Structure of histamine releasing guaianolides from Thapsia species

doi:10.1016/S0031-9422(00)83463-9

Phytochemistry

Volume 23, Issue 8, 1984, Pages 1659-1663

https://doi.org/10.1016/S0031-9422(00)83463-9 Get rights and content

Abstract

The structures of six hexaoxygenated guaianolides esterified with four non isomeric carboxylic acids have been established by ¹H NMR and ¹³C NMR spectroscopy. The acyl residues have been located by chemical ionisation mass spectrometry. Some of the acyl residues are novel for sesquiterpene lactones. The acyl residues in two additional guaianolides esterified with isomeric acids have been located by partial hydrolysis.

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Cited by (39)

Large scale purification of the SERCA inhibitor Thapsigargin from Thapsia garganica L. roots using centrifugal partition chromatography
2013, Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences
Citation Excerpt :
Commercial Tg is mainly obtained by extraction from vegetal sources, although one total synthesis of Tg has been described by Ley's group [7,8]. Tg occurs exclusively in Thapsia genus, in association with about twenty penta- and hexaoxygenated guaianolides (thapsigargins), thapsanes, phenylpropanoids, and coumarins [9–12]. Among the seven described Thapsia species [13], chemotaxonomic studies showed that Tg has been identified both in fruits and roots of T. garganica, T. gymnesica and T. villosa [14].
Thapsigargin (Tg) is a selective and irreversible inhibitor of the sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA)-dependent pump at subnanomolecular concentrations. As such, it has become a powerful tool in the study of Ca²⁺ signaling pathway. Purification of Tg from Thapsia species requires repeated chromatographic steps with normal-phase alumina or silica and reverse phase chromatography. We thus developed an innovative procedure coupling high pressure automatized extraction with centrifugal partition chromatography allowing a fast and safe large-scale isolation of highly pure Tg, in two steps from Thapsia garganica L. roots. Comparison of influence of extraction procedures, storage conditions and harvesting areas on Tg content in different Algerian specimens of Thapsia garganica L. roots has been precised by mean of HPLC quantification procedure. Highest Tg content were found in the fresh material of the sample from Setif area.
Trilobolide and related sesquiterpene lactones from Laser trilobum possessing immunobiological properties
2013, Fitoterapia
Citation Excerpt :
The 1H and 13C 1D spectra together with 1H, 1H–COSY and 1H, 13C–HMQC spectra were used for complete structure assignment of carbon and proton signals (Table 1). Characteristic NMR data of compounds 2 and 4 correspond with the data of trilobolide (1) [3], thapsigargin (3) and their analogs [11,27], as are summarized in [26]. Data of the new eudeslaserolide (8) correspond with the data of earlier reported analog lasolide from L. trilobum [3].
Three new and five known sesquiterpene lactones were isolated from the roots of Laser trilobum (L.) Borkh. Chemical identity of the known compounds and structural analysis of the new ones were determined by HR MS and NMR spectroscopy. The two new sesquiterpene lactones: 2-acetoxytrilobolide and 2-hydroxy-10-deacetyltrilobolide belong to the guaianolide type, and the third one, eudeslaserolide, to the biogenetically related eudesmanolide type. Both types, together with their biogenetic precursor of germacranolide type (laserolide) are present in L. trilobum, as well as in the related Laserpitium species. Purposefully selected set of these native sesquiterpene lactones was tested for specific immunobiological properties. The obtained results demonstrate that trilobolide and its acetoxy analog are strong activators of cytokine secretion. On the contrary, the other L. trilobum and Laserpitium siler constituents are only very mild activators, or even inhibitors of the cytokine and nitric oxide production.
Structure-activity relationships of sesquiterpene lactones
2006, Studies in Natural Products Chemistry
Sesquiterpene lactones (STLs) are one of the largest biogenetically homogenous groups of natural products known. Currently, the Dictionary of Natural Products holds a total of over 11000 entries on sesquiterpenes, of which almost 5000 contain at least one lactone group. One reason for the large number of individual compounds and the associated structural diversity of this class of natural products is most certainly related to their enormously broad spectrum of biological activities, rendering them a highly valuable defense tool for those organisms synthesizing them. It is thus no surprise that the plant family from which most STLs have been isolated, i.e. the Compositae, is among the largest and ecologically most diverse plant families on our planet.
