Eudesmane Sesquiterpenoids Research Articles

Penijanacoranes A—F, Acorane‐Type Sesquiterpenes from a Deep Sea‐Derived Fungus Penicillium janthinellumSH0301

Comprehensive SummarySix new acorane‐type sesquiterpenes, named penijanacoranes A—F (1—6), as well as one known eudesmane sesquiterpenoid 1α,6β,11‐eudesm‐triol (7) have been isolated from a deep‐sea‐derived fungus Penicillium janthinellum SH0301. Their structures and absolute configurations were established by the comprehensive spectroscopic analysis, TDDFT‐ECD calculations, and X‐ray diffraction. Penijanacorane A (1) was identified as a rare acorane‐type sesquiterpene lactone featuring a novel 6/5/6 tricyclic system, while penijanacoranes E and F (5 and 6) represented undescribed examples of nor‐acorane sesquiterpenes at C‐1. Penijanacorane C (3) exhibited significant inhibitory activity against LPS‐induced NO production in Raw264.7 macrophages with an IC50 value of 6.23 μM, which was more potent than that of positive control dexamethasone (IC50 = 11.49 μM). This study expanded the chemical diversity of acorane‐type sesquiterpenoids and revealed that compound 3 was a potential molecule for anti‐inflammatory agents.

Dobinin K Displays Antiplasmodial Activity through Disruption of Plasmodium falciparum Mitochondria and Generation of Reactive Oxygen Species.

Dobinin K is a novel eudesmane sesquiterpenoids compound isolated from the root of Dobinea delavayi and displays potential antiplasmodial activity in vivo. Here, we evaluate the antiplasmodial activity of dobinin K in vitro and study its acting mechanism. The antiplasmodial activity of dobinin K in vitro was evaluated by concentration-, time-dependent, and stage-specific parasite inhibition assay. The potential target of dobinin K on Plasmodium falciparum was predicted by transcriptome analysis. Apoptosis of P. falciparum was detected by Giemsa, Hoechst 33258, and TUNEL staining assay. The reactive oxygen species (ROS) level, oxygen consumption, and mitochondrial membrane potential of P. falciparum were assessed by DCFH-DA, R01, and JC-1 fluorescent dye, respectively. The effect of dobinin K on the mitochondrial electron transport chain (ETC) was investigated by enzyme activity analysis and the binding abilities of dobinin K with different enzymes were learned by molecular docking. Dobinin K inhibited the growth of P. falciparum in a concentration-, time-dependent, and stage-specific manner. The predicted mechanism of dobinin K was related to the redox system of P. falciparum. Dobinin K increased intracellular ROS levels of P. falciparum and induced their apoptosis. After dobinin K treatment, P. falciparum mitochondria lost their function, which was presented as decreased oxygen consumption and depolarization of the membrane potential. Among five dehydrogenases in P. falciparum ETC, dobinin K displayed the best inhibitory power on NDH2 activity. Our findings indicate that the antiplasmodial effect of dobinin K in vitro is mediated by the enhancement of the ROS level in P. falciparum and the disruption of its mitochondrial function.

Novel Sesquiterpenoids with Renoprotective Activities from the Fruits of Alpinae oxyphylla as Potent TGF-β1/Smads Phosphorylation Inhibitors.

The fruit of Alpinia oxyphylla Miq is an important food spice in southern China and has been used in the treatment of kidney disorders for centuries. In order to discover the natural products with potent renoprotective activities in A. oxyphylla and provide some references for its usage, systematic phytochemical studies were carried out and 24 new diverse sesquiterpenoids, including seven guaiane sesquiterpenoids (1-7), 10 eudesmane sesquiterpenoids (9-13, 18, 19, and 21-23), six cadinane sesquiterpenoids (31-35 and 38), and an eremophilane sesquiterpenoid (40), along with 24 known analogues were isolated and elucidated by analysis of spectroscopic data and quantum-chemical calculations. Biological evaluation showed that 6 sesquiterpenoids could significantly inhibit the expression of extracellular matrix components, α-SMA in TGF-β1 induced kidney proximal tubular cells (NRK-52e) at low concentrations, and 9 sesquiterpenoids could also downregulate fibronectin and collagen I in a concentration-dependent manner, showing their potential in renal fibrosis. Further action mechanism study displayed that TGF-β1/Smads pathway might be involved in the antifibrotic effects of active sesquiterpenoids 15 and 43. These studies suggest that A. oxyphylla may have a potential to serve as a functional food in preventing renal fibrosis-associated diseases.

