Sesquiterpenoid Dimers Research Articles

Spirolindemers A and B, Lindenane Sesquiterpenoid Oligomers Equipped with Oxaspiro[4.5]decane from Chloranthus henryi

Comprehensive SummarySpirolindemers A and B, unprecedented lindenane sesquiterpenoid dimer (1) and trimer (2) equipped with oxaspiro[4.5]decane unit, were discovered from the medicinal plant Chloranthus henryi. Their structures including absolute configurations were achieved by HRMS, NMR, ECD, X‐ray diffraction analyses, and quantum chemical calculations. Biogenetically, hetero‐ and homo‐Diels‐Alder additions may dominate the formation of oxaspiro[4.5]decane and spiro[4.5]decane skeletons, respectively. Compound 1 showed anti‐inflammatory activity by inhibiting the expression of iNOS and COX‐2.

Sarcanolides C-E: three new lindenane sesquiterpenoid dimers with anti-inflammatory activities from Sarcandra glabra.

Three new lindenane-type sesquiterpenoid dimers, sarcanolides C-E (1-3), were isolated from the roots of Sarcandra glabra. Sarcanolide C (1) possesses a unique decacyclic scaffold with an unusual orthoformate unit. The structures of 1-3 were determined through extensive spectroscopic analysis, while their absolute configurations were determined by comparison of calculated and experimental electronic circular dichroism (ECD) spectra. Compounds 1-3 were evaluated for their inhibitory activity against LPS-induced nitric oxide (NO) production in RAW264.7 macrophages. All the isolates displayed a moderate inhibitory effect against NO production with IC50 values in the range of 13.4-17.2 μM, comparable to that of the positive control L-NMMA.

One uncommon bis-sesquiterpenoid from Xisha soft coral Litophyton nigrum

One uncommon sesquiterpenoid dimer (1), a new nardosinane-type sesquiterpenoid (3), along with two known sesquiterpenoids (2 and 4) were isolated from soft coral Litophyton nigrum using a structure-oriented HR-MS/MS approach. The configurations of the isolates were determined by spectroscopic data analyses, including HR-ESI-MS, 1D/2D NMR, single crystal X-ray diffraction, and DP4+ statistical analyses. Compound 3 exhibited potent PTP1B inhibitory activity (IC50 = 10.67 ± 1.81 μg/mL) compared to the positive control.

Artematrovirenolides A—D and Artematrolides S—Z, Sesquiterpenoid Dimers with Cytotoxicity against Three Hepatoma Cell Lines from Artemisia atrovirens

Comprehensive SummaryInspired by the intriguing structures and remarkable activities of sesquiterpenoid dimers, 12 new sesquiterpenoid dimers, artematrovirenolides A—D (1—4) and artematrolides S—Z (8—12), were isolated from the EtOAc fraction of Artemisia atrovirens through a bioactivity‐guided approach. Their structures were elucidated by comprehensive spectroscopic data and absolute configuration was assigned based on single crystal X‐ray diffraction data and ECD calculations. Structurally, all compounds are presumably formed via [4+2] cycloaddition involving three connecting model. Compounds 1—4 are four novel hetero‐dimeric [4+2] Diels–Alder adducts dimerized from a rotundane‐type unit and a guaiane‐type monomer, and compounds 5—12 are eight new homo‐dimeric [4+2] adducts derived from two guaianolide moieties. A putative biosynthetic pathway for compounds 1—4 was also proposed. Compounds 4, 6, 7, and 10 demonstrated moderate cytotoxicity against HepG2, SMMC‐7721, and Huh7 cell lines with IC50 values ranging from 9.3 to 62.3 μmol/L. Interestingly, compounds 5 and 11 manifested cytotoxicity with IC50 values of 13.6 and 12.8 (HepG2), 18.5 and 13.1 (SMMC‐7721), and 16.5 and 19.4 μmol/L (Huh7), respectively, which were equivalent to the positive control, sorafenib. This investigation suggests that compounds 5 and 11 might be considered as potent antihepatoma candidates and deserve further structural modification and mechanism study.

Three new carabrane sesquiterpenoid derivatives from the whole plant of Carpesium abrotanoides L.

