Cytotoxic activity of sesquiterpene lactones from Inula britannica on human cancer cell lines

Five new sesquiterpene lactones (1–5) were isolated from Inula britannica collected in the wild from Serbia along with five known compounds (6–10). Sesquiterpene lactones were isolated using centrifugal partition chromatography followed by combination of flash chromatography and semi-preparative HPLC. Isolated compounds were screened for cytotoxic activity on four different human cancer cell lines and their multi-drug resistant counterparts, as well as on normal human keratinocytes. Sesquiterpene lactones showed similar cytotoxic activity toward drug sensitive and drug resistant cancer cell lines.     

Fungicidal activity of natural and synthetic sesquiterpene lactone analogs

Fungicidal activity of 36 natural and synthetic sesquiterpene lactones with guaianolide, trans, trans-germacranolide, cis, cis-germacranolide, melampolide, and eudesmanolide carbon skeletons was evaluated against the phytopathogenic fungi Colletotrichum acutatum, C. fragariae, C. gloeosporioides, Fusarium oxysporum, Botrytis cinerea, and Phomopsis sp. Dose-response data for the active compounds dehydrozaluzanin C, dehydrocostuslactone, 5alpha-hydroxydehydrocostuslacone, costunolide, and zaluzanin C are presented. A new 96-well microbioassay procedure for fast and easy evaluation of antifungal activity was used to compare these compounds with commercial fungicide standards. Some structure-activity conclusions are also presented.     

Further Amphoricarpolides from the Surface Extracts of Amphoricarpos Complex from Montenegro

Analysis of composition of sesquiterpene lactone fraction of leaf cuticular neutral lipids of Amphoricarpos complex from two different localities in north Montenegro, i.e., canyon of river Tara (A. autariatus ssp. autariatus) and mountain Zeletin (A. autariatus ssp. bertisceus) afforded sesquiterpene lactones with guaianolide skeletons (17 compounds), so called amphoricarpolides, typical for this genus. Nine of them, 9 – 17 , were new compounds, and their structures were elucidated by detailed analyses of IR, NMR, and MS data.     

Anticancer sesquiterpene lactones of Michelia compressa (magnoliaceae)

Investigation of the cytotoxic active components of Michelia compressa afforded two new cytotoxic sesquiterpene lactones, michelenolide and micheliolide. Parthenolide, costunolide, santamarine, reynosin and liriodenine were also isolated and exhibited cytotoxic activity. The known sesquiterpene lactones, lanuginolide and dihydroparthenolide, were isolated but were not active. Two other new inactive sesquiterpene lactones, compressanolide and dihydroreynosin, were also obtained. The structures of michelenolide and micheliolide were confirmed by partial synthesis from parthenolide and the structure of compressanolide by partial synthesis from dihydroparthenolide.     

Design, synthesis, and anti-tumor activity of (2-O-alkyloxime-3-phenyl)-propionyl-1-O-acetylbritannilactone esters

The extracts of Inula britannica have anti-inflammatory, anti-bacterial, anti-hepatitic, and anti-tumor activities. Various sesquiterpene lactones with cytotoxic properties including 1-O-acetylbritannilactone (1) have been isolated from this Chinese medicinal plant. Eight derivatives of 1-O-acetylbritannilactone, (2-O-alkyloxime-3-phenyl)-propionyl-1-O-acetylbritannilactone esters were designed and synthesized. Four of these compounds were tested to show inhibitory activity on the growth of human leukemia HL-60 and cancer Bel-7402 cell lines.     

The molecular structure of 2alpha-hydroxyneoanisatin and structure-activity relationships among convulsant sesquiterpenes of the seco-prezizaane and picrotoxane types

The molecular structure of 2alpha-hydroxyneoanisatin, a positional isomer of the potent neurotoxin anisatin, was determined by X-ray crystallographic analysis. This compound and four further seco-prezizaane type sesquiterpene lactones previously isolated from Illicium floridanum, which represent different structural types with respect to the mode of cyclisation, did not induce anisatin/picrotoxinin-like convulsions in mice. Based on these results and literature data for other seco-prezizaanes, structural requirements for convulsant activity are discussed. Comparison of the three dimensional molecular shape and electrostatic properties of active and inactive seco-prezizaane type lactones with compounds of the picrotoxane type resulted in the identification of a common pharmacophore structure for these different skeletal classes of convulsant natural products.     

Sesquiterpene lactones of Podanthus mitiqui

Ovatifolin and two new sesquiterpene lactones, deacetylovatifolin and arturin (1β-hydroxy-8β-angeloyloxy-eudesmane-4(15),11(13)-diene-6α,12-olide, have been isolated from stems and leaves of Podanthus mitiqui. Two of these compounds showed cytotoxic activity.     

