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.     

Antifungal activity of helenin and isohelenin

Two sesquiterpene lactones, helenin and isohelenin, were examined for their activity against 16 species of fungi. These compounds varied greatly in their antifungal activities. At concentrations of 10 μg/ml, the lactones strongly inhibited the growth of Microsporum cookei, Trichophyton mentagrophytes and Trichothecium roseum, while other fungi were only inhibited by considerably higher levels (100–1000 μg/ml). It is suggested that these secondary plant metabolites might be of potential use as antifungal agents, especially if their activity and specificity could further be enhanced through modifications in their chemical structure.     

Pungent sesquiterpene lactones of the european liverworts Chiloscyphus polyanthus and Diplophyllum albicans

The characteristic pungency of the European liverwort, Chiloscyphus polyanthus, is due to a mixture of four sesquiterpene lactones, two new structures ent-5β-hydroxydiplophyllin and ent-3-oxodiplophyllin, and the previously known diplophyllin and diplophyllolide. A new dihydrodiplophyllin, together with the pungent diplophyllolide and diplophyllin, has been isolated from Diplophyllum albicans. Ent-dihydrodiplophyllolides derived from the above pungent diplophyllolides produce intense numbness of the tongue. All pungent sesquiterpene lactones showed inhibitory activity towards the germination and root elongation of rice husks.     

Deterrent activity of sesquiterpene lactones from the umbelliferae against storage pests

The deterrent activity of eight native sesquiterpene lactones isolated from the species Laserpitium siler L., L. archangelica Wulf. and Laser trilobum (L.) Borkh. and one synthetically prepared lactone have been tested against selected storage pest insects. All nine lactones under investigation showed deterrent activity differing according to their structure.     

Sesquiterpene Lactones from Centaurea zuccariniana and Their Antimicrobial Activity

Twenty‐nine compounds were isolated from the aerial parts of the Greek plant C. zuccariniana DC. The structures of the isolated compounds were established by means of NMR‐ (¹H,¹H‐COSY, ¹H,¹³C‐HSQC, HMBC, NOESY, and ROESY) and mass‐spectral analyses. These compounds comprise 13 sesquiterpene lactones, 14 flavonoids, two lignans, and one simple lactone. Among the isolated sesquiterpene lactones, three are new, namely one heliangolide, (1E,4Z)‐15‐hydroxy‐8α‐O‐(4′‐acetoxy‐3′‐hydroxy‐2′‐methylidenebutanoyl)‐6βH,7αH‐germacra‐1,4,11(13)‐trien‐6,12‐olide; and two eudesmanolides, 8α‐(4′,5′‐diacetoxyangeloyl)sonchucarpolide and one unusual eudesmanolide with an oxygenated bridge linking C(1) and C(4), named zuccarinin. The main sesquiterpene lactones were malacitenolide, cnicin, and 4′‐O‐acetylcnicin. These results are in agreement with those obtained from the previously studied Greek Centaurea sp. belonging to the section Acrolophus (Cass .) DC.; this finding could be of chemotaxonomic significance for the genus Centaurea. The in vitro antimicrobial activities of the isolated new sesquiterpene lactones were against eight bacteria and eight fungal species. A 96‐well microbioassay procedure for fast and easy evaluation of antibacterial and antifungal activities was applied to compare these compounds with commercial antibiotic and fungicide standards, and with previously isolated analogous sesquiterpene lactones tested by the same bioassay. All of the compounds tested showed moderate antibacterial, but significant antifungal activities; the present results corroborate with previous data, indicating that these types of compounds exhibit low or moderate antibacterial, but potent antifungal activities. The unusual eudesmanolide zuccarinin proved to be the most potent among the present tested sesquiterpene lactones, as well as among all previously tested eudesmanolides isolated from Greek Centaurea sp.     