Three New Ionone Glycosides from Rhododendron capitatum Maxim.

Six ionone glycosides (1-3 and 5-7), including three new ones, named capitsesqsides A-C (1-3), together with an eudesmane sesquiterpenoid glycoside (4) and three known triterpenoid saponins (8-10) were isolated from Rhododendron capitatum. The structures of these compounds were determined by extensive spectroscopic techniques (MS, UV, 1D-NMR, and 2D-NMR) and comparison with data reported in the literature. The absolute configurations were determined by comparison of the experimental and theoretically calculated ECD curves and LC-MS analyses after acid hydrolysis and derivatization. The anti-inflammatory activities of these compounds were evaluated in the LPS-induced RAW264.7 cells. Molecular docking demonstrated that 2 has a favorable affinity for NLRP3 and iNOS.

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.

Eudesmane sesquiterpenoids with inhibitory effects on NO production from Artemisia princeps

Five undescribed eudesmane methyl esters (1−5), three undescribed eudesmane-12,6-olides (6−8), and 21 known analogues (9−29) were isolated from the aerial part of Artemisia princeps Pamp. Their structures were established by detailed analysis of the NMR and HRESIMS data. The absolute configurations of 1−8 were determined based on single-crystal X-ray diffraction analysis and ECD calculations. Moreover, the inhibitory effects on LPS-induced NO production in BV-2 microglial cells of all the isolated compounds were assessed. Except for compounds 2, 4, 10, and 11, the others showed significant inhibitory activities, with IC50 values of 0.73–18.66 μM, wherein the potential structure-activity relationship was also discussed.

Pitsubcosides M−S: Novel antibacterial cadinane sesquiterpenoid glycoside esters from Pittosporum subulisepalum

A previous study on Pittosporum subulisepalum led to twelve novel, antibacterial eudesmane sesquiterpenoid glycoside esters (ESGEs). To continue the work on P. subulisepalum, this study focused on the exploration of cadinane sesquiterpenoid glycoside esters (CSGEs) with antibacterial activities and their mechanism of actions. Chemical exploration of the ethyl acetate (EtOAc) soluble phase of the leaves and stems of P. subulisepalum resulted in seven previously unreported cadinane sesquiterpenoid glycosides (CSGs), pitsubcosides M-S (1 −7), along with three known analogs. Based on one- and two-dimensional NMR (1D and 2D NMR), HRESIMS, and experimental/calculated electronic circular dichroism (ECD) spectroscopic analyses, the structures of the isolated compounds were elucidated. The novelty of these sesquiterpenoid glycosides was characterized by the highly esterified glycoside moieties. Compounds 1 − 5 exhibited marked inhibitory effects on Bacillus subtilis, Staphylococcus aureus, methicillin-resistant Staphylococcus aureus, Bacillus cereus, Erwinia carotovora, and Pseudomonas syringae pv. actinidiae with the minimum inhibitory concentration (MIC) values of 3.13 μM− 50 μM. Of these, compounds 1 − 2 displayed significant antibacterial activity against B. subtilis (MIC = 3.13 and 6.25 μM). The live masses and the biofilms of B. subtilis were quantified after being treated with compounds 1 and 2. The preliminary antibacterial mechanism was revealed as to prevent bacterial biofilm formation or to destroy the formed cell membranes. These results indicated that CSGEs from P. subulisepalum are potential antibacterial lead agents.

Eudesmane-type sesquiterpenoids from the aerial parts of Artemisia lavandulaefolia and their anti-pancreatic cancer activities

