Cytotoxic sesquiterpene lactones from Artemisia anomala

Two new sesquiterpene lactones, 8α-acetoxy-1,10α-epoxy-2-oxo-guaia-3,11(13)-dien-12,6α-olide (1) and 13-acetoxy-1-oxo-4α-hydroxy-eudesman-2(11)-dien-12,6α-olide (2), along with six known analogs (3-8), were isolated from the whole plant of Artemisia anomala S. Moore. Their structures were elucidated by extensive analysis of spectroscopic data. Compounds 6 and 7 exhibited in vitro moderate cytotoxicity against A549 cells with IC₅₀ values of 0.6 and 0.9 μM, and HepG2 cells with IC₅₀ values of 5.4 and 3.0 μM, respectively.     

Antimalarial sesquiterpene lactones from Distephanus angulifolius

Combined use of bioassay-guided fractionation based on in vitro antiplasmodial assay and dereplication based on HPLC-PDA-MS-SPE-NMR led to isolation of (6S,7R,8S)-14-acetoxy-8-[2-hydroxymethylacrylat]-15-helianga-1(10),4,11(13)-trien-15-al-6,12-olid and (5R,6R,7R,8S,10S)-14-acetoxy-8-[2-hydroxymethylacrylat]-elema-1,3,11(13)-trien-15-al-6,12-olid, along with vernodalol, vernodalin, and 11,13β-dihydroxyvernodalin from extract of Distephanus angulifolius. All compounds were identified by spectroscopic methods, including 1D and 2D homo- and heteronuclear NMR experiments. The isolated compounds showed IC₅₀ values in the range 1.6-3.8 μM and 2.1-4.9 μM against chloroquine sensitive D10 and chloroquine resistant W2 Plasmodium falciparum strains, respectively.     

Three new sesquiterpene lactone dimers from Carpesium faberi

Three new 2,4-linked sesquiterpene lactone dimers (SLDs), faberidilactones F-H (1–3), have been isolated from Carpesium faberi. Unlike 1 and 2, 3 was a modified Diels-Alder adduct, characteristic by a 1′-OH and a Δ^5′(6′) double bond. Furthermore, the relative configuration of 1′-OH in 3 was assigned as β-configuration by comparison the experimental NOESY data with those of its two possible epimers. The exo/endo stereochemistry of 1–3 was determined by the spectrographic features of 2,4-linked SLDs that we discovered in our previous works. Compounds 1 and 2 showed potent cytotoxicity against human leukemia (CCRF-CEM) cells with IC₅₀ value of 5.62 and 3.74 μM, respectively.     

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.     

Ent-kaurane glycosides and sesquiterpene lactones of the hirsutinolide type from Vernonia triflosculosa

Investigation of the aerial parts of Vernonia triflosculosa afforded three hirsutinolides of which 8alpha-(4alpha-hydroxymethacryloyloxy)-10alpha-hydroxy-1,13-dimethoxy-hirsutinolide is new, three ent-kaurane diterpenes, among which the 19-[alpha-L-arabinopyranosyl-(1-->2)-beta-D-glucopyranosyl] esters of 16beta-hydroxy-ent-kauran-19-oic acid and of 16beta,17-hydroxy-ent-kauran-19-oic acid are also new. Diterpenes are reported here for the first time in the large genus Vernonia. Their structures were elucidated using 1D and 2D NMR measurement as well as ESI, CIMS, and HRMS analysis. Two hirsutinolides were studied for their NF-kappaB DNA binding activity in HaCaT cells (a human cell line similar to keratinocytes) and for their inhibition on IL-8 production in HeLa cells.     

Allelopathic potential of two sesquiterpene lactones from Magnolia grandiflora L.

