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Henrik Toft Simonsen - One of the best experts on this subject based on the ideXlab platform.
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Thapsigargins and induced chemical defence in Thapsia garganica
Chemoecology, 2020Co-Authors: Karen Martinez-swatson, Nina Ronsted, Carmen Quiñonero-lópez, Madeleine Ernst, Christopher James Barnes, Henrik Toft SimonsenAbstract:Thapsigargin and related compounds are produced by Thapsia garganica L. (Apiaceae) and are thought to be a defence compound against herbivory. Thapsigargin inhibits the sarco-endoplasmic reticulum Ca^2+-ATPase (SERCA) in both vertebrates and invertebrates. This activity is responsible for its potent toxicity, as well as the potential use to treat solid tumours. However, the ecological role and regulation of thapsigargin are not well understood, and the aim of this study was to investigate if thapsigargin biosynthesis was responsive to leaf damage. To test the response to potential leaf damage during a herbivory, greenhouse plants were subjected to clipping to mimic the physical damage. Unclipped versus clipped plants were sampled for chemical analysis and the gene expression for the two known thapsigargin biosynthetic genes (TgTPS2 and TgCYP76AE2) was investigated. Data obtained by LC–ESI–MS/MS were used to perform molecular networking to identify chemical constituents related to thapsigargin and its biosynthesis. The results show a significant change in a plant’s chemical profile after mimicking an herbivory event. Both the chemical analysis and gene expression data show that T. garganica plants can induce the biosynthesis of this class of defence compounds at the site of an attack. Thapsigargins are clearly the dominant defence compounds in these plants, and they seem to be produced through a common biosynthetic pathway with little diversity. This likely means that T. garganica has a relatively simple response to herbivory, as opposed to many other plant species that have been shown to have complex metabolite responses to herbivory.
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Exploring evolutionary theories of plant defence investment using field populations of the deadly carrot
Annals of botany, 2019Co-Authors: Karen Martinez-swatson, Henrik Toft Simonsen, Nina Ronsted, Federico Cozzi, Rasmus Kjøller, Christopher J. BarnesAbstract:Background and aims There are a number of disparate models predicting variation in plant chemical defences between species, and within a single species over space and time. These can give conflicting predictions. Here we review a number of these theories, before assessing their power to predict the spatial-temporal variation of thapsigargins between and within populations of the deadly carrot (Thapsia garganica). By utilizing multiple models simultaneously (optimum defence theory, growth rate hypothesis, growth-differentiation balance hypothesis, intra-specific framework and resource exchange model of plant defence), we will highlight gaps in their predictions and evaluate the performance of each. Methods Thapsigargins are potent anti-herbivore compounds that occur in limited richness across the different plant tissues of T. garganica, and therefore represent an ideal system for exploring these models. Thapsia garganica plants were collected from six locations on the island of Ibiza, Spain, and the thapsigargins quantified within reproductive, vegetative and below-ground tissues. The effects of sampling time, location, mammalian herbivory, soil nutrition and changing root-associated fungal communities on the concentrations of thapsigargins within these in situ observations were analysed, and the results were compared with our model predictions. Key results The models performed well in predicting the general defence strategy of T. garganica and the above-ground distribution of thapsigargins, but failed to predict the considerable proportion of defences found below ground. Models predicting variation over environmental gradients gave conflicting and less specific predictions, with intraspecific variation remaining less understood. Conclusion Here we found that multiple models predicting the general defence strategy of plant species could likely be integrated into a single model, while also finding a clear need to better incorporate below-ground defences into models of plant chemical defences. We found that constitutive and induced thapsigargins differed in their regulation, and suggest that models predicting intraspecific defences should consider them separately. Finally, we suggest that in situ studies be supplemented with experiments in controlled environments to identify specific environmental parameters that regulate variation in defences within species.
