Isolation of C-29 oxygenated oleanane triterpenoids and a (+)-muurolene type sesquiterpenoid from the fruiting bodies of Fuscoporia torulosa and their bioactivities.

Basidiomycetes with a wide variety of skeletons of secondary metabolites can be expected to be the source of new interesting biological compounds. During our research on basidiomycetes, two new C-29 oxygenated oleanane-type triterpenes (1 and 2) and torulosacid (3), a muurolene type sesquiterpenoid with a five-membered ether ring along with nine known compounds (4-12), were isolated from the MeOH extract of the fruiting bodies of Fuscoporia torulosa. The structures of 1-3 were determined by NMR and HREIMS analysis. Further studies on the stereochemistry of 3 were conducted using X-ray crystallographic analysis and comparison of experimental and calculated ECD spectra. In the antimicrobial assay of isolates, 1, 7, and 9 showed growth inhibitory activity against methicillin-resistant Staphylococcus aureus and other gram-positive strains. Isolation of oleanane type triterpenes from fungi including basidiomycetes, is a unique report that could lead to further isolation of new compounds and the discovery of unique biosynthetic enzymes.

Sesquiterpenoids from Carpesium abrotanoides and their anti-inflammatory activity both in vitro and in vivo.

Twenty-nine sesquiterpenoids, including pseudoguaiane-type (1-11), eudesmane-type (12-23), and carabrane-type (24-29), have been identified from the plant Carpesium abrotanoides. Of them, compounds 1-4, 12-15, and 24-27, namely carpabrotins A-L, are twelve previously undescribed ones. Compound 3 possessed a pseudoguaiane backbone with a rearrangement modification at C-11, C-12 and C-13, while compound 4 suffered a carbon bond break between the C-4 and C-5 to form a rare 4,5-seco-pseudoguaiane lactone. Compounds 1-3, 5, 13-16 and 25-27 exhibited anti-inflammatory activity by inhibiting NO production in LPS-induced RAW264.7 macrophages with IC50 values less than 40 µM, while compounds 1, 2, 5, 13, 14, 16, and 25-27 showed significant inhibitory activity comparable to that of dexamethasone. The anti-atopic dermatitis (AD) effects of compounds 5 and 16 were tested according to 2,4-dinitrochlorobenzene (DNCB)-induced AD-like skin lesions in KM mice, and the results revealed that the major products 5 and 16 improved the histological features of AD-like skin lesions and mast cell infiltration in mice. This study suggested that sesquiterpenoids in C. abrotanoides should play a key role in its anti-inflammatory use.

Lindenane sesquiterpenoid dimers with NLRP3 inflammasome inhibitory activities from Chloranthus holostegius var. shimianensis.

Thirteen previously undescribed lindenane sesquiterpenoid dimers (LSDs), named chlorahololides G-S (1-13), were isolated from the whole plants of Chloranthus holostegius var. shimianensis, along with ten known analogues (14-23). The structures and absolute configurations of compounds 1-13 were elucidated through comprehensive spectroscopic analysis, NMR and electronic circular dichroism (ECD) calculations, and X-ray single-crystal diffraction. Chlorahololide G (1) represents the first instance of LSDs formed via a C-15-C-9' carbon-carbon single bond, whose plausible biosynthetic pathway was also proposed. Chlorahololides I and J (3 and 4) were deduced to be rare 8,9-seco and 9-deoxy LSDs with C-11-C-7' carbon-carbon bond, respectively. The inhibitory activity against NLRP3 inflammasome activation was evaluated for all isolates, with six compounds (5, 7, 8, 17, 22, and 23) exhibiting significant effects, and IC50 values ranging from 2.99 to 8.73 µM. Additionally, a preliminary structure-activity relationship analysis regarding their inhibition of NLRP3 inflammasome activation was summarized. Compound 17 exhibited dose-dependent inhibition of nigericin-induced pyroptosis in J774A.1 cells. Molecular docking studies suggested a strong interaction between compound 17 and NLRP3.

Evaluation of Bauhinia ungulata Essential Oil as a New Acetylcholinesterase Inhibitor from an in silico and in vitro Perspective in the Northern Amazon of Brazil.

