Guaianolide-type Sesquiterpene Research Articles

Antibacterial Sesquiterpene Lactones from Kaunia lasiophthalma.

Phytochemical study of the species Kaunia lasiophthalma enabled the isolation of three undescribed and three known guaianolide-type sesquiterpene lactones, and one new benzofuran. The bioguided fractionation methodology was successful in detecting antimicrobial metabolites against Staphylococcus aureus strains and permitted the description of undescribed guaianolide-type sesquiterpene lactones with substitution patterns matching all those described in the Oxylobinae subtribe.

Guaianolide-type sesquiterpene lactones from Achillea millefolium L. and their anti-inflammatory activity

Seventeen undescribed guaianolide sesquiterpene lactones, millefoliumines A−Q, and seven known analogues were isolated from the whole plant of Achillea millefolium L. growing in Xinjiang, China. Their structures were elucidated based on the HRESIMS and NMR data analyses. The absolute configurations of millefoliumines A−Q were determined by single-crystal X-ray crystallography, ECD data analysis along with quantum-chemical ECD calculations. The anti-inflammatory effects of these compounds on the LPS-induced RAW264.7 cell model were evaluated. As a result, millefoliumine G exhibited potential inhibitory effects on the release of NO, the level of pro-inflammatory cytokines including TNF-α and IL-6. Above results indicated a potential of the guaianolides from A. millefolium in the anti-inflammatory drug development.

Discovery of Michael reaction acceptors from the leaves of Ailanthus altissima by a modified tactic

Structural characteristics-guided investigation of Ailanthus altissima (Mill.) Swingle resulted in the isolation and identification of seven undescribed potential Michael reaction acceptors (1–7). Ailanlactone A (1) possesses an unusual 1,7-epoxy-11,12-seco quassinoid core. Ailanterpene B (6) was a rare guaianolide-type sesquiterpene with a 5/6/6/6-fused skeleton. Their structures were determined through extensive analysis of physiochemical and spectroscopic data, quantum chemical calculations, and single crystal X-ray crystallographic technology using Cu Kα radiation. The cytotoxic activities of isolates on HepG2 and Hep3B cells were evaluated in vitro. Encouragingly, ailanaltiolide K (4) showed significant cytotoxicity against Hep3B cells with IC50 values of 1.41 ± 0.21 μM, whose covalent binding mode was uncovered in silico.

Effect of Plant Growth Regulators on Different Explants of Artemisia ludoviciana under Photoperiod and Darkness Conditions and Their Influence on Achillin Production

Species of the genus Artemisia mainly biosynthesize sesquiterpene lactones. Achillin is a guaianolide-type sesquiterpene lactone isolated from Artemisia ludoviciana; it has shown antibacterial and anti-inflammatory activities. In addition, achillin exhibits a significant chemosensitizing effect on hepatocellular carcinoma cells resistant to paclitaxel (PTX). The objective of this study was to establish a callus culture from different explants under conditions of light and total darkness to produce achillin. To obtain in vitro cultures, explants of leaves, nodes, internodes, and roots were used, and they were cultured in MS medium with 0.1 mg/L of kinetin (KIN) or benzyl amino purine (BAP) and/or naphthaleneacetic acid (NAA), 2,4-dichlorophenoxyacetic acid (2,4-D), indole-3-acetic acid (IAA) and 4-amino-3,5,6-trichloro-2-pyridine carboxylic acid (PIC) at 0.1 and 1.0 mg/L. Of all treatments, internodes with BAP (0.1 mg/L) and PIC (1.0 mg/L) grown under photoperiod showed the best friable callus induction, however, GC-MS analysis showed higher achillin content (1703.05 µg/mL) in leaf calluses with PIC (1.0) and KIN (0.1) under photoperiod, and in node plantlets (1880.01 µg/mL) with PIC (0.1) and BAP (0.1). From 12.34 g of dry leaves of Artemisia ludoviciana, 257 mg of achillin were isolated and purified, which was used as a reference in the quantification of achillin in the in vitro culture.

Cytotoxic Guaianolide Sesquiterpenoids from Ainsliaea fragrans.