Antileishmanial activity and ultrastructural changes of sesquiterpene lactones isolated from Calea pinnatifida (Asteraceae)

Bioactivity-guided fractionation of antileishmanial active CH₂Cl₂ phase of MeOH extract from leaves of Calea pinnatifida led to isolation of two sesquiterpene lactones calein C (1) and calealactone C (2), which structures were stablished on the basis of spectroscopic analysis. Compounds 1 and 2 displayed potent activity against Leishmania amazonensis promastigotes with EC₅₀ of 1.7 and 4.6 µg mL⁻¹, respectively. Compound 2 presented low cytotoxicity for J774 macrophages and displayed activity against amastigote forms of L. amazonensis similar to miltefosine with CC₅₀ values of 31.73 and 27.18 µg mL⁻¹, respectively. Additionally, compounds 1 and 2 caused ultrastructural changes in promastigotes leading to a loss of their classical structural morphology, as evidenced by electron microscopy. Also compound 2 decreased the mitochondria membrane potential. To the best of our knowledge, this is the first occurrence of 1 and 2 in C. pinnatifida. The results obtained highlighted the importance of studying sesquiterpene lactones isolated from Calea pinnatifida in terms of antileishmanial activity, in order to understand the mechanism of action of the isolated compounds in promastigotes forms of L. amazonensis.     

Structure-antimicrobial activity relationships among the sesquiterpene lactones and related compounds

Thirty-six sesquiterpene lactones and related compounds were evaluated for antimicrobial activity against six strains of bacteria. The results obtained show that the beta unsubstituted cyclopentenone ring moiety contributes to moderate antimicrobial activity against Gram positive bacteria. The corresponding saturated compounds gave a more than ten-fold decrease in activity. The significant antimicrobial activity appears to be independent of the presence or absence of an α-methylene-γ-lactone moiety. A more than ten-fold diminution in antimicrobial activity was also observed when the beta position of the cyclopentenone ring was substituted. A similar result was found when the beta unsubstituted enone system was present in a six-membered ring. Enhanced activity was obtained by esterification of the hydroxyl group of helenalin as well as epoxidation of mexicanin-A.     

Insecticidal effects of Vernonanthura nebularum against two economically important pest insects

Vernonanthura nebularum (Cabrera) H. Rob. (Asteraceae), an endemic species from the north of Argentina, is a rich source of elephantopus-type sesquiterpene lactones. These compounds have proved to be promising antiparasitic agents, but there is no report about their action against pest insects. In this work we studied for the first time the antifeedant and toxic effects of V. nebularum natural products against the fall army warm Spodoptera frugiperda Smith and the oviposition deterrent activity against the fruit fly Ceratitis capitata Wiedemann. As a result, we found that extracts, fractions composed of sesquiterpene lactones and pure sesquiterpene lactones altered larval feeding behavior in the food choice test. Nutritional parameters of S. frugiperda larvae were also affected. Fraction II (300 μg/g of diet.), containing compounds 1, 2 and 3, was the most toxic substance with 80% pupal mortality and wing malformations in adults. In oviposition deterrent experiments against Ceratitis capitata, we observed a moderate effect at 30 μg/cm² of the test compound. The most active substances were the methanolic extract, dichloromethane subextract and lactone 2. According to our results, V. nebularum natural products could be used for maximizing the effectiveness and specificity in future insecticide design with specific or multiple target sites, while ensuring the economic and ecological sustainability, in addition to combat the increasing resistance rates developed by synthetic pesticides.     

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.     

Three bourbonenolides and other sesquiterpene lactones from two vernonia species

A re-investigation of V. arkansana afforded several new sesquiterpene lactones, three bourbonenolides, obviously closely related to those isolated from this plant previously, a glaucolide and a methoxy derivative most probably formed by fragmentation of the corresponding bourbonenolide. From V. profuga in addition to known lactones a new guaianolide was isolated. The biogenetic relationships of the Vernonia sesquiterpene lactones are discussed briefly.     

