Sesquiterpenoid Dimers Research Articles

Sesquiterpenes from the leaves of Artemisia argyi and evaluation of their in vitro anti-inflammatory activities

Two unreported sesquiterpenoids, 7-en-13-hytanaphallin (1) and 8´-en-achillinin C (2) along with two known sesquiterpenoid dimers were obtained from chloroform parts in the leaves of Artemisia argyi Lévl. et Vant, belonging to Asteraceae family. The planar structures and absolute configurations of two new compounds were characterized by HR-ESI-MS, IR, 1D and 2D NMR, and electronic circular dichroism analyses. Two known sesquiterpenoids, argyinolide O (3) and (+)-8-acetylarteminolide (4), exhibited potent activities against NO production from LPS-induced RAW264.7 cells with IC50 values of 3.6 and 9.8 μM, respectively.

Structurally diversified sesquiterpenoids from Chloranthus henryi and their neuroprotective activities on H2O2 damaged PC12 cells

Fifteen undescribed sesquiterpenoid monomers, including six pairs of sesquiterpenoid enantiomers (1a/1b-3a/3b and 5a/5b-7a/7b) and three analogues (4, 8, and 9), together with two known sesquiterpenoid dimers (10 and 11) were isolated from the whole plant of Chloranthus henryi Hemsl. Their structures were characterized by spectroscopic data analysis, ECD calculations, and single crystal X-Ray diffractions. Compounds 1a and 1b were highly aromatic cadinane-type sesquiterpenoids. At a concentration of 10μM, compounds 8, 10, and 11 exhibited potent neuroprotective activity against H2O2-induced PC12cell damage. Compounds 10 and 11 significantly decreased the level of ROS. In addition, compound 11 increased the levels of p-AMPK, p-SIRT1, and SIRT3 in the H2O2-induced PC12cell damage via activated the AMPK/SIRT signaling pathway.

Immunomodulatory of sesquiterpenoids and sesquiterpenoid dimers-based toll-like receptor 4 (TLR4) from Dysoxylum parasiticum stem bark

In recent decades, the interest in natural products with immunomodulatory properties has increased due to their therapeutic potential. These products have a wider range of pharmacological activities and demonstrate lower toxicity levels when compared to their synthetic counterparts. Therefore, this study aimed to investigate the immunomodulatory effects of sesquiterpenoids (SQs) and sesquiterpenoid dimers (SQDs) isolated from Dysoxylum parasiticum (Osbeck) Kosterm. stem bark on human and murine cells, particularly focusing on toll-like receptor 4 (TLR4). Utilizing the secreted alkaline phosphatase (SEAP) assay on engineered human and murine TLR4 of HEK-Blue cells, antagonist TLR4 compounds were identified, including SQs 6, 9, and 10, as well as SQDs 17 and 22. The results showed that 10-hydroxyl-15-oxo-α-cadinol (9) had a potent ability to reduce TLR4 activation induced by LPS stimulation, with minimal toxicity observed in both human and murine cells. The SEAP assay also revealed diverse immune regulatory effects for the same ligand. For instance, SQs 12, 14, and 16 transitioned from antagonism on human to murine TLR4. The SQs (4, 7, 11, and 15) and SQDs (18–20) offered partial antagonist effect exclusively on murine TLR4. Furthermore, these selected SQs and SQDs were assessed for their influence on the production of proinflammatory cytokines TNF-α, IL-1α, IL-1β, and IL-6 of the NF-κB signaling pathway in human and murine macrophage cell lines, showing a dose-dependent manner. Additionally, a brief discussion on the structure-activity relationship was presented.

