Identification of diterpenoids from Salvia castanea Diels f. tomentosa Stib and their antitumor activities.

Four new diterpenoid tropolones, salvirrddones A-D (1-4), and four new icetexanes, salvirrddices A-D (9-12), along with thirteen new 11,12-seco-norabietane diterpenoids, salvirrddnor A-M (14-24, 31, 32) and sixteen known compounds (5-8, 13, 25-30, 33-37), were isolated from the roots and rhizomes of Salvia castanea Diels f. tomentosa Stib. Their structures were elucidated by comprehensive spectroscopic analyses, quantum chemical calculations, and X-ray crystallography. Structurally, compounds 1-8 represent a class of rare natural products featuring a unique cyclohepta-2,4,6-trienone moiety with diterpenoid skeletons. Bioassays showed that only diterpenoid tropolones 3, 5, 6, and 7 exhibited significant activity against several human cancer cell lines with IC50 values ranging from 3.01 to 11.63 µM. Additionally, 3 was shown to inhibit Hep3B cell proliferation, block the G0/G1 phase of the cell cycle, induce mitochondrial dysfunction and oxidative stress, promote apoptosis, as well as inhibit migration and invasion in vitro. Meanwhile, 3 demonstrated anti-proliferative, pro-apoptotic, and migration-inhibitory effects in the Hep3B xenograft zebrafish model in vivo. Network pharmacological analysis and molecular docking results suggested that 3 may treat hepatocellular carcinoma (HCC) through the PI3K-Akt signaling pathway, as well as by binding PARP1 and CDK2 targets. Overall, the present results extremely expand the repertoire of diterpenoids from natural products and may provide a novel chemical scaffold for the discovery of new antitumor drugs.

(±)-Salvicatone A: A Pair of C27-Meroterpenoid Enantiomers with Skeletons from the Roots and Rhizomes of Salvia castanea Diels f. tomentosa Stib.

(±)-Salvicatone A (1), a C27-meroterpenoid featuring a unique 6/6/6/6/6-pentacyclic carbon skeleton with a 7,8,8a,9,10,10a-hexahydropyren-1 (6H)-one motif, was isolated from the roots and rhizomes of Salvia castanea Diels f. tomentosa Stib. Its structure was characterized by comprehensive spectroscopic analyses along with computer-assisted structure elucidation, including ACD/structure elucidator and quantum chemical calculations with 1H/13C NMR and electronic circular dichroism. Biogenetically, compound 1 was constructed from decarboxylation following [4 + 2] Diels-Alder cycloaddition reaction between caffeic acid and miltirone analogue. Bioassays showed that (-)-1 and (+)-1 inhibited nitric oxide production in lipopolysaccharide-induced RAW264.7 macrophage cells with an IC50 value of 6.48 ± 1.25 and 15.76 ± 5.55 µM, respectively. The structure-based virtual screening based on the pharmacophores in ePharmaLib, as well as the molecular docking and molecular dynamics simulations study, implied that (-)-1 and (+)-1 may potentially bind to retinoic acid receptor-related orphan receptor C to exert anti-inflammatory activities.

A novel ent-pimarane-type diterpenoid from Sigesbeckia glabrescens with anti-inflammatory activity.

A novel ent-pimarane-type diterpenoid, sigesbeckia J (1), along with two known diterpenoids, siegesbeckia acid (2) and ent-18-acetoxy-16R,17-dihydroxykauran-19-oic acid (3), were isolated from the aerial parts of Sigesbeckia glabrescens Makino. Their chemical structures were elucidated based on extensive spectroscopic interpretation. The absolute configuration of ent-pimarane-type diterpenoid (1) was determined by comparing experimental and calculated ECD spectra. Compared with the positive control minocycline (IC50 32.84 µM), compound 1 exhibited moderate cell growth anti-inflammatory activities in vitro by testing their inhibition of LPS-induced NO production in BV2 microglial cells, with IC50 value of 58.74 µM.

Two novel polyketones from the leaves and twigs of Clerodendrum trichotomum.