Twelve guaianolide-type sesquiterpene oligomers with diverse structures were isolated from the whole plants of Ainsliaea fragrans, including a novel trimer (1) and two new dimers (2, 3). The chemical structures of the new compounds were elucidated through spectroscopic data interpretation and computational calculations. Ainsfragolide (1) is an unusual guaianolide sesquiterpene trimer generated with a novel C-C linkage at C2'-C15″, which may be biosynthesized prospectively through a further Michael addition. Cytotoxicity results showed that ainsfragolide (1) was the most potent compound against five cancer cell lines with IC50 values in the range of 0.4-8.3 μM.

Achillin Increases Chemosensitivity to Paclitaxel, Overcoming Resistance and Enhancing Apoptosis in Human Hepatocellular Carcinoma Cell Line Resistant to Paclitaxel (Hep3B/PTX).

Multidrug resistance (MDR) has become a major obstacle in the treatment of cancer, and is associated with mechanisms such as increased drug outflow, reduction of apoptosis, and/or altered drug metabolism. These problems can be mitigated by the coadministration of agents known as chemosensitizers, as they can reverse resistance to anticancer drugs and eventually resensitize cancer cells. We explore the chemosensitizing effect of Achillin, a guaianolide-type sesquiterpene lactone isolated from the Mexican medicinal plant Artemisia ludovisiana, to reverse MDR in Hep3B/PTX cells of hepatocellular carcinoma, which present resistance to paclitaxel (PTX). Achillin showed an important effect as chemosensitizer; indeed, the cytotoxic effect of PTX (25 nM) was enhanced, and the induction of G2/M phase cell cycle arrest and apoptosis were potentiated when combining with Achillin (100 μM). In addition, we observed that Achillin decreases P-gp levels and increases the intracellular retention of doxorubicin in Hep3B/PTX cells; in addition, homology structural modeling and molecular docking calculations predicted that Achillin interacts in two regions (M-site and R-site) of transporter drug efflux P-glycoprotein (P-gp). Our results suggest that the chemosensitizer effect demonstrated for Achillin could be associated with P-gp modulation. This work also provides useful information for the development of new therapeutic agents from guaianolide-type sesquiterpene lactones like Achillin.

Bioassay-guided isolation of cytotoxic compounds from Chrysophthalmum montanum (DC.) Boiss

Bioassay-guided isolation of the 80% methanol extract of the aerial parts of Chrysophthalmum montanum (DC.) Boiss. (Asteraceae) led to the isolation of four known guaianolide-type sesquiterpene lactones, 6α-acetoxy-4α-hydroxy-1βH-guaia-9.11(13)-dien-12.8α-olide (1), 6α-acetoxy-4α-hydroxy-9β.10β-epoxy-1βH-guaia-11(13)-en-12.8α-olide (2), 4α,6α-dihydroxy-1β,5α,7αH-guaia-9(10),11(13)-dien-12,8α-olide (3), and (4α,5α,8β,10β)-4,10-dihydroxy-1,11(13)-guaidien-12,8-olide (4), along a steroidal glycoside mixture (5a and 5b). The structures of the compounds were identified on the basis of spectroscopic data. Among them, 2, 4 and a steroidal glycoside mixture were obtained from C. montanum for the first time. All isolates were also first time assayed for in vitro cytotoxicities against four human cancer cell lines, i.e. breast (MCF-7, MDA-MB 231), colon (HT-29), and lung (PC3). Among the isolates, 1–3 showed significant inhibitory effect on the proliferation of cancer cells with viability ranging from 6.86 to 26.51%, while steroidal glycoside mixture showed no cytotoxicity, except against HT-29 (viability 61.99%). Compound 4 exhibited strong and selective cell growth inhibition against HT-29 with viability 20.99% and was identified as a promising compound with high selectivity between cancer cells and normal human lung cells (BEAS-2B), especially against HT-29 (IC50 = 12.2 μg/mL) compared to that of cisplatin. These results suggested that 4 is worthy of further study to determine its cytotoxicity mechanisms.