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Biosynthesis of tovarol and other sesquiterpenoids in Thapsia laciniata Rouy
Phytochemistry, 2018Co-Authors: Trine Bundgaard Andersen, Søren Brøgger Christensen, Silas Anselm Rasmussen, Henrik Toft SimonsenAbstract:Abstract The genus Thapsia produces a wide variety of sesquiterpenoids. The Mediterranean plant Thapsia laciniata Rouy is known to have a product profile that differs from several other species in the genus. Thus, the biosynthesis of sesquiterpenoids in Thapsia laciniata Rouy was investigated. Here we describe three terpene synthases, TlTPS820, TlTPS509 and TlTPS18983. TlTPS18983 is a multi-product enzyme with farnesene as the major product, while TlTPS509 produces guaiol and bulnesol along with other major and several minor unknown products. TlTPS820 is orthologous to TgTPS2 from Thapsia garganica L. and is an epikunzeaol synthase. TgCYP76AE2 from Thapsia garganica performs a triple hydroxylation of epikunzeaol at C-12 to make dihydrocostunolide. It was therefore investigated if the cytochrome P450, TlCYP76AE4 was able to use epikunzeaol as a substrate. It was found that TlCYP76AE4 hydroxylates epikunzeaol at C-8 to yield tovarol instead of dihydrocostunolide.
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Domesticating deadly carrots: Predicting the biosynthetic pathway of thapsigargins for the treatment of solid tumors
Planta Medica, 2016Co-Authors: K Martinez, Henrik Toft Simonsen, Nina Ronsted, T. Bundgaard Andersen, Christopher J. Barnes, Berin A. Boughton, Federico CozziAbstract:Thapsigargin, a guaianolide sesquiterpene lactone, is the active component of a pro-drug currently in phase 2 of clinical trials for the treatment of solid tumours. Thapsigargin is currently only being isolated from Thapsia garganica L. (Apiaceae); a member of the taxonomically complex genus Thapsia L. found in the Mediterranean. Thapsia species do not grow well out of their natural habitat and on-going research seeks to solve the potential resource problem for Mipsagargin, a new thapsigargin derived drug, by transferring the biosynthetic pathway to other heterologous hosts for efficient production [1]. Plant material of Thapsia garganica has been collected from around the species' Mediterranean range, as part of a revision of the genus. The amount of thapsigargin and other closely related guaianolides was quantified between individuals across its range, in planta and during the growing season. Secondly the expression levels of the terpene synthases TgTPS1 and TgTPS2, as well as a cytochrome P450, thought to be involved in the biosynthesis of thapsigargin, were investigated. These tests have also been carried out in conjunction with soil analyses to test if fluctuations in the levels of thapsigargin can be linked to environmental factors. Thapsigargin has been found to be extremely variable over its geographical distribution even over small areas. Lastly, to see whether candidates for the biosynthesis of thapsigargin could shed light on where the compound is made within the plant, root sections have been investigated from greenhouse plants provided by ThapsIbiza. Using light microscopy and MALDI-imaging epithelial cells containing thapsigargin and surrounding secretory channels within the vascular cambium were observed, indicating for the first time that this is the localisation of thapsigargin biosynthesis. It is hoped that these results will fast track the discovery of new enzymes involved in the biosynthetic pathway of thapsigargin.
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Insight into Biochemical Characterization of Plant Sesquiterpene Synthases
Analytical Chemistry Insights, 2016Co-Authors: Tom Manczak, Henrik Toft SimonsenAbstract:A fast and reproducible protocol was established for enzymatic characterization of plant sesquiterpene synthases that can incorporate radioactivity in their products. The method utilizes the 96-well format in conjunction with cluster tubes and enables processing of >200 samples a day. Along with reduced reagent usage, it allows further reduction in the use of radioactive isotopes and flammable organic solvents. The sesquiterpene synthases previously characterized were expressed in yeast, and the plant-derived Thapsia garganica kunzeaol synthase TgTPS2 was tested in this method. KM for TgTPS2 was found to be 0.55 μM; the turnover number, kcat, was found to be 0.29 s−1, kcat for TgTPS2 is in agreement with that of terpene synthases of other plants, and kcat/ KM was found to be 0.53 s−1 μM−1 for TgTPS2. The kinetic parameters were in agreement with previously published data.
Ulla Wagner Smitt - One of the best experts on this subject based on the ideXlab platform.