Two novel polyketones, along with four known compounds, were isolated from the leaves and twigs of Clerodendrum trichotomum. Their structures were determined to be clerodendruketone A (1), clerodendruketone B (2), ecdysanols E (3), ecdysanols D (4), 5,5'-dimethoxy-7-oxolariciresinol (5), and (-)-(7'S,8S,8'R)-4,4'-dihydroxy-3,3',5,5'-tetramethoxy-7',9-epoxy-lignan-9'-ol-7-one (6) through the methods of NMR, HRESIMS and ECD data analyses. The antioxidant effects against free radical were tested by DPPH assay. The antibacterial activity against Escherichia coli and Staphylococcus aureus were tested by turbidimetry assay. The results demonstrated that compounds 1 and 2 had significative antibacterial activity, and compound 3 had moderate antioxidant activity.

[A new norsesquiterpenoid from Schisandra chinensis].

This study investigated the chemical components from the leaves and stems of Schisandra chinensis. Three norsesquiterpenoids were isolated from S. chinensis by various column chromatographies(silica gel, Sephadex LH-20, and MCI), reversed-phase medium-pressure preparative, and semi-preparative high-performance liquid chromatography(HPLC). Their structures were identified based on physicochemical properties, mass spectrometry(MS), nuclear magnetic resonance(NMR), ultraviolet(UV), and electro-nic circular dichroism(ECD) as(3R,4R,5R,6S,7E)-3,4,5,6-tetrahydroxy-7-megastigmen-9-one(1),(3S,5R,6R,7E)-3,5,6-trihydroxy-7-megastigmen-9-one(2), and(3S,4R,9R)-3,4,9-trihydroxymegastigman-5-ene(3). Compound 1 was a new compound, and its absolute configuration was determined by ECD. Compounds 2 and 3 were isolated from the Schisandra plant for the first time.

Euphorfistrines A-G, cytotoxic and AChE inhibiting triterpenoids from the roots of Euphorbia fischeriana.

Seven new triterpenoids including two cycloartanes (1-2), a lanostane (3), a tirucallane (4), a dammarane (5), an ursane (6), and an oleanane (7), along with nineteen known triterpenoids (8-26), have been obtained from the roots of Euphorbia fischeriana. Their structures were established by NMR, HRESIMS, single-crystal X-ray diffraction analysis, Mosher's method, NMR calculations, ECD analysis, and comparison with structurally related known analogues. Among them, compounds 1 and 8 were a pair of cycloartane-type triterpenoids epimers. Our bioassays have established that compounds 1-5 and 10 displayed moderate cytotoxic effects, and the structure-activity relationships of cycloartane-type triterpenoids (CTTs) were further examined. Notably, some triterpenoids displayed moderate inhibitory effects against AChE by an in vitro screened experiment. Triterpenoid 7 (Euphorfistrine G, ETG) displayed the potent inhibitory effect with IC50 = 2.45 and Ki = 2.30 µM (inhibition kinetic). And, in silico docking analyses have been performed to investigate the inhibitory mechanism of compound 7.

Two new alcohol glycosides from the roots of Paeonia intermedia C. A. Meyer.

Two new alcohol glycosides, 1-O-ß-d-glucopyranosyl-deoxypaeonisuffrone (1) and 9-O-ß-d-apiofuranoyl-(1→6)-ß-d-glucopyranosyl-xanthoarnol (2), together with eight known compounds (3-10), have been isolated from the dried roots of Paeonia intermedia C. A. Meyer. Their structures were mainly elucidated on the basis of ESIMS, one- and two-dimensional NMR techniques. Antibacterial activities of compounds 1-10 were evaluated, and compounds 9 and 10 showed antibacterial activities against Staphylococcus argenteus CMCC26003 and Escherichia coli CMCC44103. [Formula: see text].

Constituents from the Seeds of Sophora Alopecuroides L.

Three new isoflavone glucosides, kudonol A-C (1-3), two new ester derivatives of phenylpropanoid, kudolignan A and B (4-5) and five known compounds, (-)-maackiain (6), neoliquiritin (7), methyl 4-coumarate (8), methyl ferulate (9) and (+)-wikstromol (10), were isolated from an extract of dried seeds of the traditional Chinese medicinal plant Sophora alopecuroides L. Their structures were established by NMR and HRESIMS data analyses. The monosaccharide part's configuration of isoflavone glucosides was confirmed by acid hydrolysis and analyzed by a JAsco OR-4090 chiral detector, comparing it to standard substance D-glucose. The cytotoxicity effects against HeLa, Hep3B, MCF-7 and H1299 cells were tested by CCK-8 assay.