The allelopathic effects of the two sesquiterpene lactones, costunolide and parthenolide, isolated from the leaves of Magnolia grandiflora L. were evaluated on the wheat (Triticum aestivum L.), lettuce (Lactuca sativa L.), radish (Raphanus sativus L.) and onion (Allium cepa L.). Seed germination of the test species was significantly reduced at 500 μg/ml by both compounds. Both sesquiterpenes showed pronounced inhibition of root length of the test species and the inhibitory effect was concentration-dependent. In addition, shoot growth of the four species was significantly inhibited at all the concentrations tested (10–500 μg/ml). Parthenolide reduced germination and inhibited seedling growth more than costunolide. Inhibition of root growth was generally greater than that of shoot growth. The results encourage the use of these sesquiterpenes as models for development of new herbicides.     

An unusual dimeric guaianolide with antiprotozoal activity and further sesquiterpene lactones from Eupatoriumperfoliatum

The CH₂Cl₂ extract of aerial parts of Eupatorium perfoliatum L. exhibits antiprotozoal activity under in vitro conditions, especially against Plasmodium falciparum (IC₅₀ = 2.7 μg/ml). The search for active compounds yielded seven sesquiterpene lactones: Four structurally similar guaianolides, one dimeric guaianolide, and two germacranolides. The guaianolides differ in the degree of oxidation at C-14, ranging from a hydroxyl group up to a free carboxylic acid. The dimeric guaianolide, structurally closely related to the monomers, displays an unusual type of interguaianolide linkage between C-14 and C-4. Except for the germacranolide euperfolitin, all STLs described here were hitherto unknown. Furthermore, the flavonoid aglycones eupafolin, hispidulin, patuletin, and kaempferol were identified in the extract, which, except for kaempferol, have not been described as constituents of E. perfoliatum before. The dimeric guaianolide was shown to be the most active constituent against Plasmodium falciparum (IC₅₀ = 2.0 μM) and was less cytotoxic against rat skeletal myoblasts (IC₅₀ = 16.2 μM, selectivity index of about 8).     

Sesquiterpene lactones from Achillea collina J. Becker ex Reichenb

The flower heads of Achillea collina afforded 31 individual sesquiterpene lactones, among which nine guaianolides (1, 16, 20, 21, 23, 27-30), a germacranolide (18) and a dimeric guaianolide (31) were found to be new natural products. The lactones 2-4, 12, 14, 15, 17, 19 and 25 were isolated for the first time from the investigated species. Their structures were established by spectral methods.     

New sesquiterpene lactones from Inula oculus-christi L.

Investigation of the aerial parts of Inula oculus-christi L. led to the identification of four new sesquiterpene lactones: an eudesmanolide (4α,15α-epoxypulchellin E) and three guaianolides (2α-acetoxy-4α,9β-dihydroxy-1β-guaia-11(13),10(14)-dien-12,8α-olide, 9β,10β-epoxygaillardin, 9α,10α-epoxy-2-epi-gaillardin), in addition to the known gaillardin, pulchellin E, pulchellin C and 3-O-palmitates of 16β-hydroxylupeol, 16β-hydroxy-β-amyrin, and faradiol. The structures of all compounds have been elucidated on the basis of their spectral data.     

Ineupatorolide-like sesquiterpene lactones from Dittrichia viscosa

Dittrichia viscosa afforded, in addition to known compounds, minute amounts of nine sesquiterpene lactones, all closely related to ineupatorolide B     

Koanolides B-D,new sesquiterpene lactones from Koanophyllon gibbosum

Three new germacrane-type sesquiterpene lactones, koanolides B–D (1-3) have been isolated from the aerial parts of Koanophyllon gibbosum (Asteraceae), along with the previously reported sesquiterpene lactone koanolide A and the flavonoid eupatorin. The structures of the new compounds were elucidated using spectroscopic and spectrometric data analyses, including 1D and 2D NMR, and by comparison with known spectral data. The antiproliferative activities of the new compounds were evaluated in a panel of six representative human solid tumor cell lines and showed GI₅₀ values ranging from 1.3 to 16 μM for the new molecules.     