Mode of Action of the Sesquiterpene Lactones Psilostachyin and Psilostachyin C on Trypanosoma cruzi

Trypanosoma cruzi is the causative agent of Chagas’ disease, which is a major endemic disease in Latin America and is recognized by the WHO as one of the 17 neglected tropical diseases in the world. Psilostachyin and psilostachyin C, two sesquiterpene lactones isolated from Ambrosia spp., have been demonstrated to have trypanocidal activity. Considering both the potential therapeutic targets present in the parasite, and the several mechanisms of action proposed for sesquiterpene lactones, the aim of this work was to characterize the mode of action of psilostachyin and psilostachyin C on Trypanosoma cruzi and to identify the possible targets for these molecules. Psilostachyin and psilostachyin C were isolated from Ambrosia tenuifolia and Ambrosia scabra, respectively. Interaction of sesquiterpene lactones with hemin, the induction of oxidative stress, the inhibition of cruzipain and trypanothione reductase and their ability to inhibit sterol biosynthesis were evaluated. The induction of cell death by apoptosis was also evaluated by analyzing phosphatidylserine exposure detected using annexin-V/propidium iodide, decreased mitochondrial membrane potential, assessed with Rhodamine 123 and nuclear DNA fragmentation evaluated by the TUNEL assay. Both STLs were capable of interacting with hemin. Psilostachyin increased about 5 times the generation of reactive oxygen species in Trypanosoma cruzi after a 4h treatment, unlike psilostachyin C which induced an increase in reactive oxygen species levels of only 1.5 times. Only psilostachyin C was able to inhibit the biosynthesis of ergosterol, causing an accumulation of squalene. Both sesquiterpene lactones induced parasite death by apoptosis. Upon evaluating the combination of both compounds, and additive trypanocidal effect was observed. Despite their structural similarity, both sesquiterpene lactones exerted their anti-T. cruzi activity through interaction with different targets. Psilostachyin accomplished its antiparasitic effect by interacting with hemin, while psilostachyin C interfered with sterol synthesis.     

Oxepane diterpenoids sesquiterpene lactones from ‘zoapatle’ (montanoa tomentosa), a mexican plant with oxytocic activity

Investigation of the ‘tea’ prepared from the leaves of ‘zoapatle’ (Montanoa tomentosa), resulted in the isolation of the known biologically active oxepane diterpenoids zoapatanol and montanol, the known sesquiterpene lactones zoapatanolide A, C and D as well as two new biologically active oxepane diterpenoids and a new sesquiterpene lactone. The structures of the new compounds were established by spectroscopic methods.     

Terpenoids and bibenzyls of 25 liverwort Frullania species

Twenty-five Frullania species (liverworts) were chemically investigated. Fourteen species produce allergy-inducing sesquiterpene lactones. Eighteen species contain bibenzyls. The sesquiterpene lactones and bibenzyls are obtained as the major components and they are valuable chemosystematic markers of Frullania species. On the basis of their chemical constituents, Frullania species can be divided into five chemotypes: sesquiterpene lactone-bibenzyl type; sesquiterpene lactone type; bibenzyl type; monoterpene type and cyclocolorenone type.     

Ecogeographic distribution of secondary constituents in Parthenium (compositae)

Over 20 taxa of the genus Partenium (Compositae) representing four sections or five ecological groupings from throughout the Americas, were examined for sesquiterpene lactones, flavonoids and alkaloids. The tropical thorn-forest, arborescent members (sect. Parthenichaeta) were found to contain three different sesquiterpene lactone types and derivatives of the flavonols; quercetin, kaempferol and quercetagetin. The desert shrubs were remarkable for their high production of methylated quercetagetin flavonols and alkaloids, but lacked any appreciable amounts of sesquiterpene lactones. The temperate, submontane perennials (sect. Bolophytum), contained lactones and flavonols in extremely low concentrations. The herbaceous annuals (sect. Argyrochaeta) contained pseudoguaianolides only and together with quercetin, and kaempferol $\text{O-}\text{glycosides}$. The herbaceous perennials contained twice as many lactones and flavonoids as the annuals. It is suggested that the ecogeographical distribution of secondary products in Parthenium is probably a result of adaptive responses to various physical and biotic factors (herbivore pressure) in the environment.     