Chromosomal aberrations caused by sesquiterpene lactones in chinese hamster ovary cells

The cytotoxic behaviour of 20 sesquiterpene lactones toward Chinese hamster ovary cells was examined. The structural pre-requisite for cytotoxicity was the α-methylene γ-lactone moiety. Certain sesquiterpene lactones caused chromosomal aberrations suggesting that DNA was the cellular target. The cellular target for most of these compounds, however, is probably not the nucleus and the cytotoxicity may be accounted for by Michael-type additions with sulphydryl groups of enzymes and other proteins.     

Sesquiterpene lactones as taxonomic characters in the asteraceae

The Asteraceae is characterized by structurally diverse sesquiterpene lactones and furanosesquiterpenes. In this review the tribal, subtribal and generic distribution of sesquiterpene lactones is examined and the compounds’ utility as taxonomic characters discussed. Sesquiterpene lactones fulfill the major requirements for good analytic and synthetic characters. Studies of infraspecific sesquiterpene lactone variation indicate that different elements within complex taxa are often defined by distinct chemistries, termed chemotypes. Chemotypes have been identified within many of the thoroughly investigated taxa:Ambrosia camphorata, A. chamissonis, A. confertiflora, theA. cumanensis-A. psilostachya-A. artemisiifolia complex,A. dumosa, Artemisia tridentata, Gaillardia pulchella andMelampodium leucanthum. Such an analytic usage is mostly restricted to the infraspecific level. Synthetic usage at the interspecific level and above profits from the application of a biogenetically based methodology for sorting out the complex molecules’ carbon-skeletal and substitutional features into unit characters. Cladistics or Hennigian phylogenetic systematics provides a useful framework for such an analysis. Preliminary surveys indicate that sesquiterpene lactones are especially good characters for differentiating subtribes within several major tribes: the Vernonieae, Heliantheae and Mutisieae. As yet, too few data are available for other tribes to discern such patterns. Species surveys inVernonia, Ambrosia, Iva, Parthenium,Tetragonotheca andArtemisia demonstrate that sesquiterpene lactones are useful in discerning infrageneric groups. The biogenetic cladistic analysis of the interspecific sesquiterpene lactone variation inIva shows the efficacy of this analytical methodology. At present, such biogenetically based approaches are impeded by limited biosynthetic evidence and the erratic distribution of sesquiterpene lactones within the family. Instances of apparent displacement of sesquiterpene lactones by other terpenoids (i.e. sesquiterpene furans, alcohols and acids, diterpenes, diterpene acids, etc.) at various taxonomic levels suggest that ultimately sesquiterpene lactones must be interpreted as taxonomic characters in the context of the family’s total terpene chemistry. All taxa from which sesquiterpene lactones have been reported are listed together with the compound names, major structural features and the literature cited. A less-complete listing is provided for taxa producing furanosesquiterpenes. Structures for all reported compounds are included. Two appendices listing alphabetically taxa and compounds and relevant text page numbers permit cross-indexing of plants and compounds.     

The molecular structure of 2α-hydroxyneoanisatin and structure–activity relationships among convulsant sesquiterpenes of the seco-prezizaane and picrotoxane types

The molecular structure of 2α-hydroxyneoanisatin, a positional isomer of the potent neurotoxin anisatin, was determined by X-ray crystallographic analysis. This compound and four further seco-prezizaane type sesquiterpene lactones previously isolated from Illicium floridanum, which represent different structural types with respect to the mode of cyclisation, did not induce anisatin/picrotoxinin-like convulsions in mice. Based on these results and literature data for other seco-prezizaanes, structural requirements for convulsant activity are discussed. Comparison of the three dimensional molecular shape and electrostatic properties of active and inactive seco-prezizaane type lactones with compounds of the picrotoxane type resulted in the identification of a common pharmacophore structure for these different skeletal classes of convulsant natural products.     

Sesquiterpene lactones and their precursors as chemosystematic markers in the tribe Cichorieae of the Asteraceae

This review summarizes all reports on sesquiterpene lactones and their immediate precursors from the Cichorieae (Lactuceae) tribe of the Asteraceae. A total of 360 compounds have been reported from this tribe. The reported substances belong to three classes of sesquiterpenoids: guaianolides (243 compounds), eudesmanolides (73 compounds), and germacranolides (44 compounds). Sources of these compounds encompass 139 taxa from 31 different genera. The distribution of these lactones within the tribe Cichorieae is discussed in a chemosystematic context. Moreover, some general ideas about the interpretation of chemosystematic data are discussed.     

