612–1615
Jakobs A, Steinmann S, Henrich SM et al (2016b) Helenalin acetate, a natural sesquiterpene lactone with anti-inflammatory and anti-cancer activity, disrupts the cooperation of CCAAT-box/enhancer-binding protein beta (C/EBPβ) and co-activator p300. J Biol Chem 291:26098–26108
Kimani NM, Matasyoh JC, Kaiser M, Brun R, Schmidt TJ (2018a) Antiprotozoal sesquiterpene lactones and Other Constituents from Tarchonanthus camphoratus and Schkuhria pinnata. J. Nat. Prod. 81:124–130
Kimani MN, Matasyoh JC, Kaiser M, Brun R, Schmidt TJ (2018b) Sesquiterpene lactones from Vernonia cinerascens Sch. Bip. and their in vitro antitrypanosomal activity. Molecules 23:248
Kimani NM, Matasyoh JC, Kaiser M et al (2017) Anti-trypanosomatid elemanolide sesquiterpene lactones from Vernonia lasiopus O. Hoffm. Molecules 22:597
Kreuger MRO, Grootjans S, Biavatti MW et al (2012) Sesquiterpene lactones as drugs with multiple targets in cancer treatment: focus on parthenolide. Anti-Cancer Drugs 23:883–896
Lang G, White JR, Argent-Katwala MJ et al (2005) Myb proteins regulate the expression of diverse target genes. Oncogene 24:1375–1384
Lenz M, Krauth-Siegel L, Schmidt TJ (2015) 4,15–isoatriplicolide-esters: new inhibitors of trypanothione reductase. Planta Med 81:PM_102. https://doi.org/10.1055/s-0035-1565479
Lipsick JS, Wang DM (1999) Transformation by v-Myb. Oncogene 18:3047–3055
Liu F, Lei W, O’Rourke JP et al (2006) Oncogenic mutations cause dramatic, qualitative changes in the transcriptional activity of c-Myb. Oncogene 2:5795–5805
Lone SH, Bhat KA, Khuroo MA (2015) Arglabin: from isolation to antitumor evaluation. Chem Biol Interact 240:180–198
Lyss G, Schmidt TJ, Merfort I et al (1997) Helenalin, an anti-inflammatory sesquiterpene lactone from Arnica selectively inhibits transcription factor NF-kappaB. Biol Chem 378:951–961
Lyss G, Knorre A, Schmidt TJ et al (1998) The anti-inflammatory sesquiterpene lactone helenalin inhibits the transcription factor NF-kappa B by directly targeting p65. J Biol Chem 273:33508–33516
Lyss G, Schmidt TJ, Pahl HL et al (1999) Studies for the anti-inflammatory activity of Arnica tincture using the transcription factor NF-kappa B as molecular target. Pharm Pharmacol Lett 9:5–8
Maas M, Hensel A, da Costa FB et al (2014) An unusual dimeric guaianolide with antiprotozoal activity and further sesquiterpene lactones from Eupatorium perfoliatum. Phytochemistry 72:635–644
Malaterre J, Carpinelli M, Ernst M et al (2007) c-Myb is required for progenitor cell homeostasis in colonic crypts. Proc Natl Acad Sci USA 104:3829–3834
Merfort I (2011) Perspectives on sesquiterpene lactones in inflammation and cancer. Current Drug Targets 12:1560–1573
Mucenski ML, McLain K, Kier AB et al (1991) A functional c-myb gene is required for normal murine fetal hepatic hematopoiesis. Cell 65:677–689
Natsuka S, Akira S, Nishio Y et al (1992) Macrophage differentiation-specific expression of NF-IL6, a transcription factor for interleukin-6. Blood 79:460–466
Nogueira MS (2016) The use of Chemometric and Chemoinformatic Tools for Identification and Targeted Isolation of Compounds from Asteraceae with Antiprotozoal Activity. Dr. rer. nat. thesis, University of Münster
Nour AMM, Khalid SA, Brun R et al (2009) The antiprotozoal activity of sixteen Asteraceae species native to Sudan and bioactivity-guided isolation of xanthanolides from Xanthium brasilicum. Planta Med 75:1363–1368
Oh IH, Reddy EP (1999) The myb gene family in cell growth, differentiation and apoptosis. Oncogene 18:3017–3033
Ojha PK, Roy K (2015) The current status of antimalarial drug research with special reference to application of QSAR models. Comb Chem High Throughput Screen 18:91–128
Ramsay RJ, Gonda TJ (2008) Myb function in normal and cancer cells. Nat Rev Cancer 8:523–534
Rüngeler P, Castro V, Mora G et al (1999) Inhibition of transcription factor NF-kappa B by sesquiterpene lactones – a proposed molecular mechanism of action. Bioorg Med Chem 7:2343–2352
Rushton JJ, Davis LM, Lei W et al (2003) Distinct changes in gene expression induced by A-Myb, B-Myb and c-Myb proteins. Oncogene 22:308–313
Sandberg ML, Sutton SE, Pletcher MT et al (2005) c-Myb and p300 regulate hematopoietic stem cell proliferation and differentiation. Dev Cell 8:153–166
Schmidt TJ (1999a) Quantitative structure-cytotoxicity relationships within a series of helenanolide type sesquiterpene lactones. (Helenanolide type sesquiterpene lactones IV). Pharm Pharmacol Lett 9:9–13
Schmidt TJ (1999b) Toxic activities of sesquiterpene lactones – structural and biochemical aspects. Curr Org Chem 3:577–605
Schmidt TJ (2006) Structure-activity relationships of sesquiterpene lactones. In: Atta-ur-Rahman (ed) Studies in natural products chemistry, vol 33. Elsevier, Amsterdam, pp 309–392
Schmidt TJ, Heilmann J (2002) Quantitative structure-cytotoxicity relationships of sesquiterpene lactones derived from partial charge (Q)-based fractional accessible surface area descriptors (Q_frASAs). Quant Struct-Act Relat 21:276–287