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Sesquiterpenes from Thapsia nitida var. meridionalis and Thapsia nitida var. nitida.
Journal of natural products, 2006Co-Authors: Juan J. Rubal, F.j. Moreno-dorado, Francisco M. Guerra, Zacarías D. Jorge, Guillermo M. Massanet, Ulla Wagner Smitt, S. Brøgger Christensen, Helmer Søhoel, Karla Frydenvang, Charlotte NielsenAbstract:Nine new eudesmanolides (1−9), two new guaianolides (12 and 13), and a new germacrane (10), along with a previously reported guaianolide (11), have been isolated from the roots of Thapsia nitida va...
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Composition of the Essential Oils from the Roots of Thapsia maxima Miller and T. villosa L.
Journal of Essential Oil Research, 2000Co-Authors: Pinarosa Avato, Ulla Wagner SmittAbstract:The chemical composition of the essential oils from the roots of plants identified as Thapsia maxima morphological types I and II and T. villosa diploid types 1 and 2, tetraploid types 3 and 4 and hexaploid type 5 has been investigated by GC and GC/MS. The oils from the different specimens of Thapsia were characterized by a high proportion of sesquiterpenoid components. The results are compared with those previously obtained from the fruits of the same plants.
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Sesquiterpenoids from Thapsia Species and Medicinal Chemistry of the Thapsigargins
Fortschritte der Chemie organischer Naturstoffe = Progress in the chemistry of organic natural products. Progres dans la chimie des substances organiq, 1997Co-Authors: Søren Brøgger Christensen, Annette Andersen, Ulla Wagner SmittAbstract:For centuries preparations containing resin from the root of Thapsia garganica L. (Fig. 1) have been used in Arabian and European medicine for treatment of pulmonary diseases, catarrh and as counterirritants for relief of rheumatic pains (1). The properties of the resin were described already by Theophrastos (372-287 B.C.), Dioscorides (approximately a.d. 50), and Plinius (A.D. 24–79) (2). Radix Thapsiae and Resina Thapsiae have been included in several pharmacopoeias, the latest in the French pharmacopoeia from 1937.
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Quantitative determination of thapsigargins in roots and fruits from Thapsia gymnesica.
Planta medica, 1997Co-Authors: Anita V. Christiansen, Antonio Pujadas, Henrik Paalum, Søren M. Andersen, Ulla Wagner SmittAbstract:Three sesquiterpene lactones, thapsigargin (1), thapsigargicin (2), and nortrilobolid (3), and 6-methoxy-7-geranyloxycoumarin have been isolated from the roots of Thapsia gymnesica (Apiaceae) for the first time. The concentrations of the three thapsigargins in the roots and the fruits have been determined by HPLC analysis.
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Essential oils from fruits of three types of Thapsia villosa
Phytochemistry, 1996Co-Authors: Pinarosa Avato, Gina Trabace, Ulla Wagner SmittAbstract:Thapsia villosa has been divided into five types and previous analyses of the essential oils from the fruits of two of these types showed that limonene and methyl eugenol were the major constituents. The composition of the essential oils from the fruits of the other three types of T. villosa, with the chromosome numbers 2n = 22 (2x), 2n = 22 (2x) and 2n = 44 (4x), is reported here. The oil from all three types shows a similar chemical profile, with geranyl acetate as the main constituent accounting for 78-92% of the total oil. The composition of the essential oils from these plants is clearly different from the first two types of T. villosa mentioned, and also from the other species within the genus Thapsia.
Guillermo M. Massanet - One of the best experts on this subject based on the ideXlab platform.
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A phenylpropanoid, a slovenolide, two sulphur-containing germacranes and Ca2+-ATPase inhibitors from Thapsia villosa.