Synthesis and Antiproliferative Activity of Conjugates of Anthracycline Antibiotics with Sesquiterpene Lactones of the Elecampane

The daunorubicin and doxorubicin anthracycline antibiotics were modified with the Inula helenium L. sesquiterpene lactones (alantolactone, isoalantolactone, and alloalantolactone) and with their epoxy derivatives. Antiproliferative properties of these conjugates were studied on tumor and normal cell lines. The daunorubicin conjugates with the sesquiterpene lactones (isoalantolactone, allantolactone, and alloalantolactone) and with their epoxy derivatives were found to exhibit the higher activity against human tumor cell lines than the corresponding doxorubicin conjugates. The daunorubicin conjugate with epoxyisoalantolactone proved to be the most effective compound, because it was more cytotoxic than daunorubicin towards a number of cell lines, including those daunorubicin-resistant, and did not affect normal human cells.     

Systematic implications of sesquiterpene lactones in Lactuca species

A chemosystematic study of eleven species from the genus Lactuca (Asteraceae) was performed, based on the distributional data for eight sesquiterpene lactones as diagnostic characters. The lactones were identified in leaf and root extracts by comparison of their HPLC retention times and on-line UV spectra with those of reference compounds. Our results support the status of the section Lactuca, subsection Lactuca as a recognizable group within the genus, although Lactuca aculeata is a distinct species. Moreover, sesquiterpene lactone patterns of Lactuca perennis, Lactuca tatarica, Lactuca indica and Lactuca capensis are also given. It is worth noting that the sesquiterpene lactones are absent from Lactuca tenerrima. The chemosystematic impact of lactucin-type guaianolides and the germacranolide lactuside A is discussed briefly.     

Constituents of glandular trichomes of Tithonia diversifolia: relationships to herbivory and antifeedant activity

The herbivory activity of the bordered patch larvae (Chlosyne lacinia, Lepidoptera) on leaves of a Brazilian population of Tithonia diversifolia and the antifeedant potential of its leaf rinse extract were investigated. The caterpillars fed only on the adaxial face, where the density of glandular trichomes is very low, and avoided the abaxial face, which contains high levels of trichomes. Deterrent activity against the larvae was observed in leaf discs treated with leaf rinse extract at concentrations of 1-5% of fresh leaf weight. High-performance liquid chromatography (HPLC) analysis indicated that sesquiterpene lactones are the main constituents of the glandular trichomes. Dichloromethane rinse extracts of the leaves and inflorescences were chemically investigated, and 16 compounds were isolated and identified: 14 sesquiterpene lactones, a flavonoid and a diterpenoid. In this study, five sesquiterpene lactones are described for the first time in the genus, including two lactones, one of which has an unusual seco-guaianolide skeleton. Our findings indicate that the caterpillars avoid the sesquiterpene-lactone-rich glandular trichomes, and provide evidence for the antifeedant activity of the dichloromethane leaf rinse extract. In addition, a study of the seasonal variation of the main constituents from the leaf surface throughout a year demonstrated that a very low qualitative but a very high quantitative variation occurs. The highest level of the main metabolite tagitinin C was observed between September and October and the lowest was from March to June, the later corresponding to the period of highest infestation by the larvae.     

Inhibition of inosine monophosphate dehydrogenase by sesquiterpene lactones

Inosine monophosphate (IMP) dehydrogenase had previously been determined to be a likely target enzyme for the sesquiterpene lactones, a class of potential anti-neoplastic drugs. IMP dehydrogenase was purified approx. 770-fold from the P-388 lymphocytic leukemia tumor cell line. The Km values for the substrates, IMP and NAD, were determined to be 12 microM and 25 microM, respectively. Xanthine monophosphate (XMP) was shown to be a competitive inhibitor with a Ki of 67 microM. Mycophenolic acid gave mixed-type inhibition with a Ki of 8 nM for the noncompetitive component and a Ki of 2 nM for the competitive component. Dissociation constants (Kd) and rate constants for inhibition of IMP dehydrogenase by nine different sesquiterpene lactones were determined. The highest Kd was seen with 2,3-dihydrohelenalin while the lowest Kd was observed with bis-helenalinyl malonate. Binding of the drugs by IMP dehydrogenase increased as the size of the drug increased. Also, changes in structure at position 6 had a relatively large effect on the Kd. There was no correlation with hydrophobicity, as determined by octanol/water partition. The first-order rate constants for the reaction of the sesquiterpene lactones with IMP dehydrogenase (k1) and the second-order rate constants for the reaction of the sesquiterpene lactones with glutathione (k2) were also determined. The rate constants for most of the sesquiterpene lactones with the alpha-methylene-gamma-lactone moiety were similar and were approximately twice as great as the rate constants for those sesquiterpene lactones with only the alpha, beta-unsaturated cyclopentenone ring. Microlenin had approximately 5-times the reactivity of the other sesquiterpene lactones towards IMP dehydrogenase, but had approximately the same reactivity towards glutathione, suggesting that it was bound to the enzyme in a way which facilitated its reaction with one or more essential sulfhydryls. The same procedure was used for a series of N-substituted maleimide compounds with the N-substituent ranging in size from a methyl group to a benzyl group. The binding of the maleimide compounds was generally tighter than for the sesquiterpene lactones and there was an increase in binding with size.     

