Sesquiterpene lactones

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Basic structure of some sesquiterpene lactone classes:
A : Germacranolide, B : Heliangolide, C + D : Guaianolide,
E : Pseudoguaianolide, F : Hypocretenolide, G : Eudesmanolide
Biosynthesis of costunolide and 8β-hydroxy-germacrene A acid. The catalytic enzymes (printed in bold) and their products are shown. The intermediate products of the three-stage oxidation by GAO are not shown.

Sesquiterpene lactones are naturally occurring terpene derivatives , more precisely sesquiterpene derivatives , which have a lactone function on which they often have an exocyclic methylene group . Almost 5000 representatives of this group of substances are known which can be found as secondary metabolites in many plants, especially in representatives of the sunflower family ( Asteraceae ). Among other things, they can be used as a taxonomic characteristic for Asteraceae . Sesquiterpene lactones play an important role in the defense against predators of the plants, they act like hormones and are of medical interest as bioactive substances.

Structure and biosynthesis

The basic structure of terpenes consists of isoprene units. These are C5 bodies (5 carbon atoms) whose number and arrangement vary depending on the type of turpentine. Sesquiterpenes consist of three isoprene units and therefore have a C15 skeleton. It is assumed that the biosynthetic pathway proceeds via the cytosolic mevalonate pathway and that farnesyl pyrophosphate is a sesquiterpene precursor. First three acetyl - CoA molecules are combined in several steps to form mevalonic acid . By Pyro phosphorylation , decarboxylation and dehydration occurs isopentenylpyrophosphate . Farnesyl pyrophosphate is then synthesized in several steps starting from isopentenyl pyrophosphate and its isomer dimethylallyl pyrophosphate. The biosynthesis of the simplest sesquiterpene lactone costunolide requires further enzymatically catalyzed steps. First, the enzyme germacrene A synthase (GAS) catalyzes the formation of germacrene A from farnesyl pyrophosphate. This is followed by a three-stage oxidation , catalyzed by germacrene A oxidase (GAO), which produces germacrene A acid. Germacrene A alcohol is initially formed as an intermediate product, which is then oxidized to germacrene A acid via the germacrene A aldehyde. The germacrene A acid oxidase (GAAO) then catalyzed the hydroxylation at the C8 atom of the germacrene A acid, so that the product 8β-hydroxy-germacrene A acid is formed. With the help of costunolide synthase (COS), 6α-hydroxy-germacrene A acid can be synthesized from germacrene A acid. The hydroxylation at the C6 atom of germacrene A acid can lead to the spontaneous formation of the γ-lactone ring characteristic of sesquiterpene lactones. While GAO, GAAO and COS are P450 monooxygenases , GAS belongs to the terpene synthases . Costunolid serves as the basic structure for the biosynthesis of other sesquiterpene lactones.

Sesquiterpene lactones are classified based on the arrangement of their carbon skeleton. So there are z. B. the class of xanthanolides, to which, inter alia, tomentosine and 8-epixanthatin belong, the class of guaianolide, represented z. B. by dehydrocostus lactone, and the class of germacranolide with costunolide as an example. There are also the classes of Heliangolide, Pseudoguaianolide, Hypocretenolide and Eudesmanolide.

Functions

The exocyclic methylene group on the γ-lactone ring of the sesquiterpene lactones leads to a strong biological activity of the compounds due to its high electrophilic reactivity. Because of this, among other things, reactions with thiol groups occur , e.g. B. the thiol group of the amino acid cysteine , which allows the compounds to influence proteins. The range of functions and effects of sesquiterpene lactones is very broad. You have z. B. antifungal , antibacterial , cytotoxic , antitumoral, anti-inflammatory and allelopathic properties. These substances can also be toxic to mammals such as humans, as they can lead to contact dermatitis . For plants, they primarily act as defense substances against herbivores and microorganisms . This function is on the one hand by their bitter taste and on the other hand by the cytotoxicity, e.g. B. by interfering with the metabolism of the pathogens . For defense purposes, they are formed in specialized cells, the head- bearing glandular hairs , on the surfaces of the plants and secreted in cuticular bladders. Sesquiterpene lactones were discovered not only in Asteraceae , but also in other plant families. So z. B. in Apiaceae , Cupressaceae , Magnoliaceae and even in mushrooms.