Chemical characteristics of the fungus Ganoderma lucidum and their inhibitory effects on acetylcholinesterase.

The chemical characteristic of a well-known folk medicine Ganoderma lucidum has been investigated by a series of chromatographic technologies, which displayed the presences of 45 lanostane type triterpenoids, including two new nor-lanostane triterpenoids (40, 41). Their structures were identified on the basis of spectroscopic data analysis (UV, IR, HRESIMS, 1D, and 2D NMR). Notably, some triterpenoids displayed moderate inhibitory effects against AChE (acetylcholinesterase) by an in vitro screened experiment. Triterpenoid 2 displayed the potent inhibitory effect with IC50 10.8 and Ki 14.95 µM (inhibition kinetic). The preliminary SAR has been discussed by the docking analyses between ganoderic acids (1, 2) and AChE.

[Phenolic acid derivatives of Euphorbia ebracteolata].

A variety of chromatographic methods were applied to research the chemical composition of the roots of Euphorbia ebracteolata. Meanwhile, the structures of these compounds were identified by spectroscopic data, such as 1D, 2D NMR and HR-ESI-MS. In the present research, a new phenolic acid compound, 1,3,4,5-tetrahydroxy-2-O-ß-D-[(6'-Gallic acyl)-glucopyranyl] isopentane(1), was isolated from the roots of E. ebracteolata, as well as three known compounds, isopropyl-2-O-ß-D-(6'-gallic acyl)-glucopyranoside(2), ellagic acid(3) and 3,4'-di-O-methylellagic acid(4) respectively. Additionally, compounds 2 and 4 were isolated from the Euphorbia genus for the first time.

Two undescribed constituents from Salvia castanea Diels and evaluation of their cytotoxic activity.

One previously undescribed abietane diterpene alkaloid containing an oxazole ring (1), one unreported abietane diterpene (2), and nine known abietane diterpenes (3-11) were isolated from the roots and rhizomes of Salvia castanea Diels. Their structures and absolute configurations were elucidated by a combination of HRESIMS, 1D and 2D NMR, and ECD. All compounds were evaluated for their cytotoxic activity against several human cancer cell lines (HepG2, A549, H460, MCF7, PC3, and Hela). The results showed that 1 exhibited a moderate cytotoxic effect on HepG2 cells (IC50: 14.22 ± 1.05 µM) and was able to inhibit the cell growth of MCF7 and Hela cells by 35.08% and 47.26% respectively, at a concentration of 20 µM, while other compounds showed low cytotoxic activity.

Salvirrane A-F, six undescribed nordrimane sesquiterpene derivatives from Salvia castanea Diels f. tomentosa Stib and their cytotoxic activities.

Six undescribed nordrimane sesquiterpene derivatives, salvirrane A-F (1-6), were isolated from the roots and rhizomes of Salvia castanea Diels f. tomentosa Stib. Comprehensive spectral analysis and a quantum chemical calculation strategy were employed to determine their structures. These compounds represent four previously unreported nordrimane carbon skeletal types in Salvia genus, including 15-nor-drimane, 11,15-di-nor-drimane, 14,15-di-nor-drimane, and 11,14,15-tri-nor-drimane sesquiterpenes. All compounds were evaluated for their cytotoxic activities against several human cancer cell lines (A549, H460, Hep3B, MCF7, PC3, and HeLa). The results showed that 3 exhibited low activity against MCF7 cells (IC50,72.72 ± 6.95 µM) and moderate activity against HeLa cells (IC50, 9.80 ± 0.64 µM). Moreover, the EdU (5-ethynyl-2'-deoxyuridine) assay demonstrates that 3 displays dose-dependent efficacy in suppressing the proliferation of HeLa cells. Network pharmacology and molecular docking technology implied that 3 may potentially bind to Src (proto-oncogene tyrosine-protein kinase) to exert anti-proliferative activity.

Natural Prenylflavonoids from Sophora flavescens Root Bark against Multidrug-Resistant Methicillin-Sensitive Staphylococcus aureus Targeting the Membrane Permeability.