Dicarabrols B and C (1 and 2), two new carabrane sesquiterpenoid dimers, along with one new carabrane sesquiterpenoid (3) were isolated from the whole plant of Carpesium abrotanoides L. Their full structures were established by extensive analysis of HR-ESI-MS and NMR spectroscopic data, and time-dependent density functional theory (TDDFT) electronic circular dichroism (ECD) calculations. Dicarabrol B possesses a novel C30 skeleton featuring a methylene-tethered bridge between two sesquiterpene moieties, while dicarabrol C presents the unique linkage of a cyclopentane ring in the molecule. Dicarabrol C exhibited potent inhibitory effects on HL-60 cells with an IC50 value of 3.7 μmol·L-1.

Chemical characterization and multifunctional neuroprotective effects of sesquiterpenoid-enriched Inula britannica flowers extract

Dried flowers of Inula britannica commercially serve as pharmaceutical/nutraceutical herbs in the manufacture of medicinal products and functional tea that has been reported to possess extensive biological property. However, the neuroprotective constituents in I. britannica flowers are not known. In the current study, phytochemicals of sesquiterpenoid-enriched I. britannica flowers extract and their potential multifunctional neuroprotective effects were investigated. Nineteen structurally diverse sesquiterpenoids, including two new sesquiterpenoid dimers, namely, inubritanolides A and B (1, 2), and four new sesquiterpenoid monomers (3–6), namely, 1-O-acetyl-6-O-chloracetylbritannilactone (3), 6-methoxybritannilactone (4), 1-hydroxy-10β-methoxy-4αH-1,10-secoeudesma-5(6),11(13)-dien-12,8β-olide (5) and 1-hydroxy-4αH-1,10-secoeudesma-5(6),10(14),11(13)-trien-12,8β-olide (6), as well as 13 known congeners (7–19) were isolated from this source. The structures of compounds 1–6 were elucidated by 1D- and 2D- NMR and HR-ESI-MS data, and their absolute configurations were discerned by electronic circular dichroism (ECD) data analysis and single crystal X-ray diffraction. Interestingly, inubritannolide A (1) is a new type [4 + 2] Diels-Alder dimer featuring a hepta-membered cycloether skeleton. Most of the compounds showed potential multifunctional neuroprotective effects, including antioxidative, anti-neuroinflammatory, and microglial polarization properties. Specifically, 1 and 6 displayed slight strong neuroprotective potency against different types of neuronal cells mediated by various inducers including H2O2, 6-hydroxydopamine (6-OHDA), and lipopolysaccharide (LPS). Overall, this is the first report on multifunctional neuroprotective effects of sesquiterpenoid-enriched I. britannica flowers extract, which supports its potential pharmaceutical/nutraceutical application in neurodegenerative diseases.

Construction of alkyl-substituted 7-norbornenones through Diels−Alder cycloaddition of electron-deficient olefins and a cyclopentadienone derivative generated in situ

Dimeric sesquiterpenoids possessing densely substituted 7-norbornenone/7-norbornenol motifs pose a considerable challenge for chemical synthesis. From a strategic perspective, one could envision intermolecular Diels−Alder cycloaddition as a straightforward method for assembling alkyl-substituted 7-norbornenones. However, this approach is hindered by lability of the required dienes, namely alkyl-substituted cyclopentadienones. Here we report a one-pot protocol for construction of alkyl-substituted 7-norbornenones from electron-deficient olefins and a cyclopentenone derivative. DDQ was found to be an effective oxidant for generating a cyclopentadienone intermediate in situ from the enone. A series of sterically congested 7-norbornenone-containing polycyclic compounds were prepared by using this protocol.

Chemotaxonomic significance of lindenane sesquiterpenoid dimers and eudesmane sesquiterpenoids from Chloranthus henryi Hemsl. var. hupehensis (Pamp.) K. F. Wu