Sesquiterpene lactones as plant hormones

In addition to the defense of the plants against pathogens and herbivores, sesquiterpene lactones obviously also have hormonal effects. The four sesquiterpene lactones tomentosin, 8-epixanthate, dehydrocostus lactone and costunolide were detected within the plant tissue. They do not occur in the trichomes on the plant surface and are much less concentrated than the compounds located in the trichomes. A physiological function of the sesquiterpene lactones as inhibitors of auxin- dependent elongation growth is assumed within the plant tissue . This thesis is supported by experiments in which it has been shown that no differentiated distribution of auxin takes place during unilateral exposure of sunflower hypocotyls . It was concluded from this that auxin inhibitors on the exposed side must be responsible for the plants' bending reaction. In addition, a downward diffusion direction of the compounds was detected. Therefore, it cannot be ruled out that sesquiterpene lactones, due to their ability to bind to thiol groups, can interact with proteins of the AUXIN RESISTANT1 and / or the PIN family and thus influence the polar auxin transport, the driving force behind phototropism and Is gravitropism . The inhibition of the downward transport of auxin was shown experimentally by the application of dehydrocostus lactone to the hypocotyls of Raphanus . The proteins mentioned are essentially involved in the polar auxin transport of the cells and thus also play a major role in light-induced auxin-dependent elongation. In experiments, thiol group adducts of the sesquiterpene lactones were also detected in the plant tissues for the first time and a previously unexplained inactivation mechanism for the putative auxin inhibitors was postulated. The binding of thiol groups could therefore also be part of the negative regulation of the compounds. Sesquiterpene lactones are also exuded into the rhizosphere in very low concentrations , which supports the assumption of downward transport. It has also been shown that the lowest concentrations (in the nanomilimolar range) of dehydrocostus lactone in the soil are able to stimulate the germination of the parasitic summer root seeds ( Orobanche cumana ). A few years later, tomentosine, costunolide and 8-epixanthatine were also identified in root exudates as germination stimulators for the seeds of Orobanche cumana .

Potential benefits in the agricultural sector

A possible commercial use of sesquiterpene lactones in the agricultural sector is discussed. There they could be used to protect crops from the parasitic summer root ( Orobanche, Striga and Phelipanche species). These parasitic flowering plants primarily affect sunflowers, tomatoes, lentils, rape, field beans and melons, where an infestation can lead to major crop failures. The summer arums produce tiny seeds (200–400 µm) that can survive in the ground for years. The germination of these seeds is induced by chemical signal substances from the host plants . These chemical signal substances are, for example, strigolactones or sesquiterpene lactones. After the seed has germinated, the radicle has to find a suitable host root within a short period of time in order to establish a haustorium there and to start the parasitosis . According to the theory, one could treat a fallow , infested area with a defined concentration of certain sesquiterpene lactones in order to induce the germination of the summer root seeds dormant in the ground. If the radicle does not reach a suitable host plant root within a short time, the seedling dies.

Medical benefit

Arnica (arnica montana )

Some representatives of the sesquiterpene lactones are of pharmacological interest because they are ascribed antitumoral, migraine and anti-inflammatory as well as antimicrobial properties and they are toxic to some important human pathogens such as. B. Trypanosomes are. Many of the effects of these substances have been used in traditional medicine for centuries. For example, the anti-inflammatory effect of arnica montana , which has been known as a medicinal plant in Europe since the Middle Ages, is due to sesquiterpene lactones. Likewise the effects of Mikania micrantha , which is native to Central and South America, and Saussurea lappa , which occurs in Asia. The anti-inflammatory effect of the sesquiterpene lactones is due to an inhibition of transcription factors such. B. NF-κB and AP-1 . NF-κB is a key regulator of cellular inflammatory and immune responses. On the basis of the sesquiterpene lactone parthenolide it could be shown that these compounds inhibit an important step in the activation of the transcription factor. In addition, Pathenolid prevents the activation of the DNA binding of NF-κB.