The Bauhinia ungulata, also known by its common name "pata de vaca", is one of the species used in Brazil for medicinal purposes, and is commonly used for the treatment of diabetes. In this study, the authors studied the interaction between the chemical constituents which are present in the essential oil of Bauhinia ungulata (EOBU), collected in Boa Vista-RR, Legal Amazon, and their effects on the enzyme acetylcholinesterase (AChE) in the essential oil. The analysis that we perform includes proton magnetic resonance ( 1H NMR), enzymatic inhibition, molecular docking, in silico toxicity prediction, enrichment analysis, and target prediction for biological interactions. According to the tests performed on the essential oil, it obtained 100% inhibition of the enzyme AChE. During 1H NMR experiments, it was found that α- Bisabolol, one of the main components, had a significant alteration in its chemical shift. A molecular docking analysis confirmed that this compound binds to the AChE enzyme, which confirms the 1H NMR analysis. The results of this work showed that the major component of EOBU acted as a possible inhibitor of AChE enzyme in vitro and in silico assays. These results show that EOBU could be potentially applied in Alzheimer's disease treatment.

Characterization of Sesquiterpene Dimers from the Flowers of Inula japonica and the Structural Revisions of Related Compounds.

Sesquiterpene dimers are mainly found in the Asteraceae family. However, conflicting reports on the structures of these compounds can be found in the literature. Herein, we describe ten sesquiterpene dimers isolated from the flowers of Inula japonica, including configurational revisions of japonicone H (1-1), japonicone D (2-1), inulanolide A (4-1), japonicone X (5-1), and inulanolide F (5-2) to compounds 1, 2, 4, and 5, respectively. Five new related metabolites (3 and 6-9) are also described. Application of GIAO NMR/DP4+ analyses and ECD/OR calculations enabled us to revise the absolute configurations of an additional 13 sesquiterpene dimers isolated from plants of the genus Inula. Compounds 1, 2, 4, and 6 exhibited inhibition of nitric oxide production in lipopolysaccharide activated RAW264.7 macrophages with IC50 values of 4.07-10.00 µM.

NMR-Guided Isolation of Anti-inflammatory Carabranolides from the Fruits of Carpesium abrotanoides L.

Carabranolides present characteristic NMR resonances for the cyclopropane moiety, which distinctly differ from those of other compounds and were used for an NMR-guided isolation in this study. As a result, 11 undescribed carabranolides (1-11), along with five known ones (12-16), were isolated from the fruits of Carpesium abrotanoides L. Compounds 1-11 are new esters of carabrol at C-4 with different carboxylic acids. Their structures were elucidated by HRESIMS and NMR spectroscopic data analysis. The biological evaluation showed that compounds 2-4, 15, and 16 exhibited significant inhibitory activity against LPS-induced NO release with an IC50 value of 5.6-9.1 µM and dose-dependently decreased iNOS protein expression in RAW264.7 cells.

Structure-guided isolation of anti-neuroinflammatory sesquiterpene coumarins from Ferula sinkiangensis.

The resin of Ferula sinkiangensis has been traditionally utilized for treating gastrointestinal disorders, inflammation, tumors, various cancers, and alopecia areata. The primary bioactive constituents, sesquiterpene coumarins, have demonstrated notable therapeutic potential against neuroinflammation. In this study, a structure-guided fractionation method was used to isolate nine novel sesquiterpene coumarins from the resin of F. sinkiangensis. These compounds were characterized and structurally elucidated using comprehensive physicochemical and spectroscopic techniques, including calculated electronic circular dichroism (ECD). Anti-neuroinflammatory assays revealed that compounds 2, 3, and 6 significantly inhibited nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated BV2 microglial cells, with IC50 values ranging from 1.63 to 12.25 µmol·L-1.

Sesquiterpene dimers with a rare skeleton from Chloranthus holostegius exhibiting multidrug resistance reversal activity in vitro and in vivo.

Two previously unreported lindenane sesquiterpene dimers (1 and 2) with a rare skeleton containing an oxaspiro[4.5]decane moiety were isolated from the roots of Chloranthus holostegius var. trichoneurus. Their structures were elucidated by HRESIMS, NMR, ECD, and NMR quantum chemical calculations, along with DP4+ probability analysis. In bioassay, compound 1 exhibited significant activity to reverse the multidrug resistance (MDR)in MCF-7/ADR cells, with an IC50 value of 4.4 µM. Further mechanistic studies revealed that compound 1 combined with doxorubicin could induce apoptosis of MCF-7/ADR cells and block the cell cycle in the G2/M phase. Mechanistically, compound 1 could inhibit the efflux function of P-glycoprotein (P-gp) using the zebrafish model. Finally, the enhanced chemotherapeutic effects of doxorubicin were further confirmed by in vivo zebrafish xenograft experiments.