Sesquiterpene lactones of Conocephalum conicum

Investigation of the plant growth inhibitory activity of the extract of the liverwort, Conocephalum conicum afforded five sesquiterpene lactones, tulipinolide, zaluzanin C, zaluzanin D, 8α-acetoxyzaluzanin C and 8α-acetoxy-zaluzanin D. The latter two compounds are reported for the first time. Tulipinolide is responsible for the characteristic pungency of the female gametophyte of C. conicum. The guaianolides showed inhibitory activity toward the germination and growth of roots of rice in the husk. The male gametophyte of C. conicum indicated no pungency, showing the lack of tulipinolide.     

Biotechnological approaches for cultivation and enhancement of secondary metabolites in Arnica montana L.

Arnica montana L. (Asteraceae) is a valuable medicinal plant with anti-inflammatory and cicatrizing properties attributed to the sesquiterpene lactones, flavonoids and essential oil produced in the flower heads. In many European countries, the populations of A. montana are close to extinction in their natural habitats because of uncontrolled eradication and indiscriminate collection of the plants. Various approaches for in vitro propagation of the species and also, biosynthesis of secondary metabolites in tissue and cell cultures are assessed in the current review. Special attention is paid to the biological activity and chemical composition of compounds produced by the species as well as the opportunities of in vitro methods to isolate high-productive clones. The influence of different factors on the micropropagation, callusogenesis, genetic transformation and identification of certain biologically active substances is discussed in detail. By the reference to the available issues we concluded that biotechnology applied to A. montana cultivation may improved the plant preservation and increased the production of sesquiterpene lactones and other secondary metabolites.     

Sesquiterpene alcohols from Artemisia pygmaea

Artemisia pygmaea Gray contains two sesquiterpene alcohols: the known cryptomeridiol (I) and pygmol (II), a new compound. No sesquiterpene lactones were found in the plant although other species of the section Tridentatae Rydb., with which A. pygmaea has been classified, are usually rich in lactones.     

11β,13-Dihydroguaianolides from Artemisia douglasiana and a thiophene acetylene from A. schmidtiana

The aerial parts of Artemisia douglasiana afforded, in addition to some known sesquiterpene lactones, 22 new closely related guaianolides. A new thiophene acetylene was isolated from the aerial parts of A. schmidtiana together with some known sesquiterpene lactones. The structures were elucidated by high field ¹H NMR spectroscopy.     

Allenic germacranolides,bourbonene derived lactones and other constituents from Vernonia species

An investigation of seven Vernonia species, mainly from northern Brazil, afforded in addition to known compounds three new unusual sesquiterpene lactones with an allenic group. Intensive NMR studies fully established the structures. Furthermore, two lactones derived from bourbonene, two new glaucolides, a new furansesquiterpene, a nerolidol derivative and two other sesquiterpenes derived from eudesmane were isolated. The biogenetic relationships of the sesquiterpene lactones present in Veronia species as well as the chemotaxonomic aspects are discussed.     

Chemotypes of Artemisia herba-alba in Israel based on their sesquiterpene lactone and essential oil constitution

Analysis of sesquiterpene lactones and essential oils of various Artemisia herba-alba populations growing in Israel revealed the existence of five different chemotypes. These vary in their chemical profile from populations of the Sinai Desert, Egypt, Morocco and Spain. On the basis of the substitution patterns of the sesquiterpene lactones isolated from the Israeli populations which bear a hydroxyl or acetoxy function at C-9 it is suggested that these constitute a chemotaxonomic subspecies in the A. herba-alba complex.