Atramacrolodes A-D (1-4), Four Undescribed Eudesmane-Type Sesquiterpenes from the Rhizome of Atractylodes macrocephala.

Four undescribed sesquiterpenes, atramacrolodes A-D (1-4), along with six known compounds 5-10 were isolated from the rhizome of Atractylodes macrocephala. Compound 3 possessed a new skeleton based on an unprecedented carton-carton connection. Their structures were determined by UV, IR, HRESIMS, NMR spectra, 13C NMR calculation with DP4+ analysis, and the comparison of experimental and calculated ECD spectra. Compounds 5 and 8 showed protective effects against paracetamol-induced liver cell injury.

Anti-inflammatory Eudesmane Sesquiterpenoids from Artemisia hedinii.

Fourteen new eudesmane sesquiterpenoids (1, 3-5, 7-16) and seven known analogues were isolated from the whole plant of Artemisia hedinii. Their structures were elucidated by spectroscopic data analysis and comparison with published NMR data, and their absolute configurations were confirmed by X-ray diffraction experiments and TDDFT ECD calculation. Compounds 1-15 were identified as eudesmane acids, which represent a kind of lactone ring-opening eudesmane-type sesquiterpenes with an acetoxyl or a hydroxy group attached to C-9. Compounds 1 and 2, 5 and 6, and 7 and 8 are three pairs of epimers isomerized at C-3, C-5, and C-11, respectively. Compounds 1-9, 11-13, 15-19, and 21 could influence the proinflammatory phenotype of the M1 macrophage. Among them, compounds 5, 8, 9, 12, 16, and 19 consistently exhibited anti-inflammatory effects, as evidenced by downregulating classic pro-inflammatory cytokines TNF-α, IL-12, IL-6, and IFN-γ in LPS-induced primary bone marrow derived M1 macrophages.

Alantolactone alleviates collagen-induced arthritis and inhibits Th17 cell differentiation through modulation of STAT3 signalling.

CONTEXT: Alantolactone, the bioactive component in Inula helenium L. (Asteraceae), exhibits multiple biological effects. OBJECTIVE: We aimed to determine the anti-inflammatory effect of alantolactone in a collagen-induced arthritis (CIA) mouse model and its immunomodulatory effects on Th17 differentiation. MATERIALS AND METHODS: A CIA mouse model was established with DBA/1 mice randomly divided into four groups (n = 6): healthy, vehicle and two alantolactone-treated groups (25 or 50 mg/kg), followed by oral administration of alantolactone to mice for 21 consecutive days after arthritis onset. The severity of CIA was evaluated by an arthritic scoring system and histopathological examination. Levels of cytokines and anti-CII antibodies as well as percentages of splenic Th17 and Th17 differentiation with or without alantolactone treatments (0.62, 1.2 or 2.5 µM) were detected with ELISA and flow cytometry, respectively. Western blot analysis was used to evaluate intracellular signalling in alantolactone-treated spleen cells. RESULTS: In CIA mice, alantolactone at 50 mg/kg attenuated RA symptoms, including high arthritis scores, infiltrating inflammatory cells, synovial hyperplasia, bone erosion and levels of the proinflammatory cytokines TNF-α, IL-6 and IL-17A, but not IL-10 in paw tissues. Alantolactone also reduced the number of splenic Th17 cells and the capability of naïve CD4+ T cells to differentiate into the Th17 subset by downregulating STAT3/RORγt signalling by as early as 24 h of treatment. DISCUSSION AND CONCLUSIONS: Alantolactone possesses an anti-inflammatory effect that suppresses murine CIA by inhibiting Th17 cell differentiation, suggesting alantolactone is an adjunctive therapeutic candidate to treat rheumatoid arthritis.

Oxygenated Geosmins and Plant-like Eudesmanes from a Bacterial Mangrove Endophyte.