Lappanolides A-N, fourteen undescribed sesquiterpenoids from Saussurea costus (Syn. Saussurea lappa) and their anti HBV activity.

Lappanolides A-N (1-14), 14 undescribed sesquiterpenoids, along with 23 known ones (15-37), were isolated from the roots of Saussurea costus, which were primarily categorized into eudesmane, guaiane, and germacrane types. Lappanolide A (1) possessed an unprecedented pseudo-disesquiterpenoids. Their structures and absolute configurations were established using physical data analyses (HRESIMS, IR, 1D and 2D NMR) and ECD calculations. All isolated compounds were tested for anti-hepatitis B virus (anti-HBV) activity. Ten compounds (1, 9, 11, 12, 19, 22, 28, 29, 31, and 36) exhibited activities against HBsAg secretions as determined by ELISA assay, with IC50 values ranging from 5.2 to 45.7 µM. In particular, compounds 28 and 29 showed inhibition of HBsAg secretion with IC50 values of 5.28 and 5.30 µM, and CC50 values of 9.85 and 6.37 µM, respectively, though they all exhibited low selectivity. Several compounds displayed cytotoxicity in the MTT assay. Among them, compound 28 was the most notable and was chosen for further study using flow cytometry. The result showed that it significantly induced HepG2 cell arrest in the S phase and induced apoptosis.

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 â†’ 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.

Sesquiterpene lactones from Tithonia diversifolia with ferroptosis-inducing activities.

Eight previously undescribed sesquiterpene lactones (1-8), together with six known ones (9-14) were isolated from the aerial parts of Tithonia diversifolia (Hemsl.) A. Gray. The absolute configurations of these compounds were elucidated using HRMS, NMR spectroscopy, optical rotation measurements, X-ray crystallography, and ECD. Among them, sesquiterpene lactones 2-4 share a unique carbon skeleton with a rare C-3/C-4 ring-opened structure. Compounds 1 and 8 showed moderate inhibitory effects toward CT26 murine colon carcinoma cells by promoting lipid ROS production, highlighting their potential as ferroptosis inducers.

Anti-inflammatory and cytotoxicity nitrogenous merosesquiterpenoids from the sponge Pseudoceratina purpurea.

Fourteen undescribed nitrogenous merosesquiterpenoids, purpurols A-D (1-4) and puraminones A-J (5-14), along with three known related compounds (15-17) were isolated from the sponge Pseudoceratina purpurea collected in the South China Sea. Their structures and absolute configurations were unambiguously elucidated by a combination of spectroscopic data, X-ray diffraction analysis, electronic circular dichroism calculations, and chemical derivatization. Purpurols A-D (1-4) incorporated nitrogenous heterocycles, compounds 1 and 2 feature an unusual benzothiazole ring, while 3 and 4 feature benzoxazole ring. Puraminones A-J (5-14) represent sesquiterpenoid aminoquinones with different amine and amino acid side chains at C-20. Additionally, twenty unreported sesquiterpenoid aminoquinone analogues were obtained through chemical derivatization. It is worth noting that all compounds are featured with unusual rearranged 4,9-friedodrimane subunit. In the bioassays, purpurols A and B showed weak anti-inflammation in zebrafish, as well as some compounds showed activities against tumor cells, therefore, preliminary structure-cytotoxicity relationships are also discussed.

Guaianolide sesquiterpene lactones from Cichorium glandulosum and their anti-neuroinflammation activities.

Eight undescribed guaianolide sesquiterpene lactones cicholosumins A-H and twelve known ones were isolated from the aerial parts of Cichorium glandulosum Boiss et Huet. Their structures were established by 1D and 2D NMR spectroscopic data, electronic circular dichroism, quantum chemical calculations and single crystal X-ray diffraction analysis. Compounds 9α-hydroxy-3-deoxyzaluzanin C, epi-8α-angeloyloxycichoralexin, 8-O-methylsenecioylaustricin and lactucin showed strong anti-neuroinflammation activity with IC50 values of 1.69 ± 0.11, 1.08 ± 0.23, 1.67 ± 0.28 and 1.82 ± 0.27 µM, respectively. The mechanism research indicated that epi-8α-angeloyloxycichoralexin inhibited neuroinflammation through the NF-κB and MAPK pathways.