Unusual cadinane-involved sesquiterpenoid dimers from Artemisia annua and their antihepatoma effect

Artemisia annua L. (“Qinghao” in Chinese) is a famous traditional Chinese medicinal herb and has been used to treat malaria and various tumors. Our preliminary screening indicated that the EtOAc extract of A. annua manifested activity against HepG2, Huh7, and SK-Hep-1 cell lines with inhibitory ratios of 53.2%, 52.1%, and 59.6% at 200 μg/mL, respectively. Bioassay-guided isolation of A. annua afforded 14 unusual cadinane-involved sesquiterpenoid dimers, artemannuins A‒N (1–14), of which the structures were elucidated by extensive spectral analyses, ECD calculations, and single-crystal X-ray diffraction. Structurally, these compounds were classified into five different types based on the coupled modes of two monomeric sesquiterpenoids. Among them, compounds 1–9 represented the first examples of sesquiterpenoid dimers formed via the C-3‒C-3′ single bond of two 5(4 → 3)-abeo-cadinane sesquiterpenoid monomers, while compounds 13 and 14 were dimers fused by cadinane and humulane sesquiterpenoids via an ester bond. Methylated derivatives of 1, 4, 6, and 8 showed antihepatoma activity against HepG2, Huh7, and SK-Hep-1 cell lines with IC50 values ranging from 30.5 to 57.2 μM.

Sarcanoids A and B, two new lindenane-type sesquiterpenoid dimers from the aerial parts of Sarcandra glabra

Sarcanoids A and B (1 and 2), two new lindenane-type sesquiterpenoid dimers with a γ-hydroxysenecioate moiety at C-15′, were isolated from the ethyl acetate extract of Sarcandra glabra. The structures were elucidated by extensive analysis of spectroscopic data, and their absolute configurations were determined by single-crystal X-ray crystallography. Compounds 1 and 2 showed moderate inhibitory activities on the nitric oxide (NO) production induced by lipopolysaccharide (LPS) in RAW264.7 macrophages.

Anti-inflammatory lindenane sesquiterpenoid dimers from the roots of Chloranthus holostegius var. trichoneurus.

Two new lindenane-type sesquiterpenoid dimers, chlotrichenes C and D (1 and 2) together with five known lindenane-type sesquiterpenoid dimers (3-7) were isolated from the roots of Chloranthus holostegius var. trichoneurus, a famous natural medicine named as "Sikuaiwa" for subduing swellings and relieving pain. The structures including absolute configuration were elucidated by their 1D and 2D NMR, HRESIMS, and ECD data. Compounds 1 and 2 were classical [4 + 2] lindenane-type sesquiterpenoid dimers that differed from known analogs in oxidation profile, side chain profile, and double bond position. The new isolates and compound 3 exhibited significant inhibitory activity on IL-1β production (IC50: 1-15μM) in LPS-induced THP-1 cells and other compounds exhibited inhibitory activity on NO production in LPS-induced RAW 264.7 cells (IC50: 24-33μM).

Discovery of sesquiterpenoids from the roots of Chloranthus henryi Hemsl. var. hupehensis (Pamp.) K. F. Wu and their anti-inflammatory activity by IKBα/NF-κB p65 signaling pathway suppression

Phytochemical analysis of Chloranthus henryi var. hupehensis roots led to the identification of a new eudesmane sesquiterpenoid dimer, 18 new sesquiterpenoids, and three known sesquiterpenoids. Among the isolates, 1 was a rare sesquiterpenoid dimer that is assembled by a unique oxygen bridge (C11-O-C8′) of two highly rearranged eudesmane-type sesquiterpenes with the undescribed C16 carbon framework. (+)-2 and (−)-2 were a pair of new skeleton dinorsesquiterpenoids with a remarkable 6/6/5 tricyclic ring framework including one γ-lactone ring and the bicyclo[3.3.1]nonane core. Their structures were elucidated using spectroscopic data, single-crystal X-ray diffraction analysis, and quantum chemical computations. In the LPS-induced BV-2 microglial cell model, 17 suppressed IL-1β and TNF-α expression with EC50 values of 6.81 and 2.76 µM, respectively, indicating its excellent efficacy in inhibiting inflammatory factors production in a dose dependent manner and without cytotoxicity. In subsequent mechanism studies, compounds 3, 16, and 17 could reduce IL-1β and TNF-α production by inhibiting IKBα/p65 pathway activation.