Geosmin (1) is a microbial terpene metabolite that is responsible for the typical smell of soil and causes an off-odor of food and water. Eudesmane sesquiterpenes are commonly found in plant essential oils. Here we describe the discovery of four geosmin-type metabolites, 7R-hydroxygeosmin (2), 3-oxogeosmin (3), 2R-hydroxy-7-oxogeosmin (4), 5-deoxy-7ß,9ß-dihydroxygeosmin (5), the plant-like eudesmanes 4ß,10α-eudesmane-5ß,11-diol (6) and (1S,5S,6S,7S,10S)-10α-eudesm-4(15)-ene-1α,6α-diol (7), and the known 1(10)E,5E-germacradiene-2,11-diol (8) from a bacterial endophyte (Streptomyces sp. JMRC:ST027706) of the mangrove plant Bruguiera gymnorrhiza. By means of NMR, MS, and ECD spectroscopy, all chemical structures as well as the absolute configurations for the new compounds were elucidated. Compounds 2-5 represent the first geosmin-related metabolites directly as bacterial natural products. The plant-derived eudesmane-5ß,11-diol (6) and (1S,5S,6S,7S,10S)-10α-eudesm-4(15)-ene-1α,6α-diol (7) are also now reported as bacterial products. The broad antimicrobial activities of 6 against a suite of fungal and bacterial pathogens including methicillin-resistant Staphylococcus aureus suggest that this terpene could be an important active principle of the medicinal plant Cymbopogon distans. The discovery of geosmin metabolites from one actinomycete indicated that these bacteria could possess enzymes for modifying geosmin and offer a possibility for bioremediation.

Structurally diverse sesquiterpenoids from the aerial parts of Artemisia annua (Qinghao) and their striking systemically anti-inflammatory activities.

Thirteen new sesquiterpenoids, arteannoides F-R (1-13), along with 13 known analogues (14-26), were isolated from the dried aerial parts of Artemisia annua L. Their structures, including absolute configurations, were unambiguously determined by a combination of physical data analyses (HRESIMS, 1D and 2D NMR, and ECD) as well as the crystal structures of 1, 5, 6, 15, 19, and 23. Among the isolated compounds, 1 features an unusual 11-oxatricyclo[6.2.1.04,9]undecan-2-ene ring system, 5 possesses an uncommon 4,11-ether bridged tricyclic framework, whereas 6 is a new eudesmane-type sesquiterpenoid formed via rearrangement of its carbon backbone. The systemically anti-inflammatory activities of all isolates were evaluated by measuring their inhibitory effects on PGE2, NO, TNF-α, and IL-6 production in LPS-stimulated RAW 264.7 macrophages. Moreover, the structure activity relationships of some compounds are summarized, this study will provide new structural templates for discovering potential anti-inflammatory agents.

Dodelates A-E: Five dimeric eudesmane sesquiterpenoids from Dobinea delavayi.

Dodelates A-E (1-5), five angeloylated eudesmane sesquiterpenoid dimers were isolated from the roots of Dobinea delavayi. Their structures were elucidated by extensive spectroscopic data and single-crystal X-ray diffraction analyses. A possible biosynthetic pathway of these five compounds was proposed. Compounds 1 and 3 exhibited moderate antimalarial activities against Plasmodium yoelii BY265RFP.

Anti-Trypanosoma cruzi activity of costic acid isolated from Nectandra barbellata (Lauraceae) is associated with alterations in plasma membrane electric and mitochondrial membrane potentials.

As part of our continuous studies on prospecting metabolites from Brazilian plant species with pharmacologic activity against Trypanosoma cruzi, the n-hexane extract from twigs of Nectandra barbellata (Lauraceae) was subjected to a bioactivity-guided fractionation to afford the sesquiterpene costic acid. As results, costic acid induced a trypanocidal effect with IC50 of 37.8 and 7.9 µM to trypomastigotes and intracellular amastigotes, respectively. When tested in L929 cells, no cytotoxicity was detected in the highest tested concentration (CC50 > 200 µM), resulting in SI values >5 and >25 to trypomastigotes and amastigotes, respectively. Based on these promising results against T. cruzi, a mechanistic study of the parasite death was investigated. The flow cytometry analysis of costic acid-treated parasites showed depolarization of the plasma membrane electric potential. Spectrofluorimetrical analysis and transmission electron microscopy showed no evidence of plasma membrane permeability alteration of trypomastigotes, but strong ultrastructural damage, evidenced by large vacuoles. Although Ca2+ and reactive oxygen species (ROS) levels were unaltered after short time incubation with costic acid, it rapidly affected the mitochondria, leading to a depolarized potential of the membrane, reducing the ATP levels. In silico studies of costic acid showed good predictions for drug-likeness, with adherence to Lipinskís rules of five (RO5), good ADMET properties and no alerts for Pan-Assay Interference Compounds (PAINS). Therefore, costic acid demonstrated promising activity against T. cruzi parasites, with high selectivity to intracellular amastigotes. Considering the lethal action of costic acid in affecting a vital and unique organelle as the mitochondria, it could be considered a new hit compound for future drug design studies for Chagas disease.