See also

Individual evidence

  1. ↑ Nikolaus H. Fischer: Sesquiterpene Lactones: Biogenesis and Biomimetic Transformations . In: Biochemistry of the Mevalonic Acid Pathway to Terpenoids . Springer US, Boston, MA 1990, ISBN 978-1-4684-8791-6 , pp. 161-201 , doi : 10.1007 / 978-1-4684-8789-3_4 .
  2. ↑ Thomas J. Schmidt: Toxic Activities of Sesquiterpene Lactones - Structural and Biochemical Aspects . In: Current Organic Chemistry 3, 1999, pp. 577-605; Abstract .
  3. ↑ L. Ruzicka: The isoprene rule and the biogenesis of terpenic compounds . In: Experientia . tape 9 , no. October 10 , 1953, ISSN  0014-4754 , p. 357-367 , doi : 10.1007 / bf02167631 .
  4. ^ Helga D. Fischer, NH Fischer, RW Franck, EJ Olivier: Progress in the Chemistry of Organic Natural Products / Progress in the Chemistry of Organic Natural Products . In: Progress in the Chemistry of Organic Natural Products . 1979, ISSN  0071-7886 , doi : 10.1007 / 978-3-7091-8548-3 .
  5. ↑ T. LAZAR: Taiz, L. and Zeiger, E. Plant physiology. 3rd edn. In: Annals of Botany . tape 91 , no. 6 , May 1, 2003, ISSN  0305-7364 , p. 750-751 , doi : 10.1093 / aob / mcg079 , PMC 4242361 (free full text) - ( oup.com [accessed September 24, 2018]).
  6. ↑ Jens C Göpfert, Gillian MacNevin, Dae-Kyun Ro, Otmar Spring: Identification, functional characterization and developmental regulation of sesquiterpene synthases from sunflower capitate glandular trichomes . In: BMC Plant Biology . tape 9 , no. 1 , 2009, ISSN  1471-2229 , p. 86 , doi : 10.1186 / 1471-2229-9-86 , PMID 19580670 , PMC 2715020 (free full text).
  7. ↑ Don Trinh Nguyen, Jens Christian Göpfert, Nobuhiro Ikezawa, Gillian MacNevin, Meena Kathiresan: Biochemical Conservation and Evolution of Germacrene A Oxidase in Asteraceae . In: Journal of Biological Chemistry . tape 285 , no. 22 , May 28, 2010, ISSN  0021-9258 , p. 16588-16598 , doi : 10.1074 / jbc.M110.111757 , PMID 20351109 , PMC 2878029 (free full text).
  8. ↑ Nobuhiro Ikezawa, Jens Christian Göpfert, Don Trinh Nguyen, Soo-Un Kim, Paul E. O'Maille: Lettuce Costunolide Synthase (CYP71BL2) and Its Homolog (CYP71BL1) from Sunflower Catalyze Distinct Regio- and Stereoselective Hydroxylations in Sesquiterpene Lactone Metabolism . In: Journal of Biological Chemistry . tape 286 , no. 24 , June 17, 2011, ISSN  0021-9258 , p. 21601-21611 , doi : 10.1074 / jbc.M110.216804 , PMID 21515683 , PMC 3122218 (free full text).
  9. ↑ Jan-Willem de Kraker, Maurice CR Franssen, Maaike Joerink, Aede de Groot, Harro J. Bouwmeester: Biosynthesis of Costunolide, Dihydrocostunolide, and Leucodine. Demonstration of Cytochrome P450-Catalyzed Formation of the Lactone Ring Present in Sesquiterpene Lactones of Chicory . In: Plant Physiology . tape 129 , no. 1 , May 1, 2002, ISSN  0032-0889 , p. 257-268 , doi : 10.1104 / pp.010957 , PMID 12011356 , PMC 155889 (free full text).
  10. ^ NH Fischer, EJ Olivier, HD Fischer: The Biogenesis and Chemistry of Sesquiterpene Lactones . In: Progress in the Chemistry of Organic Natural Products . Springer Vienna, Vienna 1979, ISBN 978-3-7091-8550-6 , pp. 47-320 , doi : 10.1007 / 978-3-7091-8548-3_2 .
  11. ↑ Frederick C. Seaman: Sesquiterpene lactones as taxonomic characters in the asteraceae . In: The Botanical Review . tape 48 , no. 2 , April 1982, ISSN  0006-8101 , pp. 121-594 , doi : 10.1007 / bf02919190 .
  12. ↑ Otmar Spring, Achim Hager: Inhibition of elongation growth by two sesquiterpene lactones isolated from Helianthus annuus L. In: Planta . tape 156 , no. 5 , December 1982, ISSN  0032-0935 , pp. 433-440 , doi : 10.1007 / bf00393314 .