New sesquiterpenes and viridin derivatives from Penicillium sp. Ameliorates NAFLD by regulating the PINK1/Parkin mitophagy pathway.

Fungi from the plant rhizosphere microbiome are considered an important source of bioactive novel natural compounds. In this study, three new sesquiterpenes, penisterpenoids A-C (1-3), and three new viridin derivatives, peniviridiols A-C (4-6), along with twenty one known compounds (7-27), were isolated from the rhizosphere fungus Penicillium sp. SMU0102 of medicinal plant Bupleurum chinense DC. Their structures were elucidated by extensive spectroscopic analysis. The absolute configurations of compounds 1-6 were determined by experimental and calculated ECD spectra, DP4 + probability analysis, modified Mosher's method, and X-ray crystallography. All new compounds were screened for their cytotoxic and lipid-lowering activities in vitro. Among them, compound 1 (20 µM) remarkably alleviated lipid accumulation both in FFA-induced LO2 cells and TAA-induced zebrafish NAFLD models. Furthermore, compound 1 enhanced ATP production and mitochondrial membrane potential (MMP), suppressed reactive oxygen species (ROS) formation, restored mitochondrial structure, and induced autophagosome formation. Moreover, compound 1 significantly upregulated the expression of representative proteins for the mitochondrial homeostasis, including OPA1, DRP1, MFF, and Fis1, as well as mitophagy representative proteins PINK1, Parkin, and P62. Further mechanistic investigations indicated that compound 1 primarily alleviated lipid accumulation through selective activation of the PINK1/Parkin mitophagy signaling pathway.

Bioactive secondary metabolites isolated from the branches and leaves of Pittosporum pulchrum Gagnep.

Five new compounds, including two sesquiterpenoid glycosides (1 and 2), two monoterpenoid glycosides (3 and 4), and a quinovose ester (5), together with four known compounds (6-9) were isolated from branches and leaves of Pittosporum pulchrum Gagnep. Their structures were established by 1D and 2D NMR, HR-ESI-MS, IR and UV spectral analyses. This is the first time to investigate the chemical constituents of P. pulchrum. Subsequently, the anti-inflammatory and antioxidant activities of different solvent fractions of ethanol extract and isolated compounds were evaluated. Dichloromethane and ethyl acetate fractions dramatically inhibited the production of NO in a concentration-dependent manner in LPS-induced RAW264.7 cells. Ethyl acetate and n-butanol fractions showed excellent DPPH radical scavenging activities with IC50 values of 24.31 µg/mL and 27.81 µg/mL, respectively. Compounds 7 and 8 might be potential natural antioxidants with IC50 values of 16.13 µM and 24.81 µM, respectively.

Cytotoxic xanthanolide sesquiterpenes from the fruits of Xanthium italicum Moretti.

One previously undescribed xanthanolide sesquiterpene dimer pungiolide P (1), possessing an unprecedented scaffold with a 5/7/5/7/5 ring system skeleton and its intermediate pungiolide Q (2), ten xanthanolide sesquiterpenes (3-12), two eudesmene sesquiterpene derivatives (13-14), one phenylpropionic acid derivative (15), together with eleven known compounds (16-26) were obtained from the fruits of Xanthium italicum Moretti. A possible biosynthetic pathway for pungiolide P (1) was also proposed, which was supported by its bio-synthetic intermediate (2). Compounds 1, 4-5, 18-21, and 25 exhibited cytotoxic activity against a variety of human cancer cell lines. Furthermore, compounds 1, 4-5, could cause blockage of the cell cycle in the G2/M phase and induce apoptosis in H460 cells. Notably, pungiolide P (1) exhibited significantly superior cytotoxicity compared to previously reported compounds, providing valuable insights for natural anti-tumor sources.

Antimicrobial Activity of Drimanic Sesquiterpene Compounds from Drimys winteri against Multiresistant Microorganisms.