The overuse of antibiotics in animal farming and aquaculture has led to multidrug-resistant methicillin-sensitive Staphylococcus aureus (MR-MSSA) becoming a common pathogen in foodborne diseases. Sophora flavescens Ait. serves as a traditional plant antibacterial agent and functional food ingredient. A total of 30 compounds (1-30) were isolated from the root bark of S. flavescens, consisting of 20 new compounds (1-20). In the biological activity assay, compound 1 demonstrated a remarkable inhibitory effect on MR-MSSA, with an MIC of 2 µg/mL. Furthermore, 1 was found to rapidly eliminate bacteria, inhibit biofilm growth, and exhibit exceptionally low cytotoxicity. Mechanistic studies have revealed that 1 possesses an enhanced membrane-targeting ability, binding to the bacterial cell membrane components phosphatidylglycerol (PG), phosphatidylethanolamine (PE), and cardiolipin (CL). This disruption of bacterial cell membrane integrity increases intracellular reactive oxygen species, protein and DNA leakage, reduced bacterial metabolism, and ultimately bacterial death. In summary, these findings suggest that compound 1 holds promise as a lead compound against MR-MSSA.

Two new sesquiterpenoids with glycosides from the leaves and stems of Schisandra chinensis (Turcz.) Baill.

Two previously undescribed glycosidic bisnorsesquiterpenoids A - B (1 - 2), together with two known compounds (3 - 4), were isolated from the leaves and stems of Schisandra chinensis. Their structures were elucidated by extensive spectroscopic data (1D, 2D NMR, and HRESIMS). The anti-inflammatory activity, ABTS+ radical scavenging activity, and DPPH radical scavenging activity of compounds 1 - 4 were tested. However, all of these compounds showed only weak anti-inflammatory or antioxidant effects.

Antiproliferative ent-abietane diterpenoids from Euphorbia fischeriana.

Euphorfinoids M and N (1 and 2), two previously undescribed ent-abietane diterpenoids, together with seven known analogues (3-9), were isolated from the roots of wild Euphorbia fischeriana. Their structures were elucidated by spectroscopic analysis, including extensive NMR, HR-ESIMS, ECD, and comparison with structurally related known analogues. Bioassays against proliferative effects of HeLa cell line showed that compound 1 was the most active with IC50 3.62 ± 0.31 µM.

Diterpenoids from Sigesbeckia glabrescens with anti-inflammatory and AChE inhibitory activities.

Fourteen previously undescribed diterpenoids, including seven ent-pimarane-type diterpenoids and seven phytane-type diterpenes, together with five known ones, were isolated from the aerial parts of Sigesbeckia glabrescens. The structures and absolute configurations of undescribed compounds were elucidated based on extensive spectroscopic techniques, ECD calculations, Mo2(OAC)4-induced ECD, Rh2(OCOCF3)4-induced ECD, calculated 13C NMR, and chemical methods. In the anti-inflammatory bioassay, siegetalis H showed potent inhibitory effect on LPS-induced NO production in RAW264.7 murine macrophages with an IC50 value at 17.29 µM. Furthermore, siegetalis H suppressed the protein expression of iNOS and COX-2 in LPS-stimulated RAW264.7 cells. Mechanistically, siegetalis H suppressed the phosphorylation and degradation of IκBα, as well as the activation of the NF-κB signaling pathway. In addition, the AChE inhibition assay displayed that 3-O-acetyldarutigenol had a remarkable inhibitory effect against AChE with an IC50 value at 7.02 µM. Kinetic study on 3-O-acetyldarutigenol indicated that it acted as a mixed-type inhibitor, and the binding mode was explored by molecular docking.