Artemyriantholides A–K, guaiane-type sesquiterpenoid dimers from Artemisia myriantha var. pleiocephala and their antihepatoma activity

Artemyriantholides A−K (1−11) as well as 14 known compounds (12−25) were isolated from Artemisia myriantha var. pleiocephala (Asteraceae). The structures and absolute configuration of compounds 2 and 8−9 were confirmed by the single crystal X-ray diffraction analyses, and the others were elucidated by MS, NMR spectral data and electronic circular dichroism calculations. All compounds were chemically characterized as guaiane-type sesquiterpenoid dimers (GSDs). Compound 1 was the first example of the GSD fused via C-3/C-11′ and C-5/C-13′ linkages, and compounds 2 and 5 were rare GSDs containing chlorine atoms. Eleven compounds showed obvious inhibitory activity in HepG2, Huh7 and SK-Hep-1 cell lines by antihepatoma assay to provide the IC50 values ranging from 7.9 to 67.1 μM. Importantly, compounds 5 and 8 exhibited the best inhibitory activity with IC50 values of 14.2 and 18.8 (HepG2), 9.0 and 11.5 (Huh7), and 8.8 and 11.3 μM (SK-Hep-1), respectively. The target of compound 5 was predicted to be MAP2K2 by a computational prediction model. The interaction between compound 5 and MAP2K2 was conducted to give docking score of −9.0 kcal/mol by molecular docking and provide KD value of 43.7 μM by Surface Plasmon Resonance assay.

Synthesis and antihepatoma activity of guaianolide dimers derived from lavandiolide I

Guaianolide dimers represent a unique class of natural products with anticancer activities, but their low content in plants has limited in-depth pharmacological studies. Lavandiolide I is a guaianolide dimer isolated from Artemisia species, and had been synthesized on a ten-gram scale in four steps with 60 % overall yield, which showed potent antihepatoma activity on the HepG2, Huh7, and SK-Hep-1 cell lines with IC50 values of 12.1, 18.4, and 17.6 µM, respectively. To explore more active dimers, 33 lavandiolide I derivatives were designed, synthesized, and evaluated for their inhibitory activity on human hepatoma cell lines. Among them, 10 derivatives were more active than lavandiolide I and sorafenib on the three cell lines. The primary structure–activity relationship concluded that the introduction of aldehyde, ester, azide, amide, carbamate and urea functional groups at C-14′ of the guaianolide dimer significantly enhanced the antihepatoma activity. Among these compounds, derivatives 25, 27, and 33 enhanced antihepatoma activity more than 1.2–5.8 folds than that of lavandiolide I, and demonstrated low toxicity to the human liver cell lines (THLE-2) and good safety profiles with selective index ranging from 1.3 to 3.4, while lavandiolide I was more toxic to THLE-2 cells. This work provides new insights into enhancing the antihepatoma efficacy and reducing the toxicity of sesquiterpenoid dimers.

Artemordins A—S, Cadinane‐Type Sesquiterpenoid Dimers from Artemisia ordosica and Their Antihepatoma Activities

Comprehensive SummaryNineteen new cadinane‐involving sesquiterpenoid dimers, artemordins A—S (1—19), together with 13 known SDs (20—32) were isolated from Artemisia ordosica. Their structures and absolute configurations were established by comprehensive spectral analyses, X‐ray single crystal diffraction, theoretical ECD, and NMR calculations. Chemically, artemordins A—F (1—6) were the first examples of two cadinane units constructed by unprecedented C‐3−C‐15′ or C‐3−C‐13′ single bond with an oxido‐rearranged 6/5/6/6 fused ring system; artemordins G—K (7—11) were biogenetically connected by [4 + 2] cycloaddition reaction and artemordins G—J (7—10) possessed a novel 5/6/6/6/6/6/5‐heptacyclic fused ring system. Artemordins L—S (12—19) were formed by esterification, which involved three different types of sesquiterpenoids. Antihepatoma assay suggested that the most active compounds, artemordins B and H (2 and 8), exhibited inhibitory activities on three hepatoma cell lines with IC50 values of 26.9 and 25.1 μmol/L (HepG2), 29.5 and 18.3 μmol/L (Huh7), 19.7 and 15.7 μmol/L (SK‐Hep‐1).