Kauniolide synthase is a P450 with unusual hydroxylation and cyclization-elimination activity

Guaianolides are an important class of sesquiterpene lactones with unique biological and pharmaceutical properties. They have been postulated to be derived from germacranolides, but for years no progress has been made in the elucidation of their biosynthesis that requires an unknown cyclization mechanism. Here we demonstrate the isolation and characterization of a cytochrome P450 from feverfew (Tanacetum parthenium), kauniolide synthase. Kauniolide synthase catalyses the formation of the guaianolide kauniolide from the germacranolide substrate costunolide. Unlike most cytochrome P450s, kauniolide synthase combines stereoselective hydroxylation of costunolide at the C3 position, with water elimination, cyclization and regioselective deprotonation. This unique mechanism of action is supported by in silico modelling and docking experiments. The full kauniolide biosynthesis pathway is reconstructed in the heterologous hosts Nicotiana benthamiana and yeast, paving the way for biotechnological production of guaianolide-type sesquiterpene lactones.

Biogenic guaianolide-type sesquiterpene lactones with antioxidative and anti-inflammatory properties from natural mangrove hybrid Rhizophora annamalayana

Previously undescribed guaianolide-type sesquiterpene lactones were isolated from the chloroform fraction of the natural hybrid mangrove Rhizophora annamalayana, and were characterised as (Z)-3α,4,5,6-tetrahydro-5α-isobutyl-2β-(methoxymethyl)-7-methyl-3H-cyclohepta[b]carbolactone (1) and (7Z)-isopentyl 3α,4,5,6,7,8-hexahydro-2β-((E)-11-methylbut-10-enyl)-1-oxo-2H-cyclohepta[b]furan-6-carboxylate (2). Compound 2 displayed greater antioxidative activities {1, 1-diphenyl-2-picrylhydrazyl (DPPH) and 2, 2′-azino-bis-3 ethylbenzothiozoline-6-sulphonic acid diammonium salt (ABTS), IC50 0.65 and 0.62 mg/mL, respectively)} compared to 1 (IC50 0.83 and 1.14 mg/mL, respectively) (p < 0.05). Compound 2 recorded no significant difference in DPPH. scavenging activities (IC50 0.65 mg/mL) compared to α-tocopherol (IC50 0.63 mg/mL). Pro-inflammatory 5-lipoxygenase inhibitory activity of 2 was found to be comparable (IC50 0.98 mg/mL) to that displayed by synthetic anti-inflammatory drug ibuprofen (IC50 0.93 mg/mL). Compound 2 showed significantly greater selectivity index (anti-cyclooxygenase-1/anti-cyclooxygenase-2 = 2.15) than non-steroidal anti-inflammatory ibuprofen (<0.5) (p < 0.05), and therefore, might be used as selective cyclooxygenase-2 inhibitor. The hitherto undescribed guaianolide lactones might be used as potential anti-inflammatory and antioxidative pharmacophore leads.

Chemical constituents from Ainsliaea acerifolia as potential anti-obesity agents

Bioassay-guided isolation of an ethanolic extract of the aerial parts from Ainsliaea acerifolia using pancreatic lipase inhibitory assay led to the isolation of a new guaianolide-type sesquiterpene lactone (1), a new dicaffeoylquinic acid derivative (4), as well as eight known secondary metabolites. Structures of the two new compounds were elucidated on the basis of spectroscopic methods. All isolated compounds were evaluated for their inhibitory effects against pancreatic lipase, and compound 2 exhibited significant inhibitory activity with an IC50 value of 15.3±0.7μM. Furthermore, compound 2 also exhibited potent inhibitory effects against 3T3-L1 adipocyte cells.