Five undescribed eudesmane sesquiterpenoids, artemilavanins A-E, and one undescribed rearranged eudesmane sesquiterpenoid, artemilavanin F, were isolated from the 95% ethanol extract of the aerial parts of Artemisia lavandulaefolia DC., along with ten known compounds. The structures and configurations of undescribed compounds were mainly elucidated by spectroscopic analyses and single-crystal X-ray diffraction analysis. Among all isolated compounds, artemilavanin F exhibited inhibitory activity on PANC-1 pancreatic cancer cells with IC50 of 9.69 ± 2.39 μM. Artemilavanin F inhibited PANC-1 cell proliferation by induction of G2/M cell cycle arrest and apoptosis mediated by downregulation of cyclin-dependent kinases and accumulation of reactive oxygen species. Moreover, artemilavanin F inhibited the colony formation, cell migration and sphere formation of PANC-1 cells, indicating the suppression of stem-cell-like phenotype of PANC-1 cells. Further results confirmed that the expression of cancer stem cell markers such as Bmi1, CD44, CD133 were inhibited by artemilavanin F. Downregulation of epithelial-mesenchymal transition (EMT) markers such as N-cadherin and Oct-4 indicated the potential of artemilavanin F in prevention of metastasis.

Two new eudesmane sesquiterpenoids with neuroprotective activity from Pogostemon cablin

Two new eudesmane sesquiterpenoids [(−)-(1R,5S,6R,8S)−1-hydroxy-nor-eudesm-11-ene-2-one (1) and (−)-(1S,5S,6R,8R)−6-hydroxyeudesm-11-ene-2-one (2)] were isolated from the aerial parts of Pogostemon cablin. Compound 1 is an unusual 1-nor-eudesmane, and its skeleton structure is similar to that of compound 2. The molecular structures and absolute conformations of the two new sesquiterpenoids were determined by NMR spectroscopy, X-ray diffraction analysis, NMR data calculations and electronic circular dichroism (ECD) calculations. The neuroprotective activity of the isolates in an H2O2-induced PC12 cell model was also assessed, and the results show that both compounds exhibit good neuroprotective effects.

A new anti-inflammatory thujane monoterpenoid glycoside ester from Pittosporum heterophyllum Franch

Phytochemical investigation of EtOH extract of Pittosporum heterophyllum led to one new esterified thujane monoterpenoid glycoside, pitheteroside A (1), together with one eudesmane sesquiterpenoid (2) and twelve lignans (3－14). Their structures were elucidated by extensive spectroscopic analysis, including 1D and 2D NMR, ECD calculation and HRESIMS spectra. Pitheteroside A is an unreported and highly esterified monoterpenoid glycoside. All isolates were evaluated for their nitric oxide production inhibition against LPS-induced BV-2 microglial cells. Among them, compounds 1, 6 and 8 showed significant activities with IC50 values less than 10 μM. The results indicated the metabolisms from P. heterophyllum possess potential anti-inflammatory effects.

Eudesmane sesquiterpenoid glycosides from the leaves of Pittosporum lenticellatum with anti-neuroinflammatory activity

Chemical investigation of the EtOAc extract of the leaves of Pittosporum lenticellatum led to the isolation of twenty-five previously undescribed eudesmane sesquiterpenoid glycosides, pitlencosides A－Y (1–25); their structures were elucidated by extensive spectroscopic analysis, including 1D and 2D NMR, HR-ESI-MS, ECD spectra, and X-ray crystallographic analysis. Among them, compounds 4, 5, 7, 8, 15 and 16 exhibited significant inhibitory effects on the production of nitric oxide in lipopolysaccharide-induced BV-2 microglial cells by suppressing the expression of inducible nitric oxide synthase and cyclooxygenase-2, with IC50 values ranging from 7.95 to 25.88 μM, which showed stereo-chemical and substituent dependents. Western blot analysis and molecular docking simulation confirmed the anti-inflammatory activity of compounds 4, 5, 7, 8, 15 and 16.

Syntheses of (+)-costic acid and structurally related eudesmane sesquiterpenoids and their biological evaluations as acaricidal agents against Varroa destructor.

Synthesis of (+)-costic acid, isolated from Dittrichia viscosa (L.) W. Greuter as a natural acaricidal sesquiterpenoid, was achieved in 16 steps from (R)-carvone with an overall yield of 4.8%, involving the radical cyclization of selenoester to construct a decalone framework as the key step. Other structurally related natural products, (+)-costal, (+)-costol, and (+)-β-selinene, were also synthesized. The acaricidal activities of these four natural products and some synthetic intermediates were also evaluated against Varroa destructor. Among them, (+)-costal especially exhibited potent acaricidal activity.