Schmidt TJ, Willuhn G, Brun R et al (2002) Antitrypanosomal activity of helenalin and some related sesquiterpene lactones. Planta Med 68:750–751
Schmidt TJ, Nour AMM, Khalid SA et al (2009) Quantitative structure-antiprotozoal activity relationships of sesquiterpene lactones. Molecules 14:2062–2076
Schmidt TJ, Khalid SA, Romanha AJ et al (2012) The potential of secondary metabolites from plants as drugs or leads against protozoan neglected diseases – Part I. Current Med Chem 19:2128–2175
Schmidt TJ, Da Costa FB, Lopes NP et al (2014) In silico prediction and experimental evaluation of furanoheliangolide sesquiterpene lactones as potent agents against Trypanosoma brucei rhodesiense. Antimicrob Agents Chemother 58:325–332
Schomburg C, Schuehly W, Da Costa FB et al (2013) Natural sesquiterpene lactones as inhibitors of Myb-dependent gene expression: structure-activity relationships. Eur J Med Chem 63:313–320
Sitzmann J, Noben-Trauth K, Klempnauer K-H (1995) Expression of mouse c-myb during embryonic development. Oncogene 11:2273–2279
Sun C, Zhou B (2016) The molecular and cellular action properties of artemisinins: what has yeast told us? Microb Cell 3:196–205
Teixeira RR, Carneiro JW, Araújo MT et al (2012) A critical view on antimalarial endoperoxide QSAR studies. Mini Rev Med Chem 12:562–572
Thomas MD, Kremer CS, Ravichandran KS et al (2005) c-Myb is critical for B cell development and maintenance of follicular B cells. Immunity 23:275–286
Trossini GHG, Maltarollo VG, Schmidt TJ (2014) Hologram QSAR studies of antiprotozoal activities of sesquiterpene lactones. Molecules 19:10546–10562
van Dijk TB, Baltus B, Raaijmakers JA et al (1999) A composite C/EBP binding site is essential for the activity of the promoter of the IL-3/IL-5/granulocyte-macrophage colony-stimulating factor receptor beta c gene. J Immunol 163:2674–2680
Villagomez R, Hatti-Kaul R, Sterner O et al (2015) Effect of natural and semisynthetic pseudoguianolides on the stability of NF-κB: DNA complex studied by agarose gel electrophoresis. PLoS One. https://doi.org/10.1371/journal.pone.0115819
Wang J, Zhang CJ, Chia WN et al (2015) Haem-activated promiscuous targeting of artemisinin in Plasmodium falciparum. Nat Commun 6:10111
Weston K (1998) Myb proteins in life, death and differentiation. Curr Opin Genet Dev 8:76–81
Wulsten IF, Costa-Silva TA, Mesquita JT et al (2017) Investigation of the anti-Leishmania (Leishmania) infantum activity of some natural sesquiterpene lactones. Molecules 22:685
Zimmermann S, Kaiser M, Brun R et al (2012) Cynaropicrin: the first plant natural product with in vivo activity against Trypanosoma brucei. Planta Med 78:553–556
Zimmermann S, Oufir M, Leroux A et al (2013) Cynaropicrin targets the trypanothione redox system in Trypanosoma brucei. Bioorg Med Chem 21:7202–7209
Zimmermann S, Fouché G, De Mieri M et al (2014) Structure-activity relationship study of sesquiterpene lactones and their semi-synthetic amino derivatives as potential antitrypanosomal products. Molecules 19:3523–3538
Acknowledgements
I feel deeply grateful to all the co-workers, mainly doctoral students, who have contributed over the years to STL research in my group. Not all my students have been working on the discovery of new STLs but even those who did not have – in different ways – contributed to this work.
Very cordial thanks are due to Marcel Kaiser and Reto Brun of the Swiss Tropical and Public Health Institute, Basel, and to Karl-Heinz Klempnauer of the Institute of Biochemistry, University of Münster, for their continuous and very fruitful cooperation over many years. I also thank the many collaborators within the Research Network Natural Products against Neglected Diseases (http://www.ResNetNPND.org), who contributed bigger or smaller pieces to STL research in the past or present: Sami A. Khalid, Fernando B. Da Costa, Norberto P. Lopes, Luise Krauth-Siegel, William Setzer, Marcelo Comini, Antonia Do Amaral and, most recently, Valeria Sülsen. Thanks also to all others who cooperate with me, but not only on the study of STLs. Finally, I would like to acknowledge gratefully once more the support and inspiration by my former mentor and Doktorvater Günter Willuhn (formerly University of Düsseldorf). Thank you for awakening my interest in this fascinating class of natural products: sesquiterpene lactones.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2018 Springer International Publishing AG, part of Springer Nature
About this chapter
Cite this chapter
Schmidt, T.J. (2018). Structure-Activity and Activity-Activity Relationships of Sesquiterpene Lactones. In: Sülsen, V., Martino, V. (eds) Sesquiterpene Lactones. Springer, Cham. https://doi.org/10.1007/978-3-319-78274-4_15
Download citation
DOI: https://doi.org/10.1007/978-3-319-78274-4_15
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-78273-7
Online ISBN: 978-3-319-78274-4
eBook Packages: Chemistry and Materials ScienceChemistry and Material Science (R0)