  13. ↑ Anna K. Picman: Biological activities of sesquiterpene lactones . In: Biochemical Systematics and Ecology . tape 14 , no. 3 , May 1986, ISSN  0305-1978 , pp. 255-281 , doi : 10.1016 / 0305-1978 (86) 90101-8 .
  14. ↑ Otmar Spring, Uta Bienert, Volker Klemt: Sesquiterpene Lactones in Glandular Trichomes of Sunflower Leaves . In: Journal of Plant Physiology . tape 130 , no. 4-5 , October 1987, ISSN  0176-1617 , pp. 433-439 , doi : 10.1016 / s0176-1617 (87) 80208-0 .
  15. ↑ Damian Paul Drew, Nadja Krichau, Kirsten Reichwald, Henrik Toft Simonsen: Guaianolides in apiaceae: perspectives on pharmacology and biosynthesis . In: Phytochemistry Reviews . tape 8 , no. 3 , May 19, 2009, ISSN  1568-7767 , p. 581-599 , doi : 10.1007 / s11101-009-9130-z .
  16. ↑ Anna K. Picman: Biological activities of sesquiterpene lactones . In: Biochemical Systematics and Ecology . tape 14 , no. 3 , May 1986, ISSN  0305-1978 , pp. 255-281 , doi : 10.1016 / 0305-1978 (86) 90101-8 .
  17. ↑ Sung-Hee Park, Sang-Un Choi, Chong Ock Lee, Sung-eun Yoo, Seok Keun Yoon: Costunolide, a Sesquiterpene from the Stem Bark of Magnolia Sieboldii, Inhibits the RAS-Farnesyl-Proteintransferase . In: Planta Medica . tape 67 , no. 4 , 2001, ISSN  0032-0943 , p. 358-359 , doi : 10.1055 / s-2001-14315 .
  18. ↑ Pattama Pittayakhajonwut, Atit Usuwan, Chakapong Intaraudom, Sukitaya Veeranondha, Prasert Srikitikulchai: Sesquiterpene Lactone 12,8-Eudesmanolides from the FungusXylaria ianthinovelutina . In: Planta Medica . tape 75 , no. 13 , May 18, 2009, ISSN  0032-0943 , p. 1431-1435 , doi : 10.1055 / s-0029-1185698 .
  19. ^ Frank M. Raupp, Otmar Spring: New Sesquiterpene Lactones from Sunflower Root Exudate as Germination Stimulants for Orobanche cumana . In: Journal of Agricultural and Food Chemistry . tape 61 , no. 44 , October 24, 2013, ISSN  0021-8561 , p. 10481-10487 , doi : 10.1021 / jf402392e .
  20. ↑ Otmar Spring, Achim Hager: Inhibition of elongation growth by two sesquiterpene lactones isolated from Helianthus annuus L. In: Planta . tape 156 , no. 5 , December 1982, ISSN  0032-0935 , pp. 433-440 , doi : 10.1007 / bf00393314 .
  21. ↑ Kaori Yokotani-Tomita, Jun Kato, Seiji Kosemura, Shosuke Yamamura, Midori Kushima: Light-induced auxin-inhibiting substance from sunflower seedlings . In: Phytochemistry . tape 46 , no. 3 , October 1997, ISSN  0031-9422 , p. 503-506 , doi : 10.1016 / s0031-9422 (97) 00307-5 .
  22. ↑ J. BRUINSMA, CM KARSSEN, M. BENSCHOP, JB VAN DORT: Hormonal Regulation of Phototropism in the Light-grown Sunflower Seedling, Helianthus annuusL .: Immobility of Endogenous Indoleacetic Acid and Inhibition of Hypocotyl Growth by Illuminated Cotyledons . In: Journal of Experimental Botany . tape 26 , no. 3 , 1975, ISSN  0022-0957 , pp. 411-418 , doi : 10.1093 / jxb / 26.3.411 .
  23. ↑ Martin Feyerabend, Elmar W. Weiler: Immunological estimation of growth regulator distribution in phototropically reacting sunflower seedlings . In: Physiologia Plantarum . tape 74 , no. 1 , September 1988, ISSN  0031-9317 , pp. 185-193 , doi : 10.1111 / j.1399-3054.1988.tb04962.x .
  24. ^ Johan Bruinsma, Koji Hasegawa: A new theory of phototropism - its regulation by a light-induced gradient of auxin-inhibiting substances . In: Physiologia Plantarum . tape 79 , no. 4 , August 1990, ISSN  0031-9317 , pp. 700-704 , doi : 10.1111 / j.1399-3054.1990.tb00047.x .