In this work, a group of ten sesquiterpene drimanes, including polygodial (1), isopolygodial (2), and drimenol (3) obtained from the bark of Drimys winteri F. and seven synthetic derivatives, were tested in vitro against a unique panel of bacteria, fungi, and oomycetes with standardized procedures against bacterial strains K. pneumoniae, S. tiphy, E. avium, and E. coli. The minimum inhibitory concentrations and bactericidal activities were evaluated using standardized protocols. Polygodial (1) was the most active compound, with MBC 8 µg/mL and MIC 16 µg/mL in E. avium; MBC 16 µg/mL and MIC 32 µg/mL in K. pneumoniae; MBC 64 µg/mL and MIC 64 µg/mL in S. typhi; and MBC 8 µg/mL and MIC 16 µg/mL and MBC 32 µg/mL and MIC 64 µg/mL in E. coli, respectively. The observed high potency could be attributed to the presence of an aldehyde group at the C8-C9 position. The antifungal activity of 1 from different microbial isolates has been evaluated. The results show that polygodial affects the growth of normal isolates and against filamentous fungi and oomycetes with MFC values ranging from 8 to 64 µg/mL. Sesquiterpene drimanes isolated from this plant have shown interesting antimicrobial properties.

Anti-inflammatory germacrane-type sesquiterpene lactones from Vernonia sylvatica.

Nine new germacranolides, sylvaticalides A-H (1-9), and three known analogues (10-12) were isolated from the aerial part of Vernonia sylvatica. Their structures were established using comprehensive spectroscopic analysis, including high-resolution electrospray ionization mass spectroscopy (HR-ESI-MS) and 1D and 2D nuclear magnetic resonance (NMR) spectra. Their absolute configurations were determined by X-ray diffraction experiments. The anti-inflammatory activities of all isolated compounds were assessed by evaluating their inhibitory effects on the nuclear factor kappa B (NF-κB) pathway, which was activated by lipopolysaccharide (LPS)-stimulated human THP1-Dual cells, and the interferon-stimulated gene (ISG) pathway, activated by STING agonist MSA-2 in the same cell model. Compounds 1, 2 and 6 showed inhibitory effects on the NF-κB and ISG signaling pathways, with IC50 values ranging from 4.12 to 10.57 µmol·L-1.

(±)-Hypernumqulins A-H: Eight pairs of unexpected [2+2] cycloaddition sesquiterpenoid alkaloid with 6/6/6/4/10 ring system from Hypericum monogynum L.

(±)-Hypernumqulins A-H (1-8), eight pairs of enantiomeric quinoline alkaloids fused with an isopentenyl and a germacrane-type sesquiterpenoid, featuring an unprecedented skeleton with 6/6/6/4/10 ring system, were isolated from Hypericum monogynum L. under the guidance of molecular networking strategy. Their structures including absolute configuration were elucidated by NMR spectroscopy analysis, X-ray crystallography and quantum chemical calculation. The proposed [2+2] cycloaddition may play a key biogenic step in building the unexpected skeleton. Most of the isolates exhibited cytotoxicity with IC50 values ranging from 2.82 ± 0.03 to 45.25 ± 1.26 µM against MCF-7, A549 or SGC7901 cells. Furthermore, compounds (±)-1 and (-)-1 could induce apoptosis by upregulating the protein expression level of Bax and downregulating of Bcl-2 in MCF-7 cells. These findings provided the first example of germacrane sesquiterpene quinoline alkaloids, and supported the possibilities for the development of new anti-tumor agents.

Four new sesquiterpenoids from the aerial parts of Pogostemon cablin (Blanco.) Benth. and their hypoglycemic activity.

Four previously undescribed sesquiterpenoids (1-4), including two natural guaiane-type sesquiterpenoids (1-2), a rearranged guaiane-type sesquiterpenoid (3), and a norsesquiterpenoid (4), were isolated from the ethanol extract of the aerial parts of Pogostemon cablin (Blanco.) Benth. Their chemical structures were determined based on extensive spectroscopic data analysis, including UV, IR, NMR, HRESIMS, and CD spectroscopy. Compound 1 exhibited a good hypoglycemic activity with glucose uptake of 124.3% and 131.2% in myotubes, respectively, at the concentrations of 20 and 40 µM and showed no cytotoxicity. These findings provide a material basis for further research on P. cablin.