Chlorajaponins A—Q, Lindenane‐Related Sesquiterpenoid Dimers from Chloranthus japonicus and Their Biological Activities

Comprehensive SummarySeventeen undescribed lindenane‐related sesquiterpenoid dimers, chlorajaponins A—Q (1—17), and 13 reported analogs (18—30) were isolated from Chloranthus japonicus Sieb. Compound 1 possesses an unprecedented 3/5/7/5/5/6/5/3 fused octacyclic scaffold, featuring a 6(5→4)‐abeo‐lindenane monomer, while 2 exhibits a 3/5/6/6/5/6/5/3 fused octacyclic scaffold. Their structures were determined through a combination of spectroscopic analyses and X‐ray crystallography. Compounds 1, 2, and 18 demonstrated significant inhibitory effects on lipid accumulation and effectively reduced the levels of triglycerides and total cholesterol, as well as the levels of aspartate aminotransferase and alanine aminotransferase in a HepG2 cell model. In addition, compounds 1, 2, and 18 significantly suppressed the protein expression of the fatty acid synthase (FASN) and the sterol regulatory element‐binding protein 1 (SREBP1). Moreover, the anti‐inflammatory assay showed that compounds 19—22 and 25 inhibited the NO production induced by lipopolysaccharide in RAW 264.7 macrophages with IC50 values of 7.89 ± 0.44, 6.25 ± 0.46, 2.98 ± 0.29, 10.77 ± 0.60, and 3.60 ± 0.28 μmol/L.

Recent advances of sesquiterpenoid dimers from Compositae: distribution, chemistry and biological activities

Recent advances of sesquiterpenoid dimers from Compositae: distribution, chemistry and biological activities

Discovery and bioinspired total syntheses of unprecedented sesquiterpenoid dimers unveiled bifurcating [4 + 2] cycloaddition and target differentiation of enantiomers.

[4 + 2] cycloaddition has led to diverse polycyclic chiral architectures, serving as novel sources for organic synthesis and biological exploration. Here, an unprecedented class of cadinane sesquiterpene [4 + 2] dimers, henryinins A-E (1-5), with a unique 6/6/6/6/6-fused pentacyclic system, were isolated from Schisandra henryi. The divergent total syntheses of compounds 1-5 and their enantiomers (6-10) were concisely accomplished in eight linear steps using a protection-free approach. Mechanistic studies illustrated the origin of selectivity in the key [4 + 2] cycloaddition as well as the inhibition of reaction pathway bifurcation via desymmetrization. The chemical proteomics results showed that a pair of enantiomers shared common targets (PRDX5 C100 and BLMH C73) and had unique targets (USP45 C588 for 4 and COG7 C419 for 9). This work provides experimental evidence for the discovery of unprecedented cadinane dimers from selective Diels-Alder reaction and a powerful strategy to explore the biological properties of natural products.

Identification of diverse sesquiterpenoids with anti-fibrotic potential from Inula japonica Thunb.