Seventeen known compounds were isolated from the 95% alcohol extract of the aerial parts of Chloranthus henryi Hemsl. var. hupehensis (Pamp.) K. F. Wu, including five lindenane sesquiterpenoid dimers (1–5) and twelve eudesmane sesquiterpenoids (6–17). In the present research, compounds 3 sarcaglabrin C, 6 neolitacumone C, 7ent-Atractylenolide III and 8 dehydrocarissone were reported from the Chloranthus genus for the first time, and compounds 1 spicachlorantin B, 2 chloramultilide C, 4 shizukaol B, 5 japonicone C, 9 6α-hydroxyeudesma-4(15),7(11),8(9)-triene-12,8-olide, 10ent-(3R)-3-hydroxyatractylenolide III, 11 8βH-hydroxyeudesma-4(14),7(11)-dien-12,8-olide, 12 lasianthuslactone A, 13 (5S,6R,8S,10R)-6-hydroxyeudesma-4(15),7(11)-diene-12,8-olide, 14 4β-hydroxy5α,8β(H)-eudesm-7(11)-en-8,12-olide, 15 4β,8β-dihydroxy-5α(H)-eudesm-7(11)-en-8,12-olide, 16 curcolonol and 17 1β, 8β-dihydroxyeudesm - 3,7(11)-dien-8α,12-olide were firstly isolated from the plant. Their structures were elucidated on the basis of extensive spectroscopic and chemical analyses. Moreover, the chemotaxonomic significance of the isolated compounds is discussed.

Linderanoids A–O, dimeric sesquiterpenoids from the roots of Lindera aggregata (Sims) Kosterm

Fifteen undescribed dimeric sesquiterpenoids, linderanoids A–O along with one known lindenane-type sesquiterpenoid dimer, lindenaneolide F, were isolated and identified from the roots of Lindera aggregata. Their structures and absolute configurations were elucidated using spectroscopy and electronic circular dichroism (ECD) analysis. All the isolated compounds were screened for transforming growth factor (TGF)-β inhibitory activity, and the results showed that linderanoid E significantly inhibited the TGF- β induced smad2 phosphorylation at a concentration of 25 μM.

Research progress on chemical constituents from Chloranthus plants and their biological activities

The genus Chloranthus has 13 species and 5 varieties in China, which can be found in the southwest and northeast regions. Phytochemical studies on Chloranthus plants have reported a large amount of terpenoids, such as diterpenoids, sesquiterpenoids, and sesquiterpenoid dimers. Their anti-inflammation, anti-tumor, antifungal, antivirus, and neuroprotection activities have been confirmed by previous pharmacological research. Herein, research on the chemical constituents from Chloranthus plants and their biological activities over the five years was summarized to provide scientific basis for the further development and utilization of Chloranthus plants.

Shotgun chemome characterization of Artemisia rupestris L. Using direct infusion-MS/MSALL

In comparison of liquid chromatography, direct infusion is a superior choice to achieve high-throughput measurements. The specificity and selectivity of tandem mass spectrometry (MS/MS) actually result in a so-called MS separation potential when chemical characterization of herbal medicines. Here, a MS/MSALL program was introduced to promote DI–MS/MS to be an eligible tool for shotgun chemome characterization of Artemisia rupestris L. that is currently drawing worldwide interests because of the promising antiviral activity. After MS1 spectral acquisition for the crude extract, the gas phase fractionation concept enabled the precursor ion cohort sequentially entered the collision cell with a stepped unit mass window (step-size as 1 Da) to generate MS2 spectra, thus generating a unique property integrating the advantages of both data-dependent and data-independent acquisition manners. Even though being free of chromatographic separation, spectrometric separations were accomplished for by MS/MSALL program unless the components shared identical nominal molecular weights. Extensive efforts such as the correlations of MS1 signals with MS2 spectra, structural annotations of fragment ion species, information retrieval in some accessible databases, and referring to the literature data, were devoted for chemical characterization, and as a result, 44 compounds, in total, were structurally identified from 50% aqueous methanol exact of A. rupestris, including 8 caffeoyl quinic acid derivatives, 13 flavonoids, 15 monomeric and dimeric sesquiterpenoids, 4 fatty acids, 2 penylpropanoids, along with 2 other compounds. However, isomers were assigned as an isomeric mixture because their precursor ions always co-existed in a single mass window. Above all, DI–MS/MSALL provides an alternative tool for chemome characterization of herbal medicines, in particular when the great measurement workload for a large sample cohort, attributing to the high-throughput advantage.

Horienoids A and B, Two Heterocoupled Sesquiterpenoid Dimers from Hedyosmum orientale.

Two eudesmane-guaiane/lindenane heterocoupled sesquiterpenoid dimers, horienoids A (1) and B (2) with new carbon skeletons, from Hedyosmum orientale were characterized by a combined method. Compound 1 featured a unique 2,10-dioxabicyclo[6.2.1]undecane core moiety with an anti-Bredt bridgehead double bond. Their biogenetic pathways were proposed to involve Diels-Alder and cascade rearrangement reactions as the key steps. Compound 2 exhibited a potent anti-inflammatory effect on LPS-induced BV-2 microglial cells.