The characteristic smell emitted from two scale insects, Ceroplastes japonicus and Ceroplastes rubens.

The volatile components emitted from two scale insects, Ceroplastes japonicus and Ceroplastes rubens, were identified using GC-MS analysis. The major volatile components of the solvent extract from C. japonicus were α-humulene (35.8%) and δ-cadinene (17.0%), while those of C. rubens were ß-selinene (10.3%) and ß-elemene (5.1%). In GC/olfactometry, linalool, butyric acid, 3-methylbutyric acid, 2-methylbutyric acid, and vanillin were identified as the odor-active components of the extract from C. japonicus, in addition to trace amounts of trans-4,5-epoxy-(2E)-decenal, 4-methyl-(3E)-hexenoic acid, and phenylacetic acid. With regard to C. rubens, trans-4,5-epoxy-(2E)-decenal, 3-methylbutyric acid, and phenylacetic acid were identified as the odor-active components. Besides, decan-1,4-olide (γ-decalactone) with milky cherry-like note and 3-hydroxy-4,5-dimethylfuran-2(5H)-one (sotolone) with brown sugar-like note were also detected as the characteristic cherry-like sweet-and-sour note of these two scale insects. ABBREVIATIONS: GC: Gas chromatography; GC/O: gas chromatography/olfactometry.

Nitric Oxide Production Inhibitory Eudesmane-Type Sesquiterpenoids from Artemisia argyi.

Six new eudesmane-type sesquiterpene derivatives, artemargyinins A-F were isolated from the leaves of Artemisia argyi. Their structures were elucidated based on the extensive analysis of spectroscopic data. Artemargyinins A-F feature a lactone ring-opening eudesmane-type sesquiterpene with an isoprenoid group at C(8). All compounds were tested for their inhibitory effects on lipopolysaccharide-induced nitric oxide (NO) production in RAW264.7 macrophages. Artemargyinins A-F showed more potent NO production inhibitory activity with IC50 values ranging from 7.66±0.53 to 61.19±2.54 µM than the positive control quercetin (IC50 =74.34±1.39 µM). Among them, artemargyinins C and D exhibited strong inhibitory activity with IC50 values of 8.08±0.21 and 7.66±0.53 µM, respectively.

2-Hydroxysorangiadenosine: Structure and Biosynthesis of a Myxobacterial Sesquiterpene-Nucleoside.

Myxobacteria represent an under-investigated source for biologically active natural products featuring intriguing structural moieties with potential applications, e.g., in the pharmaceutical industry. Sorangiadenosine and the here-discovered 2-hydroxysorangiadenosine are myxobacterial sesquiterpene-nucleosides with an unusual structural moiety, a bicyclic eudesmane-type sesquiterpene. As the biosynthesis of these rare terpene-nucleoside hybrid natural products remains elusive, we investigated secondary metabolomes and genomes of several 2-hydroxysorangiadenosine-producing myxobacteria. We report the isolation and full structure elucidation of 2-hydroxysorangiadenosine and its cytotoxic and antibiotic activities and propose a biosynthetic pathway in the myxobacterium Vitiosangium cumulatum MCy10943T.

Eudesmane Glycosides from Ambrosia artemisiifolia (Common Ragweed) as Potential Neuroprotective Agents.