Many of the biological activities of the most common types of STLs are known to be mediated by a simple general chemical mechanism, i.e. alkylation of biological macromolecules in terms of Michael type additions. These effects have been surveyed in numerous comprehensive reviews. Moreover, some very specific receptor-mediated activities of less frequent types of STLs are known. Quite surprisingly, despite the plethora of reports on STL bioactivity, only very few systematic studies on structure-activity relationships have been carried out. Detailed studies of this kind, however, would be highly desirable with respect to several aspects of medicinal/pharmaceutical, agrochemical and ecological interest. Most importantly, many STL-containing plants have been used in traditional medicines of all cultures for many centuries and continue to be utilized also in modern phytotherapy. Therapeutic use of STLs as pure chemicals is - in spite of their broad utilization in form of plants or crude extracts-restricted to very few examples, which is mainly due to a lack of knowledge on the structural requirements for selectivity with respect to a desired biological activity. It may, however, be conceived, that STLs could play a valuable role as lead structures to new therapeutic agents, if more information, especially in the form of quantitative structure-activity relationships (QSAR), existed. The present chapter attempts to present an overview on the current knowledge on structure-activity relationships of STLs of different types and different activities. Selected examples of current research in the author’s laboratory on structure-reactivity- and structure-activity relationships of STLs are presented.
Thapsigargin analogues for targeting programmed death of androgen-independent prostate cancer cells
1999, Bioorganic and Medicinal Chemistry
A number of analogues of thapsigargin, a selective inhibitor of the sarco-endoplasmic reticulum Ca²⁺-ATPases have been synthesized. In all of the prepared analogues the butanoyl residue at O-8 has been replaced with a residue containing an aromatic amine. The amine can be used as an anchoring point for attaching a peptide group sensitive to the proteolytic enzyme, prostate specific antigen, secreted by prostate cancer cells. Like thapsigargin, the analogues are capable of elevating the cytoplasmic Ca²⁺ concentration approximately sevenfold when tested at effective cytotoxic doses. The analogues in which the 8-O-butanoyl group has been replaced with 3-(4-aminophenyl)propanoyl or 4-aminocinnamoyl were found potently to induce programmed cell death of the prostate cancer cells.
Essential oils from fruits of three types of Thapsia villosa
1996, Phytochemistry
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.
A chemotaxonomic investigation of Thapsia villosa L., Apiaceae (Umbelliferae)
1995, Botanical Journal of the Linnean Society
Chemotaxonomic investigations of Thapsia villosa L., Apiaceae, have resulted in a division of the species into five different types, representing two distinctly different groups. Thapsigargins, the guaianolide sesquiterpene lactones with unique bioactivity, are present only in one of these groups, which includes two morphologically identical types, with different chromosome numbers, 2n=44 [4x] and 2n=66 [6x]. Besides thapsigargins, 6-methoxy-7-geranyloxycoumarin and phenylpropanoids are characteristic constituents of the roots, and limonene and methyl eugenol are the two major constituents of the fruit essential oil. The other group with clearly different morphological characters includes three types with the chromosome numbers 2n=22 [x], 2n=22 [2x] and 2n=44 [4x]. Different sesquiterpenes are the characteristic constituents of their roots, tovarol and hydroindene derivatives being present in all three types, whereas guaiane esters have been detected in only one of the diploid types. Geranyl acetate is the major constituent of the fruit essential oil of all three types within this group.

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Structure of histamine releasing guaianolides from Thapsia species

Abstract

Planta Med.

J. Org. Chem.