Cadinenes and other metabolites from Verbesina sphaerocephala A. Gray

The phytochemical study of the aerial parts of Verbesina sphaerocephala A. Gray afforded six sesquiterpene lactones of cadinene type, five of them described for the first time, along with known phenyl propanoids, terpenoids, and phenolic compounds. Structures on new compounds were elucidated by spectroscopic techniques including CD and X-ray analyses, and known compounds were identified by comparing their spectral data with those previously reported. Cadinene-like sesquiterpene lactones could be characteristic metabolites of V. sphaerocephala.     

Sesquiterpene lactone-based classification of three Asteraceae tribes: a study based on self-organizing neural networks applied to chemosystematics

This work describes an application of artificial neural networks on a small data set of sesquiterpene lactones (STLs) of three tribes of the family Asteraceae. Structurally different types of representative STLs from seven subtribes of the tribes Eupatorieae, Heliantheae and Vernonieae were selected as input data for self-organizing neural networks. Encoding the 3D molecular structures of STLs and their projection onto Kohonen maps allowed the classification of Asteraceae into tribes and subtribes. This approach allowed the evaluation of structural similarities among different sets of 3D structures of sesquiterpene lactones and their correlation with the current taxonomic classification of the family. Predictions of the occurrence of STLs from a plant species according to the taxa they belong to were also performed by the networks. The methodology used in this work can be applied to chemosystematic or chemotaxonomic studies of Asteraceae.     

Analysis of sesquiterpene lactones in Eupatorium lindleyanum by HPLC‐PDA‐ESI‐MS/MS

Introduction – The aerial part Eupatorium lindleyanum is commonly used as an antipyretic and detoxicant clinically in traditional Chinese medicine. Our previous research showed that germacrane sesquiterpene lactones were its main active constituents, so the development of rapid and accurate methods for the identification of the sesquiterpene lactones is of great significance. Objective – To develop an HPLC‐PDA‐ESI‐MS/MS method capable for simple and rapid analysis of germacrane sesquiterpene lactones in the aerial part E. lindleyanum. Methodology – High‐performance liquid chromatography‐photodiode array detection‐electrospray ionization‐tandem mass spectrometry was used to analyze germacrane sesquiterpene lactones of Eupatorium lindleyanum. The fragmentation behavior of germacrane sesquiterpene lactones in a Micromass Q/TOF Mass Spectrometer was discussed, and 9 germacrane sesquiterpene lactones were identified by comparison of their characteristic data of HPLC and MS analyses with those obtained from reference compounds. Results – The investigated germacrane sesquiterpene lactones were identified as eupalinolides C (1), 3β‐acetoxy‐8β‐(4′‐hydroxy‐tigloyloxy)‐14‐hydroxy‐costunolide (2), eupalinolides A (3), eupalinolides B (4), eupalinolides E (5), 3β‐acetoxy‐8β‐(4′‐oxo‐tigloyloxy)‐14‐hydroxy‐heliangolide (6), 3β‐acetoxy‐8β‐(4′‐oxo‐ tigloyloxy)‐14‐hydroxy‐costunolide (7), hiyodorilactone B (8), and 3β‐acetoxy‐8β‐(4′‐hydroxy‐tigloyloxy)‐ costunolide (9). Compounds 6, 7 and 9 were reported for the first time. Conclusion – HPLC‐PDA‐ESI‐MS/MS provides a new powerful approach to identify germacrane sesquiterpene lactones in E. lindleyanum rapidly and accurately. Copyright © 2009 John Wiley & Sons, Ltd.     

Sesquiterpene Glucosides from Chloranthus japonicus Sieb

A new lindenane sesquiterpene glucoside named yinxiancaoside A (1), a new, rare bidesmosidic megastigmane sesquiterpene glucoside named yinxiancaoside B (5), and three known sesquiterpene glucosides, chloranoside A (2), pisumionoside (3), and sarcaglaboside A (4), were isolated from the whole plant of Chloranthus japonicus Sieb. The structures of the new compounds were established by an extensive study of their spectral data, especially 1D- and 2D-NMR. The cytotoxic activity of the isolated compounds against human hepatoma (Hepg-2), human ovarian carcinoma (OV420), and human breast cancer (MCF-7) cells was investigated.