Sesquiterpenoids from the roots of Aucklandia costus and their anti-inflammatory activities

Five undescribed sesquiterpenoid dimers, aucklandiolides A–E (1–5), one new sesquiterpenoid glycoside, β-cyclocostunolide-15-β-D-glucopyranoside (6), and seventeen known analogues (7–23) were isolated from the roots of Aucklandia costus. Their structures were elucidated by comprehensive HRESIMS and NMR spectroscopic data analysis, and their configurations were confirmed by the computational calculations of ECD and NMR chemical shifts. Aucklandiolides A and B are the first examples of dimeric sesquiterpenoids with a unique 6/6/6/5/6/6 ring system originated from a proposed Diels–Alder cycloaddition between two eudesmane sesquiterpenoids. Besides, compounds 9–11, 20, and 22 showed significant inhibition of nitric oxide production in LPS-stimulated RAW 264.7 cells at a concentration of 20 μM.

Sesquiterpene lactones from Artemisia verlotorum and their anti-inflammatory activities

Seven new sesquiterpenoids (1–7) and 19 known analogues were isolated from the whole plant of Artemisia verlotorum. Their structures were determined by extensive analysis of 1D and 2D NMR and HRESIMS data, electronic circular dichroism (ECD) spectra, density functional theory (DFT) NMR calculations, and time dependent density functional theory (TDDFT) ECD calculations. The absolute configurations of 1, 3, 5 and 7 were confirmed by single crystal X-ray diffraction experiments. Compounds 1 and 2 possess a rarely reported 5/8-bicyclic skeleton, while both compounds 3 and 4 were uncommon iphionane-type sesquiterpenoids. Eudesmane sesquiterpenoids (5–17) reported in this study are all 7,8-cis-lactones, of which, compound 7 represents the first eudesmane sesquiterpene with an oxygen bridge connecting C-5 and C-11. All the compounds were tested in vitro for their anti-inflammatory activities in LPS-stimulated RAW 264.7 murine macrophages. Compound 18 showed a potent inhibitory effect on NO production, with IC50 values of 3.08 ± 0.61 μM.

Pitsubcosides A-L, highly esterified eudesmane sesquiterpenoid glycosides with antibacterial activity from Pittosporum subulisepalum and their mechanism.

Plants from the genus Pittosporum are traditionally used as antibacterial, antifungal and antiviral agents. A bioassay evaluation of the extract of Pittosporum subulisepalum revealed antibacterial activity. This study focused on the discovery of the antibacterial metabolism in P. subulisepalum, as well as the modes of action of its active components. A chemical investigation of an ethyl acetate (EtOAc) extract of the aerial parts of P. subulisepalum led to the isolation of 12 previously undescribed eudesmane sesquiterpenoid glycoside esters (ESGEs), pitsubcosides A-L (1-12). Their structures were elucidated by extensive spectroscopic analysis, including one- and two-dimensional NMR, high-resolution electrospray ionization mass spectrometry, electronic circular dichroism spectra and single-crystal X-ray crystallography analysis or by comparing with authentic samples. The new ESGEs were characterized by their highly esterified glycoside moieties. Among them, compounds 1-3, 5 and 8 showed a moderate inhibitory effect against Staphylococcus aureus, methicillin-resistant S. aureus (MRSA), Bacillus cereus, Bacillus subtilis, Pseudomonas syringae pv. actinidiae (Psa) and Erwinia carotovora with minimum inhibitory concentrations (MICs) ranging from 3.13 to 100 μm. Among them, compounds 3 and 5 showed remarkable antibacterial activity against S. aureus and Psa with MIC values of 6.25 and 3.13 μm, respectively. Live bacterial mass and the biofilms of S. aureus and Psa were quantified using methyl tetrazolium and crystal violet assays. Fluorescence microscopy and scanning electron microscopy experiments revealed an antibacterial mechanism of cell membrane architectural disruption. The results suggest that ESGEs possess great potential for the development of antibacterial agents to control plant pathogens. © 2023 Society of Chemical Industry.