Planta medica, 2009Co-Authors: Juan J. Rubal, F.j. Moreno-dorado, Francisco M. Guerra, Zacarías D. Jorge, Søren Brøgger Christensen, Helmer Søhoel, María Del Carmen Galán, Ginés M. Salido, Guillermo M. MassanetAbstract:A phenylpropanoid 1, a slovenolide 2, and two germacranes bearing a methylthiopropenoate moiety, 3 and 4, along with twenty known metabolites have been isolated from the roots of Thapsia VILLOSA var. VILLOSA L. The structures of two known phenylpropanoids 5 and 6 have been corrected. Compounds 7 and 8 showed activity as potential inhibitors of the sarco- and endoplasmic Ca 2+ -dependent ATPases (SERCA) pump. Compounds 9, 10 and 11 increased significantly the cytoplasmic free calcium concentration ([Ca 2+ ] c ) in human platelets in a concentration-dependent manner.
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A pyran-2-one and four meroterpenoids from Thapsia transtagana and their implication in the biosynthesis of transtaganolides.
Phytochemistry, 2007Co-Authors: Juan J. Rubal, F.j. Moreno-dorado, Francisco M. Guerra, Zacarías D. Jorge, Abderrahmane Saouf, Mohamed Akssira, Fouad Mellouki, Raúl Romero-garrido, Guillermo M. MassanetAbstract:Four meroterpenoids (3a, 3b, 4 and 5), a prenylated pyran-2-one (2) along with the known compounds 7-O-geranylscopoletin (1), and thapsitranstagin (6) have been isolated from the roots of Thapsia transtagana. The presence of 1 and 2 supports the biogenetic hypothesis that transtaganolides, a group of bioactive metabolites, are meroterpenoids which come from an O-prenylated coumarin via successive pericyclic reactions.
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Phenylpropanoids from Thapsia transtagana
Phytochemistry, 2006Co-Authors: Abderrahmane Saouf, Juan J. Rubal, F.j. Moreno-dorado, Francisco M. Guerra, Zacarías D. Jorge, Mohamed Akssira, Fouad Mellouki, Guillermo M. MassanetAbstract:Five phenylpropanoids have been isolated from the roots of Thapsia transtagana. Their structures have been elucidated by spectroscopic means.
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Sesquiterpenes from Thapsia nitida var. meridionalis and Thapsia nitida var. nitida.
Journal of natural products, 2006Co-Authors: Juan J. Rubal, F.j. Moreno-dorado, Francisco M. Guerra, Zacarías D. Jorge, Guillermo M. Massanet, Ulla Wagner Smitt, S. Brøgger Christensen, Helmer Søhoel, Karla Frydenvang, Charlotte NielsenAbstract:Nine new eudesmanolides (1−9), two new guaianolides (12 and 13), and a new germacrane (10), along with a previously reported guaianolide (11), have been isolated from the roots of Thapsia nitida va...
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Transtaganolides A-D: novel metabolites from Thapsia transtagana.
Organic letters, 2005Co-Authors: Abderrahmane Saouf, Juan J. Rubal, F.j. Moreno-dorado, Francisco M. Guerra, Zacarías D. Jorge, Mohamed Akssira, Fouad Mellouki, Antonio Pujadas, Matias Lopez, Guillermo M. MassanetAbstract:Four novel and unusual C-19 compounds from Thapsia transtagana, named transtaganolides A−D, have been isolated. Their structures were established by physical methods, including X-ray analysis of transtaganolides A and B. This is the first time that a 7-methoxy-4,5-dihydro-3H-oxepin-2-one ring has been found in a natural product.
Søren Brøgger Christensen - One of the best experts on this subject based on the ideXlab platform.
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Biosynthesis of tovarol and other sesquiterpenoids in Thapsia laciniata Rouy
Phytochemistry, 2018Co-Authors: Trine Bundgaard Andersen, Søren Brøgger Christensen, Silas Anselm Rasmussen, Henrik Toft SimonsenAbstract:Abstract The genus Thapsia produces a wide variety of sesquiterpenoids. The Mediterranean plant Thapsia laciniata Rouy is known to have a product profile that differs from several other species in the genus. Thus, the biosynthesis of sesquiterpenoids in Thapsia laciniata Rouy was investigated. Here we describe three terpene synthases, TlTPS820, TlTPS509 and TlTPS18983. TlTPS18983 is a multi-product enzyme with farnesene as the major product, while TlTPS509 produces guaiol and bulnesol along with other major and several minor unknown products. TlTPS820 is orthologous to TgTPS2 from Thapsia garganica L. and is an epikunzeaol synthase. TgCYP76AE2 from Thapsia garganica performs a triple hydroxylation of epikunzeaol at C-12 to make dihydrocostunolide. It was therefore investigated if the cytochrome P450, TlCYP76AE4 was able to use epikunzeaol as a substrate. It was found that TlCYP76AE4 hydroxylates epikunzeaol at C-8 to yield tovarol instead of dihydrocostunolide.