In the chemical investigation of Inula japonica, a total of 29 sesquiterpenoids (1–29) were obtained, including pseudoguaine-, xanthane-, eudesmane-, and 1,10-secoeudesmane-type compounds, as well as their dimers. Among them, six new dimeric sesquiterpenoids, bisinulains A–F (1–5, 7), characterized by a [4 + 2] biogenetic pathway between different sesquiterpenoid monomers were identified. Additionally, three new monomers named inulaterins A-C (13, 18 and 21) were discovered. The structures of these compounds were determined through analysis of spectroscopic data, X-ray crystallographic data, and ECD experiments. To assess their potential anti-inflammatory activities, the sesquiterpenoid dimers were tested for their ability to inhibit NO production in LPS-stimulated RAW 264.7 cells. Furthermore, the compounds that exhibited anti-inflammatory effects underwent evaluation for their anti-fibrotic potential using a TGF-β-induced epithelial-mesenchymal transition model in A549 cells. As a result, bisinulain B (2) was screened out to significantly inhibit the production of cytokines involved in pulmonary fibrosis such as NO, α-SMA, collagen I and fibronectin.

Plant-microbial interactions inspired the discovery of novel sesquiterpenoid dimeric skeletons of hidden natural products from Hibiscus tiliaceus

Hidden natural products are representative of defensive strategies produced in vivo in diseased plants, a process that is induced by the plant immune system. The first transcriptome library of uninfected and pathogen infected Hibiscus tiliaceus stems was constructed by transcriptome sequencing technology, genes related to cadinene-type sesquiterpenoid biosynthesis were screened and combined with ultra-performance liquid chromatography-quadrupole-time of flight mass spectrometry (UPLC-QTOF-MS) analysis data, which indicated pathological tissue had potential to produce novel carbon skeletons of cadinane sesquiterpenoid dimers. Successfully, two cadinane-derived sesquiterpenoid dimers with unprecedented carbon skeletons, hibisceusanols A (1) and B (2) were isolated for the first time from the stems of H. tiliaceus induced by plant-microbial interactions. Their structures and absolute configurations were unambiguously established by spectroscopy, advanced chemistry development (ACD) and electronic circular dichroism (ECD) methods. Compounds 1 and 2 exhibited significant antitumor activity in vitro with half maximal inhibitory concentration (IC50) values of 2.3–7.2 µmol/L. The anticancer effect was generated via the induction of HepG2 cell apoptosis by inhibiting the phosphatidylinositol 3-kinase (PI3K) pathway.

Lindenane sesquiterpenoid dimers from Chloranthus japonicus improve LDL uptake by regulating PCSK9 and LDLR

UPLC-TOF-MS/MDF directed phytochemical research of Chloranthus japonicus led to the isolation of 46 lindenane sesquiterpenoid dimers, which included 13 new analogs. Their structures with absolute configurations were elucidated by analysis of spectroscopic data. Fourteen compounds with ester chains significantly decreased PCSK9 protein level in medium of HepG2 cells, especially for compounds 14 and 29 (5 µM) with inhibition rates of 69.0% and 72.8%, respectively. Compound 14 in HepG2 cells was evaluated via DiI-LDL uptake assays and found to increase LDL uptake by upregulating LDLR mRNA and protein level. Meanwhile, 14 decreased the secretion of PCSK9 protein in medium and downregulated intracellular PCSK9 protein and mRNA level. The discovery of these natural small molecule compounds provides a novel structure basis for design PCSK9 regulators, making them a promising lead for development of new lipid-lowering agents.

Artemongolins A-K, undescribed germacrane-guaiane sesquiterpenoid dimers from Artemisia mongolica and their antihepatoma activities.

Artemongolins A-K (1-11), which are undescribed sesquiterpenoid dimers, were obtained from Artemisia mongolica and characterized through comprehensive spectral data, including HRESIMS, IR, 1D and 2D NMR, and ECD calculations. The absolute configurations of compounds 1, 4, and 7 were undoubtedly determined by a single-crystal X-ray crystallography. Artemongolins A-K (1-11) featured a rare 5/7/5/5/5/10 hexacyclic system composed of a germacrene and a guaianolide by a fused 2-oxaspiro[4,4]nonane-1-one ring system. Antihepatoma evaluation against three human hepatoma cell lines demonstrated that the most active compounds 5 and 6 displayed inhibitory activity with IC50 values of 88.6 and 57.0 (HepG2), 59.1 and 26.4 (Huh7), and 67.5 and 32.5 (SK-Hep-1) µM, respectively.