The application of Heck reaction in the synthesis of guaianolide sesquiterpene lactones derivatives selectively inhibiting resistant acute leukemic cells

A series of guaianolide-type sesquiterpene lactones derivatives with arylation of α-methylene-γ-lactone moiety was synthesized using Heck reactions, and was evaluated for their activities against acute myelogenous leukemia (AML) cell line HL-60 and doxorubicin-resistant cell line HL-60/A. Although all compounds were significantly less active against HL-60 than the parent molecules, surprisingly, compounds 3a, 4c–4e, 5e, and 8d exhibited high potency against doxorubicin-resistant cell line HL-60/A (IC50=6.2–19μM), and their activities against HL-60/A were comparable to that of their parent molecules. In view of their novel activities against HL-60/A, compound 5e with inhibitory activity against HL-60/A (IC50=6.2±0.5μM) was selected for study its preliminary mechanism. The result reveals that compound 5e can obviously induce apoptosis.

New Guaianolide-Type Sesquiterpene Lactones from Inula verbascifolia

The aerial parts of Inula verbascifolia afforded two new guaianolide-type sesquiterpene lactones. Their structures were determined by spectroscopic methods (IR, MS, 1H NMR, 13C NMR, DEPT, 1H-1H COSY, HMQC, and HMBC).

Ainsliatrimers A and B, the First Two Guaianolide Trimers from Ainsliaea fulvioides

Ainsliatrimers A (1) and B (2), the first two guaianolide-type sesquiterpene lactone trimers, together with one new structurally related sesquiterpene dimer ainsliadimer B (3), were isolated from the aerial part of Ainsliaea fulvioides. Their structures were elucidated by spectroscopic techniques, including X-ray crystal diffraction. Both 1 and 2 showed potent cytotoxicites against LOVO and CEM cell lines.

Lipophilicity of some guaianolides isolated from two endemic subspecies of Amphoricarpos neumayeri (Asteraceae) from Montenegro

In this study 10 guaianolide-type sesquiterpene gamma-lactones named amphoricarpolides, isolated from the aerial parts of two endemic subspecies of Amphoricarpos neumayeri (ssp. neumayeri and ssp. murbeckii Bosnjak), were investigated by means of reversed-phase thin-layer chromatography. Methanol-water and tetrahydrofuran-water binary mixtures were used as mobile phase in order to determine lipophilicity parameters R (0) (M) and C(0). Some of the investigated compounds were screened for their cytotoxic activity against HeLa and B16 cells. Chromatographically obtained lipophilicity parameters were correlated with calculated logP values and IC(50) values. Principal component analysis identified the dominant pattern in the chromatographically obtained data.

Supercritical fluid extraction of cynaropicrin and 20‐hydroxyecdysone from Leuzea carthamoides DC

Leuzea carthamoides is an adaptogenic plant containing biologically active compounds as ecdysteroids and guaianolide-type sesquiterpene lactones, conventionally extracted from the plant with ethanol. It may be a potential source of the mentioned natural compounds. Ethanol-modified near-critical CO(2) was used as selective solvent with the aim to increase the level of 20-hydroxyecdysone in the extract from L. carthamoides roots and to remove selectively cynaropicrin, a sesquiterpene lactone of bitter taste, from the leaves. The extraction conditions were varied (pressure 20-28 MPa, temperature 40-60 degrees C, ethanol concentration in the solvent 0-7.1%) and the extraction yield and extract composition were compared with the results of ethanolic extraction. The supercritical fluid extraction (SFE) from finely powdered plant was controlled by phase equilibrium. Cynaropicrin was quantitatively removed from the leaves where 89% of 20-hydroxyecdysone was retained. The extraction yield of 20-hydroxyecdysone from roots with ethanol-modified CO(2 )was lower by 30% than with ethanol but its concentration in the extract was higher by 67%.

Two New Sesquiterpene Lactones from Ixeris chinensis.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Two New Sesquiterpene Lactones from Ixeris chinensis