In Alzheimer's disease, amyloid-ß (Aß) accumulation in the brain results in neuronal cell death and is one of the major causes of dementia. Because the current therapeutic agents are not yet sufficiently effective or safe, there have been attempts to find new neuroprotective chemicals against Aß-induced cytotoxicity. A 70% EtOH extract of whole plants of Ambrosia artemisiifolia (common ragweed) was selected after the screening of a natural extract library. Seven new eudesmane-type glycosides (1-7) and seven known compounds (8-14) were obtained through bioactivity-guided fractionation from the aerial parts of this plant. Their structures were determined on the basis of their nuclear magnetic resonance spectra, high-resolution electrospray ionization mass spectrometry analysis, and electronic circular dichroism calculations. Among them, compounds 1, 2, 4-6, 8, 9, 11, 13, and 14 showed protective effects against Aß-induced cytotoxicity in Aß42-transfected HT22 cells. The most active compounds, 5 and 6, exhibited moderate protective activity dose-dependently (10, 20, and 40 µM).

[A new eudesmane type sesquiterpene from cultivated Clerodendranthus spicatus in Hainan].

Six compounds were isolated from the aerial part of cultivated Clerodendranthus spicatus in Hainan with various chromatographic techniques,and their structures were determined as:1-dehydroxy-1-oxo-rupestrinol(1),N-trans-feruloyltyramine(2),methyl 3,4-dihydroxyphenyllactate(3),caffein acid(4),methyl caffeate(5) and ethyl caffeate(6),via analysis of physicochemical properties and spectroscopic evidence.Compound 1 was a new compound,while compounds 2 and 3 were isolated from C.spicatus for the first time.Biological activity results showed that compounds 2-4 exhibited α-glucosidase inhibitory activity with different inhibition ratio.

Eudesmane-Type Sesquiterpene Glycosides from Dictamnus dasycarpus Turcz.

Eudesmane-type sesquiterpenes have been reported to exhibit varieties of biological activities. During the process of investigating this kind of natural product from the root bark of Dictamnus dasycarpus Turcz., 13 eudesmane-type sesquiterpene glycosides including six new isolates, named as dictameudesmnosides A1 (1), A2 (2), B (3), C (4), D (5), and E (6), together with seven known ones (7-13), were obtained. Herein, their structures were determined by the analysis of physical data, spectroscopic analysis, and chemical methods. The existence of α-configuration glucose units in their structures (1-5, 8) is not very common in natural glycosidic components. Meanwhile, compounds 3-5, 7, and 9-13 displayed TG accumulation inhibitory effects on HepG2 cells.

3-Oxo-γ-costic acid fungal-transformation generates eudesmane sesquiterpenes with in vitro tumor-inhibitory activity.

While select eudesmane sesquiterpenes exhibit anti-neoplastic activity, tumor-inhibition for costic-acids has not been established. Here biological activity of 3-oxo-γ-costic acid (1), previously isolated from Chiliadenus montanus, as well as new sesquiterpenes (2-5) and the known derivative, 3-oxoeudesma-1,4,11(13)-trien-7-1061αH-l2-oic acid (6), all produced from 1 by the fungus Athelia rolfsii, are reported. Structures were elucidated using MS and NMR spectroscopy with activity-screening utilizing human colon- and lung-tumor lines, Caco-2 and A549 respectively. Compound 1 exhibited anti-proliferative activity against Caco-2 (IC50 39µM) and 2 was active against A549 (IC50 74µM) suggesting therapeutic potential for the original substrate and a bio-transformed product.

Novel bioactive molecules from Lentzea violacea strain AS 08 using one strain-many compounds (OSMAC) approach.

A new eudesmane sesquiterpenoid (1), and a new homologue of virginiae butanolide E (2) along with butyl isobutyl phthalate (3) were isolated from, actinomycete-Lentzea violacea strain AS08 isolated from north western Himalayas by stressing on modified one strain-many compounds (OSMAC) method. The structures of the new compounds were elucidated by extensive spectroscopic analyses including 1D, 2D NMR along with HR-ESI-MS and FT-IR data. Herein, a distinctive method was added for inspecting secretory profile of the strain by quantification of extract value of cell free supernatant in different types of culture media fallowed by HPLC profiling of respective extracts, which revealed a highly altered metabolic profile of the strain and formed the base for the selection of media. The compounds 1 and 2 showed moderate activity against Gram negative (MIC ∼32-64µgml-1) in comparison to Gram positive bacterial pathogens. Compound 1 exhibited significant activity in human cancerous cell lines (IC50 ∼19.2µM).

Eudesmane sesquiterpenes from Chinese liverwort are substrates of Cdrs and display antifungal activity by targeting Erg6 and Erg11 of Candida albicans.