Lindenane sesquiterpenoid dimers from Chloranthus holostegius with anti-neuroinflammatory activities in BV-2 microglia

Fifteen undescribed lindenane-type sesquiterpenoid dimers, designated chloranholides F−T (1−15), together with twenty-five known analogs (16−40), were isolated from the whole plants of Chloranthus holostegius. The isolate structures were elucidated by analysis of spectroscopic data and chemical methods, and their absolute configurations were determined by X-ray crystallography and electronic circular dichroism spectra. In anti-neuroinflammatory assays, all isolates were evaluated by examination of their inhibitory effect on nitric oxide (NO) in LPS-stimulated BV-2 cells, and the results showed that 21−24, 26, 30, 32 and 36 significantly inhibited the production of the inflammatory mediator NO, with IC50 values ranging from 3.18 to 11.46 μM, which was better than that of quercetin. Structure-activity relationship analysis revealed that two essential functional groups played an indispensable role in the anti-inflammatory effects. Moreover, 22 and 24 inhibited the LPS-induced upregulation of iNOS and COX-2 enzymes in BV-2 microglia at the protein level.

Artemiprincepsolides A—F, Novel Germacrane‐guaiane and Eudesmane‐guaiane Sesquiterpenoid Dimers from Artemisia princeps and Their Antihepatoma Activity

Comprehensive SummaryArtemiprincepsolides A—F (1—6) were isolated from Artemisia princeps guided by bioactivity and elucidated by comprehensive spectral data and ECD calculation. Compounds 1—3 represented the first connecting model of germacrane‐guaiane hetero‐dimeric adducts, and compounds 4—6 were eudesmane‐guaiane hetero‐coupled sesquiterpenoid dimers, meanwhile, all these were presumably formed by Diels‐Alder cycloaddition. Compounds 1—6 were evaluated for their hepatomatic cytotoxicity on three hepatoma cell lines, and demonstrated cytotoxicity with IC50 values in the range of 5.0—67.3 μmol/L. Interestingly, compound 1 manifested significant cytotoxicity against HepG2, Huh7, and SK‐Hep‐1 cells with IC50 values of 9.9, 9.2, and 5.0 μmol/L, which were almost equivalent to the positive control, sorafenib. Flow cytometry data and Western blot assays revealed the most active compound 1 dose‐dependently inhibited cell migration and invasion, and significantly induced HepG2 cells arrest in G2/M phase by downregulating proteins pcdc2 and upregulating the level of protein CyclinB1; and induced apoptosis by downregulating of Bcl‐2 expression and upregulating Bax level.

Building Block Extractor: An MS/MS Data Mining Tool for Targeted Discovery of Natural Products with Specified Features.

The utilization of a building-block-based molecular network is an efficient approach to investigate the unknown chemical space of natural products. However, structure-based automated MS/MS data mining remains challenging. This study introduces building block extractor, a user-friendly MS/MS data mining program that automatically extracts user-defined specified features. In addition to the characteristic product ions and neutral losses, this program integrates the abundance of the product ions and sequential neutral loss features as building blocks for the first time. The discovery of nine undescribed sesquiterpenoid dimers from Artemisia heptapotamica highlights the power of this tool. One of these dimers, artemiheptolide I (9), exhibited in vitro inhibition of influenza A/Hongkong/8/68 (H3N2) with an IC50 of 8.01 ± 6.19 μM. Furthermore, two known guaianolide derivatives (16 and 17) possessed remarkable antiviral activity against influenza A/Puerto Rico/8/1934 H1N1, H3N2, and influenza B/Lee/40 with IC50 values ranging from 3.46 to 11.77 μM. In addition to the efficient discovery of novel natural products, this strategy can be generally applied to grab derivatives with specific fragments and enhance the annotation power of LC-MS/MS analysis.