  25. ↑ SHIBAOKA, HIROH: STUDIES ON THE MECHANISM OF GROWTH INHIBITING EFFECT OF LIGHT . In: Plant and Cell Physiology . tape 2 , no. May 2 , 1961, ISSN  1471-9053 , doi : 10.1093 / oxfordjournals.pcp.a077675 ( oup.com [accessed September 21, 2018]).
  26. ↑ Junichi Ueda, Yuta Toda, Kiyotaka Kato, Yuichi Kuroda, Tsukasa Arai: Identification of dehydrocostus lactone and 4-hydroxy-β-thujone as auxin polar transport inhibitors . In: Acta Physiologiae Plantarum . tape 35 , no. 7 , March 29, 2013, ISSN  0137-5881 , p. 2251-2258 , doi : 10.1007 / s11738-013-1261-6 .
  27. ↑ Jürgen Kleine-Vehn, Pankaj Dhonukshe, Ranjan Swarup, Malcolm Bennett, Jiří Friml: Subcellular Trafficking of the Arabidopsis Auxin Influx Carrier AUX1 Uses a Novel Pathway Distinct from PIN1 . In: The Plant Cell . tape 18 , no. 11 , November 1, 2006, ISSN  1040-4651 , p. 3171-3181 , doi : 10.1105 / tpc.106.042770 , PMID 17114355 , PMC 1693951 (free full text).
  28. ↑ Daniel M. Joel, Swapan K. Chaudhuri, Dina Plakhine, Hammam Ziadna, John C. Steffens: Dehydrocostus lactone is exuded from sunflower roots and stimulates germination of the root parasite Orobanche cumana . In: Phytochemistry . tape 72 , no. 7 , May 2011, ISSN  0031-9422 , p. 624-634 , doi : 10.1016 / j.phytochem.2011.01.037 .
  29. ^ Frank M. Raupp, Otmar Spring: New Sesquiterpene Lactones from Sunflower Root Exudate as Germination Stimulants for Orobanche cumana . In: Journal of Agricultural and Food Chemistry . tape 61 , no. 44 , October 24, 2013, ISSN  0021-8561 , p. 10481-10487 , doi : 10.1021 / jf402392e .
  30. ↑ Daniel M. Joel, Swapan K. Chaudhuri, Dina Plakhine, Hammam Ziadna, John C. Steffens: Dehydrocostus lactone is exuded from sunflower roots and stimulates germination of the root parasite Orobanche cumana . In: Phytochemistry . tape 72 , no. 7 , May 2011, ISSN  0031-9422 , p. 624-634 , doi : 10.1016 / j.phytochem.2011.01.037 .
  31. ^ Frank M. Raupp, Otmar Spring: New Sesquiterpene Lactones from Sunflower Root Exudate as Germination Stimulants for Orobanche cumana . In: Journal of Agricultural and Food Chemistry . tape 61 , no. 44 , October 24, 2013, ISSN  0021-8561 , p. 10481-10487 , doi : 10.1021 / jf402392e .
  32. ↑ SP Hehner, TG Hofmann, W. Dröge, ML Schmitz: The antiinflammatory sesquiterpene lactone parthenolide inhibits NF-kappa B by targeting the I kappa B kinase complex . In: Journal of Immunology (Baltimore, Md .: 1950) . tape 163 , no. 10 , November 15, 1999, ISSN  0022-1767 , p. 5617-5623 , PMID 10553091 .
  33. ↑ Anna K. Picman: Biological activities of sesquiterpene lactones . In: Biochemical Systematics and Ecology . tape 14 , no. 3 , May 1986, ISSN  0305-1978 , pp. 255-281 , doi : 10.1016 / 0305-1978 (86) 90101-8 .
  34. ↑ Thomas J. Schmidt, Fernando B. Da Costa, Norberto P. Lopes, Marcel Kaiser, Reto Brun: In Silico Prediction and Experimental Evaluation of Furanoheliangolide Sesquiterpene Lactones as Potent Agents against Trypanosoma brucei rhodesiense . In: Antimicrobial Agents and Chemotherapy . tape 58 , no. 1 , January 1, 2014, ISSN  0066-4804 , p. 325-332 , doi : 10.1128 / AAC.01263-13 , PMID 24165182 , PMC 3910805 (free full text).
  35. ↑ Steffen Wagner: Sesquiterpene lactones: Neural networks as a QSAR model and pharmacokinetic studies using the example of Arnica montana . Dissertation, 2006. PDF; 6.03 MB .
  36. ↑ SP Hehner, TG Hofmann, W. Dröge, ML Schmitz: The Antiinflammatory Sesquiterpene Lactone Parthenolide Inhibits NF-kappa B by Targeting the I kappa B Kinase Complex . In: Journal of Immunology (Baltimore, Md .: 1950) . tape 163 , no. 10 , November 15, 1999, ISSN  0022-1767 , p. 5617-5623 .