Antimicrobial activities of sesquiterpene lactones and inositol derivatives from Hymenoxys robusta

Six compounds from the aerial parts of the Argentinean plant Hymenoxys robusta (Rusby) Parker were isolated and their structures elucidated using extensive spectroscopic analyses. These compounds comprise two inositol derivatives and four 3,4-seco-pseudoguaianolides, including vermeerin. Bioactivity assays of these compounds against bacterial and fungal pathogens showed that only vermeerin possessed antimicrobial activity specific against Staphylococcusaureus, and showed no toxicity when exposed to human-derived macrophages.     

Sesquiterpene lactones and other constituents from Matricaria chamomilla L.

An ethanolic extract of the aerial parts of Matricaria Chamomilla L. collected at Oued Tonga near El-Kala is eastern Argelia yielded two new substances named matricolone and chamolol, together with four known compounds. The structure of the new compounds were determined by chemical transformations and NMR spectroscopy with ¹H-¹H (COSY and ROESY), ¹H-¹³C (one bond and long range correlations) two dimensional experiments. The results obtained indicate the presence of sesquiterpene lactones of the eudesmanolide, germacranolide and guaianolide types. These products can be considered to be of great interest from a chemotaxonomical point of view for this wild-growing plant, because these types of lactones have not been found together in other Matricaria species.     

Sesquiterpene lactones from the aerial parts of Anthemis arvensis L.

Two known sesquiterpene lactones, antheindurolides A and B, together with five new related lactones with the same unusual skeleton were isolated from the aerial parts of Anthemis arvensis growing in Serbia. The originally proposed structure of antheindurolide B was revised. This (antheindurolide) type of lactones, detected so far only in the genus Anthemis (Anthemis indurata, Anthemis pseudocotula and Anthemis cotula) could be of chemotaxonomic significance.     

Sesquiterpene lactones from the endemic Cape Verdean Artemisia gorgonum

Leaves and flowers of Artemisia gorgonum (Asteraceae) collected in Fogo, Cape Verde islands, were phytochemically investigated and resulted in isolation and characterization of three guaianolides 1, 2, 5, and a secoguainolide 4, in addition to eight known guaianolides 6-11 and two known germacranolides 12, 13. Structures were elucidated by 1D and 2D NMR experiments. Careful examination of the ¹³C NMR spectrum led to revision of the structure of a previously described guaianolide from 2 to 3. Most compounds exhibited mild antiplasmodial activities, ridentin (13) being the most interesting with an IC₅₀ of 3.8 ± 0.7 μg ml⁻¹ against Plasmodium falciparum FcB1 and weak cytotoxicity in a vero cell line (IC₅₀ 71.0 ± 3.9 μg ml⁻¹).     

Cloning and expression of sesquiterpene synthase genes from lettuce (Lactuca sativa L.)

Sesquiterpenoid lactones (SLs) from lettuce (Lactuca sativa L.) include constitutive components of latex such as lactucin and the induced phytoalexin, lettucenin A. A redundant primer strategy was used to recover two full length cDNA clones (LTC1 and LTC2) encoding sesquiterpene synthases from a cDNA library derived from seedlings with the red spot disorder, which accumulate phytoalexins. Recombinant enzymes produced from LTC1 and LTC2 in Escherichia coli catalysed the cyclisation of farnesyl diphosphate to germacrene A, potentially an early step in the biosynthesis of SLs. RT-PCR analysis showed LTC1 and LTC2 were expressed constitutively in roots, hypocotyls and true leaves but not in cotyledons. Expression in cotyledons was induced by challenge with the downy mildew pathogen Bremia lactucae in the disease resistant cultivar Diana. Southern hybridisation experiments showed that LTC1 and LTC2 were not part of a multigene family. The germacrene A synthases provide targets for modified expression to generate beneficial modifications to the SL profile in lettuce.