Linderaggrenolides A-N, Oxygen-Conjugated Sesquiterpenoid Dimers from the Roots of Lindera aggregata.

Linderaggrenolides A–N (1–14), 14 new lindenane sesquiterpenoid dimers with oxygen bridges were isolated from the roots of Lindera aggregata. Their structures were elucidated on the basis of comprehensive spectroscopic data analysis, with the absolute configurations established by empirical approaches, electronic circular dichroism calculations, and X-ray crystallography. Compounds 8 and 9 were found to exhibit significant transforming growth factor-β inhibitory activity, with IC50 values of 25.91 and 21.52 μM, respectively.

Shizukaol A exerts anti-inflammatory effect by regulating HMGB1/Nrf2/HO-1 pathway

BackgroundSarcandra glabra (Thunb.) Makino (Chloranthaceae) has a long history of being used in Traditional Chinese medicines (TCMs) to treat painful joints, fractures, arthritis, and other diseases caused by inflammation. It has been reported that lindenane-type sesquiterpenoid dimers are main anti-inflammatory ingredient of S. glabra. Meanwhile, shizukaol A, the precursor of these sesquiterpene dimers, possesses a good inhibitory effect on nitric oxide (NO) in our previous study. But its anti-inflammatory mechanism is still unclear. PurposeThis study aimed to explore the possible anti-inflammatory mechanism and potential targets of shizukaol A in lipopolysaccharide (LPS)-induced RAW 264.7 cells. MethodsThe release of NO and inflammatory cytokines in LPS-stimulated RAW 264.7 cells were measured by Griess reagent and ELISA, respectively. The relevant proteins including inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), nuclear factor kappa B (NF-κB) p65, High mobility group box 1 (HMGB1) were detected by western blot. Nuclear translocation of p65, HMGB1 and nuclear factor E2-related factor 2 (Nrf2) were examined by immunofluorescence. The level of reactive oxygen species (ROS) was tested by flow cytometry. The target of shizukaol A was investigated by molecular docking and Drug Affinity Responsive Target Stability (DARTS). ResultsShizukaol A had a good inhibitory effect on NO with half maximal inhibitory concentration (IC50) of 13.79 ± 1.11 μM. Shizukaol A could down-regulate the expression of iNOS and COX-2. Further studies demonstrated that shizukaol A can significantly inhibit phosphorylation and nuclear translocation of NF-κB. Meanwhile, shizukaol A decreased the level of ROS and enhanced the expression of heme oxygenase-1 (HO-1) and NAD(P)H: quinone oxidoreductase 1 (NQO1). Furthermore, shizukaol A up-regulated the expression of Nrf2 and its nuclear translocation. More importantly, shizukaol A could inhibit activation of HMGB1 by targeting HMGB1. ConclusionShizukaol A inhibited inflammation by targeting HMGB1 to regulate the Nrf2/HO-1 signaling pathway. Thus, shizukaol A may be an attractive therapeutic candidate for inflammatory diseases.

Medicinal Inula Species: Phytochemistry, Biosynthesis, and Bioactivities.

As a genus of the Asteraceae, Inula is widely distributed all over the world, and several of them are being used in traditional medicines. A number of metabolites were isolated from Inula species, and some of these have shown to possess ranges of pharmacological activities. The genus Inula contains abundant sesquiterpenoids, such as eudesmanes, xanthanes, and sesquiterpenoid dimers and trimers. In addition, other types of terpenoids, flavonoids, and lignins also exist in the genus Inula. Since 2010, more than 300 new secondary metabolites, including several known natural products that were isolated for the first time from the genus Inula. Most of them exhibited potential bioactivities in various diseases. The review aimed to summarize the advance of recent researches (2010-2020) on phytochemical constituents, biosynthesis, and pharmacological properties of the genus Inula for providing a scientific basis and supporting its application and exploitation for new drug development.

Nine sesquiterpenoid dimers with four unprecedented types of carbon skeleton from Chloranthus henryi var. hupehensis

Chlorahupetones A–I (1–9), nine sesquiterpenoid dimers, were isolated from Chloranthus henryi var. hupehensis.