A New Eudesmane Sesquiterpenoid from the Marine-Derived Fungus Penicillium sp. HK1-22

A New Eudesmane Sesquiterpenoid from the Marine-Derived Fungus Penicillium sp. HK1-22

Structurally Diverse Sesquiterpenoids from Chloranthus henryi var. hupehensis and Their Anti‐inflammatory Activities

Comprehensive SummaryIn this study, 27 new sesquiterpenoids: twenty monomers and seven dimers, with diverse structures, along with one known chlorajaponilide F (25) were isolated from the aerial parts of Chloranthus henryi var. hupehensis. Structurally, chlorahupetolides A (1) and B (2), two eudesmane‐type merosesquiterpenoids with an undescribed C18 carbon framework, and chlorahupetene E (18) are the first example of dimers comprising two eudesmane sesquiterpenoids bridged by a four‐membered ring in the Chloranthus. Their structures were characterized by nuclear magnetic resonance (NMR), electronic circular dichroism (ECD), and X‐ray diffraction analysis. In the RAW264.7 macrophages model of inflammation induced by LPS, compounds 12, 18, and 25 significantly reduced NO production in a dose dependent manner and without cytotoxicity. The mRNA expression of COX‐2 was considerably inhibited by treatments with compounds 12, 18, and 25.

Structurally diverse new eudesmane sesquiterpenoids with anti-inflammatory activity from the fruits of Alpinia oxyphylla

The phytochemical investigation of the fruits of Alpinia oxyphylla led to the isolation and identification of 40 structurally diverse sesquiterpenoids, including 17 new eudesmane sesquiterpenoids (1–17) and 23 known analogues (18–40). Among the isolates, 14 and 17 were unusual rearranged eudesmane sesquiterpenoids, featuring rare 5/6-fused and 6/8-fused bicyclic carbon skeleton, respectively; 15 and 16 were the novel 6,7-seco-eudesmane sesquiterpenoids isolated from plant-origin for the first time, 1 and 3–6 were rare nor-eudesmane sesquiterpenoids. Their structures were elucidated by comprehensive spectroscopic data analysis (NMR, HRESIMS, IR, UV), single crystal X-ray diffraction, and quantum chemistry calculations (ECD and 13C NMR). Moreover, all isolates were evaluated by measuring their inhibitory effect on nitric oxide (NO) in LPS-stimulated BV-2 cells. As a result, compounds 11, 20, 24 and 40 showed moderate to strong inhibition on NO productions, with IC50 values ranging from 21.63 to 60.70 μM. Meanwhile, these compounds also partially decreased the secretion of TNF-α and IL-6 in LPS-stimulated BV-2 cells. Furthermore, 20 could down-regulate protein expressions (COX-2 and iNOS) and observably inhibit the mRNA expressions of TNF-α, IL-6, COX-2 and iNOS. In this study, the discovery of structurally diverse anti-inflammatory sesquiterpenoids from the fruits of A. oxyphylla could benefit the further development and utilization of this plant.

New Verticillene Diterpenoids, Eudesmane Sesquiterpenoids, and Hydroperoxysteroids from the Further Chemical Investigation of a Taiwanese Soft Coral Cespitularia sp.

An investigation of the chemical composition of a Formosan soft coral Cespitularia sp. led to the discovery of one new verticillene-type diterpenoid, cespitulactam M (1); one new eudesmane sesquiterpenoid, cespilamide F (2); and three new hydroperoxysteroids (3-5) along with twelve known analogous metabolites (6-17). In addition, one new derivative, cespitulactam M-6,2'-diacetate (1a), was prepared from compound 1. The structures were determined by detailed spectroscopic analyses, particularly HRESIMS and NMR techniques. Moreover, the in vitro cytotoxicity, anti-inflammatory, and antibacterial activity of 1-17 and 1a were evaluated.

Polyhydroxylated eudesmane sesquiterpenoids and sesquiterpenoid glucoside from the flower buds of Tussilago farfara.

Chemical fractionation of the n-BuOH partition, which was generated from the EtOH extract of the flower buds of Tussilago farfara, afforded a series of polar constituents including four new sesquiterpenoids (1-4), one new sesquiterpenoid glucoside (5) and one known analogue (6) of the eudesmane type, as well as five known quinic acid derivatives (7-11). Structures of the new compounds were unambiguously characterized by detailed spectroscopic analyses, with their absolute configurations being established by X-ray crystallography, electronic circular dichroism (ECD) calculation and induced ECD experiments. The inhibitory effect of all the isolates against LPS-induced NO production in murine RAW264.7 macrophages was evaluated, with isochlorogenic acid A (7) showing significant inhibitory activity.