We isolated twelve sesquiterpenes from Chinese liverwort Tritomaria quinquedentata (Huds.) Buch., including four new compounds. Among them, five eudesmane sesquiterpenes were ineffective against Candida albicans wild strain SC5314 but active towards efflux pumps-deficient strain DSY654 using Alamar blue assay. Further test of the most active agent of ent-isoalantolactone (8, ent-iLL) showed that it also inhibited the yeast-to-hyphal switch of DSY654 cells. The intracellular content measurement using high performance liquid chromatography (HPLC) revealed that ent-iLL was intracellularly accumulated in C. albicans when efflux pumps were deficient or inhibited by Cdrs inhibitor riccardin D, suggesting that the activity of ent-iLL was compromised by efflux pumps Cdrs. Moreover, ent-iLL potentially inhibited the activity of Erg11 and Erg6 of DSY654 and thereby resulted in the alteration of sterol composition by decreasing ergosterol contents and increasing zymosterol and lanosterol accumulation. Our study demonstrated that eudesmane sesquiterpenes, as the substrates of Cdrs, could interfere with sterol synthesis of C. albicans to exert antifungal activity when co-applied with Cdrs inhibitors.

Anti-inflammatory Activity of Eudesmane-Type Sesquiterpenoids from Salvia plebeia.

Nine new sesquiterpenoid lactones and 11 known analogues were isolated from the aerial parts of Salvia plebeia R.Br. Their structures were elucidated via HRESIMS and NMR data, and their absolute configurations were defined via electronic circular dichroism data, X-ray crystallographic analysis, and the modified Mosher's ester method. Compounds 1-20 were investigated for their ability to inhibit LPS-stimulated nitric oxide production in murine macrophage cells. Of the isolates, epi-eudebeiolide C (20) showed the highest inhibitory effect (IC50 of 17.9 µM). mRNA and protein expression of inducible nitric oxide synthase (iNOS), but not that of cyclooxygenase-2 (COX-2), was dose-dependently decreased by 20 in LPS-activated RAW 264.7 cells. Based on a mechanistic study involving the nuclear factor-κB (NF-κB) signaling pathway, the anti-inflammatory effect of 20 was attributed to NF-κB activation blockade via inhibition of NF-κB (IκB) phosphorylation. Therefore, 20 might be a potential candidate for relieving inflammatory diseases.

New Eudesmane Sesquiterpenoids from Salvia plebeia R. Br.

Three new sesquiterpenoids, salplebeones A - C (1 - 3), were isolated from the ethanol-soluble extract of the aerial part of Salvia plebeia R. Br. Their structures were established by detailed analysis of NMR and MS spectra. Salplebeone A was an eudesmane lactone, while salplebeones B and C were rare eudesmane sesquiterpenoids, containing 12,8-lactam groups. Antiproliferative activities of salplebeones A - C to myeloid leukemia cell lines were evaluated.

Sesquiterpenoids from the twigs and leaves of Fokienia hodginsii.

A rare carotane-type sesquiterpenoid, forkienin A (1), a new eudesmane-type sesquiterpenoid, forkienin B (2), and a new natural eudesmane-type sesquiterpenoid, forkienin C (3), were isolated from the twigs and leaves of Fokienia hodginsii, along with eight known sesquiterpenoids. The structures of the new compounds were elucidated on the basis of their spectroscopic analysis, including 1D and 2D NMR methods. All compounds were evaluated for cytotoxicity against HL-60, SMMC-7721, A-549, MCF-7, and SW480 cell lines.

Vetiverianines A, B, and C: Sesquiterpenoids from Vetiveria zizanioides Roots.

Three new sesquiterpenoids-vetiverianines A (1), B (2), and C (3)-and a known eudesmane sesquiterpenoid (4) were isolated from the roots of Vetiveria zizanioides. Vetiverianine A (1) has a unique carbon framework comprising a rigid tricyclic ring system. Vetiverianines B (2) and C (3) are new eremophilane sesquiterpenoids. The structures of sesquiterpenoids 1-3, including the absolute configurations, were determined by NMR spectroscopic, X-ray crystallography, and vibrational circular dichroism data analysis. Vetiverianine C (3) exhibited weak cytotoxic activity against HL-60 cells.