Trimeric and dimeric sesquiterpenoids from Artemisia atrovirens and their cytotoxicities

Two sesquiterpenoid trimers and two sesquiterpenoid dimers possessing unprecedented scaffolds with a methylene-bridged connection were identified from Artemisia atrovirens. Compound 3 showed obvious cytotoxicity against HepG2 and Huh7 cell lines.

Resistance to Some But Not Other Dimeric Lindenane Sesquiterpenoid Esters Is Mediated by Mutations in a Plasmodium falciparum Esterase.

Unique lindenane sesquiterpenoid dimers from Chloranthecae spp. were recently identified with promising in vitro antiplasmodial activity and potentially novel mechanisms of action. To gain mechanistic insights to this new class of natural products, in vitro selection of Plasmodium falciparum resistance to the most active antiplasmodial compound, chlorajaponilide C, was explored. In all selected resistant clones, the half-maximal effective concentration (EC50) of chlorajaponilide C increased >250-fold, and whole genome sequencing revealed mutations in the recently discovered P.falciparum prodrug activation and resistance esterase (PfPARE). Chlorajaponilide C was highly potent (mean EC50 = 1.6 nM, n = 34) against fresh Ugandan P.falciparum isolates. The analysis of the structure-resistance relationships revealed that in vitro potency of a subset of lindenane sesquiterpenoid dimers was not mediated by PfPARE mutations. Thus, chlorajaponilide C, but not some related compounds, required parasite esterase activity for in vitro potency, and those compounds serve as the foundation for development of potent and selective antimalarials.

Chemophenetics of Azorean Leontodon taxa (Cichorieae, Asteraceae)

The genera Leontodon s.str. and Hedypnois are so far the only known sources of hydroxyhypocretenolides, a rare subclass of guaianolide type sesquiterpene lactones. In this study the three endemic species from the Azorean Archipelago, L. filii, L. hochstetteri, and L. rigens, were analyzed together with L. hispidus and L. × grassiorum, a hybrid originating from L. hispidus and L. hochstetteri. Flowering heads were analyzed by UHPLC-DAD-MS with regards to their phenolics' profiles, establishing qualitatively identical profiles for all taxa. The following phenolics were detected in flowering heads of all investigated taxa: caffeoyltartaric acid, cichoric acid, chlorogenic acid, 3,5-di-O-caffeoylquinic acid, luteolin, luteolin 7-O-β-d-glucopyranoside, luteolin 4′-O-β-d-glucopyranoside, and luteolin 7-O-β-d-glucuronide.In UHPLC-DAD-MS analyses of the rhizomes, no flavonoids were detected. In rhizomes, caffeoyltartaric acid was only detected in L. hispidus. However, in addition to caffeoylquinic acid derivatives already found in the flowering heads, 1,5-di-O-caffeoylquinic acid, 3,4-di-O-caffeoylquinic acid, and 4,5-di-O-caffeoylquinic acid were detected in rhizomes of all investigated taxa.The chemophenetically most interesting group of hydroxyhypocretenolides was detected in rhizomes of all investigated taxa. 11,13β-Dihydro-14-dihydroxyhypocretenolide was detected in L. filii and L. hochstetteri, while 11,13β-dihydro-14-hydroxyhypocretenolide-β-d-glucopyranoside was present in all Azorean taxa. 1,10-Epoxy-14-hydroxyhypocretenolide-β-d-glucopyranoside and 1,10-epoxy-14-hydroxyhypocretenolide-β-d-glucopyranoside-6′-O-p-hydroxyphenylacetic acid ester were restricted to the Azorean taxa and the hybrid L. × grassiorum, while the dimeric sesquiterpenoid 14-hydroxyhypocretenolide-β-d-glucopyranoside-4′,14″-hydroxyhypocretenoate ester was restricted to L. hispidus and L. × grassiorum.

Undescribed phenylpropanoid and a dimeric sesquiterpenoid possessing a rare cyclobutane ring from Tinospora sinensis

A rare dimeric sesquiterpenoid (tinosposinoside, 1) and a phenylpropanoid (cordifolioside C, 2), two undescribed metabolites, were isolated from the methanolic extract of the stems of Tinospora sinensis together with thirteen known compounds. This is the second example of a sesquiterpene dimer where two monomers linked together through a cyclobutane ring, possibly generated through [2 + 2] cycloaddition. The structures of 1 and 2 were elucidated by NMR and mass techniques.