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Thapsigargin, origin, chemistry, structure-activity relationships and prodrug development
Current pharmaceutical design, 2015Co-Authors: Søren Brøgger ChristensenAbstract:Thapsigargin was originally isolated from the roots of the Mediterranean umbelliferous plant Thapsia garganica in order to characterize the skin irritant principle. Characteristic chemical properties and semi-syntheses are reviewed. The biological activity was related to the subnanomolar affinity for the sarco/endoplasmic reticulum calcium ATPase. Prolonged inhibition of the pump afforded collapse of the calcium homeostasis and eventually apoptosis. Structure-activity relationships enabled design of an equipotent analogue containing a linker. Conjugation of the analogue containing the linker with peptides, which only are substrates for either prostate specific antigen (PSA) or prostate specific membrane antigen (PSMA) enabled design of prodrugs targeting a number of cancer diseases including prostate cancer (G115) and hepatocellular carcinoma (G202). Prodrug G202 has under the name of mipsagargin in phase II clinical trials shown promising properties against hepatocellular carcinoma.
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Targeting thapsigargin towards tumors.
Steroids, 2014Co-Authors: Nhu Thi Quynh Doan, Samuel R. Denmeade, John T. Isaacs, Eleonora S. Paulsen, Pankaj Sehgal, Jesper V. Møller, Poul Nissen, Craig A. Dionne, Søren Brøgger ChristensenAbstract:The skin irritating principle from Thapsia garganica was isolated, named thapsigargin and the structure elucidated. By inhibiting the sarco/endoplasmic reticulum Ca(2+) ATPase (SERCA) thapsigargin provokes apoptosis in almost all cells. By conjugating thapsigargin to peptides, which are only substrates for either prostate specific antigen (PSA) or prostate specific membrane antigen (PSMA) prodrugs were created, which selectively affect prostate cancer cells or neovascular tissue in tumors. One of the prodrug is currently tested in clinical phase II. The prodrug under clinical trial has been named mipsagargin.
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A phenylpropanoid, a slovenolide, two sulphur-containing germacranes and Ca2+-ATPase inhibitors from Thapsia villosa.
Planta medica, 2009Co-Authors: Juan J. Rubal, F.j. Moreno-dorado, Francisco M. Guerra, Zacarías D. Jorge, Søren Brøgger Christensen, Helmer Søhoel, María Del Carmen Galán, Ginés M. Salido, Guillermo M. MassanetAbstract:A phenylpropanoid 1, a slovenolide 2, and two germacranes bearing a methylthiopropenoate moiety, 3 and 4, along with twenty known metabolites have been isolated from the roots of Thapsia VILLOSA var. VILLOSA L. The structures of two known phenylpropanoids 5 and 6 have been corrected. Compounds 7 and 8 showed activity as potential inhibitors of the sarco- and endoplasmic Ca 2+ -dependent ATPases (SERCA) pump. Compounds 9, 10 and 11 increased significantly the cytoplasmic free calcium concentration ([Ca 2+ ] c ) in human platelets in a concentration-dependent manner.
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Sesquiterpenoids from Thapsia Species and Medicinal Chemistry of the Thapsigargins
Fortschritte der Chemie organischer Naturstoffe = Progress in the chemistry of organic natural products. Progres dans la chimie des substances organiq, 1997Co-Authors: Søren Brøgger Christensen, Annette Andersen, Ulla Wagner SmittAbstract:For centuries preparations containing resin from the root of Thapsia garganica L. (Fig. 1) have been used in Arabian and European medicine for treatment of pulmonary diseases, catarrh and as counterirritants for relief of rheumatic pains (1). The properties of the resin were described already by Theophrastos (372-287 B.C.), Dioscorides (approximately a.d. 50), and Plinius (A.D. 24–79) (2). Radix Thapsiae and Resina Thapsiae have been included in several pharmacopoeias, the latest in the French pharmacopoeia from 1937.