Phytochemical investigation of Ixeris chinensis NAKAI (Asteraceae) has resulted in the isolation of a new guaianolide-type sesquiterpene lactone, ixerochinolide (1) as well as the related glucoside, ixerochinoside (2). In addition, the known guaianolides, 8beta-hydroxy-3-oxo-guaia-4(15),10(14),11(13)-trien-1alpha,5alpha,6beta,7alphaH-12,6-olide (8beta-hydroxydehydrozaluzanin), 8beta,15-dihydroxy-2-oxo-guaia-1(10),3,11(13)-trien-5alpha,6beta,7alphaH-12,6-olide (lactucin), 3beta,8alpha,10alpha-trihydroxy-guaia-4(15),11(13)-dien-1alpha,5alpha,6beta,7alphaH-12,6-olide (10alpha-hydroxy-10,14-dihydro-desacylcynaropicrin) and 3beta-D-glucopyranosyloxy-8beta-(p-hydroxyphenylacetyloxy)-guaia-4(15),10(14),11(13)-trien-1alpha,5alpha,6beta,7alphaH-12,6-olide (8-epicrepioside) were identified. The structures were determined on the basis of spectral analyses, especially 1- and 2D NMR. Compound 1 exhibited significant cytotoxicity against human PC-3 tumor cells.

Cytotoxic versus anti-inflammatory effects in HeLa, jurkat t and human peripheral blood cells caused by guaianolide-Type sesquiterpene lactones

Four guaianolide type sesquiterpene lactones (SL), namely the new 1,2-dihydro-3-oxo-costic acid guaianyl ester 3β- O-(1,2-didehydro-3-oxo-costoyloxy)-4β,10β-dihydroxy-guaia-1(2)-en-6β,12-olide ( 1) and 3β- O-(1,2-didehydro-3-oxo-costoyloxy)-4β,10β-dihydroxy-guaia-1(2)-en-6α,12-olide ( 2), as well as the known moroccolide A [5αH-2β,4-epoxy-3β-hydroxy-guaia-1(10),11(13)-dien-6β,12-olide, 3] and 3β- O-(2-methylbutyryl)-moroccolide A [5αH-2β,4-epoxy-3β-(2-methylbutyryloxy)-guaia-1(10),11(13)-dien-6β,12-olide, 4] were examined for their cytotoxic and anti-inflammatory effects in HeLa, Jurkat T and human peripheral blood mononuclear cells. Compounds 1, 2 and 4 were found to exert a strong cytotoxicity similar in potency in all investigated cell types, whereas 3 was significantly less active. Along with the cytotoxic effect compounds 1 and 4 showed a potent and comparable down-regulation of the mRNAs of the house-keeping genes β-actin and GAP-DH in PBMCs after 20 h. In contrast, the down-regulation of the PMA-induced mRNA levels of the NF-κB-driven pro-inflammatory genes IL-2, IL-6, GM-CSF, TNF-α, and IL-1β in PBMCs is significantly stronger with compound 4. Compound 3 did not significantly modulate cytokine mRNAs levels at biochemically relevant concentrations. The electromobility shift assay (EMSA), revealed a stronger inhibition of NF-κB for 1 (IC 50 2.5 μM) than for 4 (IC 50 5 μM). Both compounds were also subjected to an IL-6 luciferase reporter gene assay and showed IC 50 values of 1.0 ( 1) and 1.2 μM ( 4). Thus, the NF-κB inhibition measured by EMSA, as well as the IL-6 luciferase assay did not reflect the differential modulation of pro-inflammatory genes measured with RT-rt-PCR.

Biosynthetic studies of lactucin derivatives in hairy root cultures of Lactuca floridana

Biosynthetic studies of the guaianolide-type sesquiterpene lactones 11 βH,13-dihydrolactucin-8- O-acetate and 8-desoxylactucin were performed in Agrobacterium rhizogenes—transformed hairy root cultures of blue-flowered lettuce, Lactuca floridana. The 13C NMR spectra of the two guaianolides labelled by incorporation of [1- 13C], [2- 13C], [1,2- 13C 2]acetate and [2- 13C]mevalolactone showed patterns of enrichment consistent with a previously proposed biogenetic pathway for guaianolide-type sesquiterpene lactones via the acetate-mevalonate-germacradiene route.

A diterpene from Garberia heterophylla

The aerial parts of Garberia heterophylla afforded the known guaianolide-type sesquiterpene lactone eupahakonesin, 2,6-dimethoxybenoquinone and the triterpene epifriedelinol. In addition, a new and novel diterpene, garberic acid, was isolated. Its structure and stereochemistry was established by spectral methods and single crystal X-ray diffraction studies.