Juan J. Rubal - One of the best experts on this subject based on the ideXlab platform.
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A phenylpropanoid, a slovenolide, two sulphur-containing germacranes and Ca2+-ATPase inhibitors from Thapsia villosa.
Planta medica, 2009Co-Authors: Juan J. Rubal, F.j. Moreno-dorado, Francisco M. Guerra, Zacarías D. Jorge, Søren Brøgger Christensen, Helmer Søhoel, María Del Carmen Galán, Ginés M. Salido, Guillermo M. MassanetAbstract:A phenylpropanoid 1, a slovenolide 2, and two germacranes bearing a methylthiopropenoate moiety, 3 and 4, along with twenty known metabolites have been isolated from the roots of Thapsia VILLOSA var. VILLOSA L. The structures of two known phenylpropanoids 5 and 6 have been corrected. Compounds 7 and 8 showed activity as potential inhibitors of the sarco- and endoplasmic Ca 2+ -dependent ATPases (SERCA) pump. Compounds 9, 10 and 11 increased significantly the cytoplasmic free calcium concentration ([Ca 2+ ] c ) in human platelets in a concentration-dependent manner.
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A pyran-2-one and four meroterpenoids from Thapsia transtagana and their implication in the biosynthesis of transtaganolides.
Phytochemistry, 2007Co-Authors: Juan J. Rubal, F.j. Moreno-dorado, Francisco M. Guerra, Zacarías D. Jorge, Abderrahmane Saouf, Mohamed Akssira, Fouad Mellouki, Raúl Romero-garrido, Guillermo M. MassanetAbstract:Four meroterpenoids (3a, 3b, 4 and 5), a prenylated pyran-2-one (2) along with the known compounds 7-O-geranylscopoletin (1), and thapsitranstagin (6) have been isolated from the roots of Thapsia transtagana. The presence of 1 and 2 supports the biogenetic hypothesis that transtaganolides, a group of bioactive metabolites, are meroterpenoids which come from an O-prenylated coumarin via successive pericyclic reactions.
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Phenylpropanoids from Thapsia transtagana
Phytochemistry, 2006Co-Authors: Abderrahmane Saouf, Juan J. Rubal, F.j. Moreno-dorado, Francisco M. Guerra, Zacarías D. Jorge, Mohamed Akssira, Fouad Mellouki, Guillermo M. MassanetAbstract:Five phenylpropanoids have been isolated from the roots of Thapsia transtagana. Their structures have been elucidated by spectroscopic means.
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Sesquiterpenes from Thapsia nitida var. meridionalis and Thapsia nitida var. nitida.
Journal of natural products, 2006Co-Authors: Juan J. Rubal, F.j. Moreno-dorado, Francisco M. Guerra, Zacarías D. Jorge, Guillermo M. Massanet, Ulla Wagner Smitt, S. Brøgger Christensen, Helmer Søhoel, Karla Frydenvang, Charlotte NielsenAbstract:Nine new eudesmanolides (1−9), two new guaianolides (12 and 13), and a new germacrane (10), along with a previously reported guaianolide (11), have been isolated from the roots of Thapsia nitida va...
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Transtaganolides A-D: novel metabolites from Thapsia transtagana.
Organic letters, 2005Co-Authors: Abderrahmane Saouf, Juan J. Rubal, F.j. Moreno-dorado, Francisco M. Guerra, Zacarías D. Jorge, Mohamed Akssira, Fouad Mellouki, Antonio Pujadas, Matias Lopez, Guillermo M. MassanetAbstract:Four novel and unusual C-19 compounds from Thapsia transtagana, named transtaganolides A−D, have been isolated. Their structures were established by physical methods, including X-ray analysis of transtaganolides A and B. This is the first time that a 7-methoxy-4,5-dihydro-3H-oxepin-2-one ring has been found in a natural product.