An integrated network pharmacology approach reveals that Darutigenol reduces inflammation and cartilage degradation in a mouse collagen-induced arthritis model by inhibiting the JAK-STAT3 pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Darutigenol (DL) is a natural active product derived from the Chinese herbal medicine Sigesbeckia glabrescens (Makino) Makino. It is administered as a traditional Chinese medicine (TCM) to dispel rheumatism, benefit the joints, and detoxify. However, its potential mechanism in the treatment of rheumatoid arthritis (RA) remains unknown. AIMS OF THE STUDY: The objectives of this research were to determine the effects and elucidate the modes of action of DL on RA-related joint inflammation. MATERIALS AND METHODS: Network pharmacology and molecular docking were used to screen and validate candidate DL targets for RA treatment, respectively. A DBA/1 mouse rheumatoid arthritis model was induced with bovine type II collagen. Intragastric DL administration was followed by the calculation of the clinical arthritis index. A section of the ankle joint was excised and stained and the pathological changes in it were observed. Enzyme-linked immunosorbent assays (ELISA) and western blotting (WB) were used to clarify the mechanisms of DL in RA treatment. RESULTS: DL effectively attenuated the inflammation, mitigated the articular cartilage degradation, and bone erosion, and alleviated the inflammatory joints associated with RA. Network pharmacology screened six key targets of DL while molecular docking revealed that it docked well with its protein targets. The DL treatment group presented with significantly less ankle joint redness and swelling, a lower arthritis index scores and serum and bone marrow supernatant IL-6 levels, more complete ankle joint surfaces, and less synovial inflammation, cartilage degradation, and bone erosion than the collagen-induced arthritis (CIA) group. The DL treatment also substantially downregulated the Janus kinase (JAK)1, JAK3, matrix metalloproteinase (MMP)2, MMP9, and phospho-signal transducer and activator of transcription (p-STAT)3 proteins in the joints. CONCLUSIONS: To the best of our knowledge, the present work was the first to demonstrate that DL has significant anti-inflammatory efficacy and reduces cartilage degradation and bone erosion. It also demonstrated that the anti-RA effect of DL may be explained by its ability to inhibit joint inflammation and reduce articular cartilage degradation through the interleukin (IL)-6/JAK1,3/STAT3 axis and downregulate MMP2 and MMP9. Hence, DL might play a therapeutic role in a mouse RA model.

Euphorfinoids A and B, a pair of ent-atisane diterpenoid epimers from the roots of Euphorbia fischeriana, and their bioactivities.

Euphorfinoids A and B (1 and 2), a pair of ent-atisane diterpenoid epimers with a vicinal 2,3-diol moiety, together with four known analogues (3-6), were isolated from the roots of wild Euphorbia fischeriana. Their structures were elucidated by spectroscopic analysis, including extensive NMR, HR-ESIMS, NMR calculations, X-ray diffraction, and comparison with structurally related known analogues. Our bioassays have established that compound 1 displayed moderate anti-proliferative effects on Hcc1806 cell line with IC50 15.53 ± 0.21 µM, and compound 5 showed remarkable inhibitory effects against AChE with IC50 32.56 ± 2.74 µM by an in vitro screened experiment.

Sophoranone A and B: two new cytotoxic prenylated metabolites and their analogs from the root bark of Sophora flavescens.

Sophora flavescens Ait. has been utilized as an anticarcinogen, antibacterial and insecticide. Two new prenylflavonoids, Sophoflavonoid A (1) and Sophoflavonoid B (2), together with four known analogues were isolated from the root bark of S. flavescens. The structures of these compounds were elucidated by the interpretation of spectroscopic data and chemical evidence. Their absolute configurations were determined by ECD analysis. The inhibitory effects of compounds 1-6 against three lung carcinoma cells were determined using the MTT assay. The results revealed that compound 3 displayed strong cytotoxic effect against H460 cell line (IC50, 4.67 µM), while compounds 1, 4-6 exhibited significant inhibitory effects against three tumor cells. Therefore, this study suggests that the isopentenyl flavonoid-rich products of S. flavescens, including the new compounds, could be valuable candidates for the development of pharmaceuticals in the prevention and treatment for tumors.

Chemical constituents of Sophora flavescens Ait. and cytotoxic activities of two new compounds.

A chemical investigation of Sophora flavescens Ait. identified 6 compounds. On the basis of spectroscopic data, they were determined to be flavonoids and their analogues, among which were two previously undescribed compounds, sophoflavanone G (1) and sophoflavanone H (2). The inhibitory effects of new compounds against five human tumour cell lines were evaluated in vitro by MTT assays, which revealed potential inhibitory effects with IC50 values < 20 mM, in particular, compound 1 has shown significant cytotoxicity for several tumour cells with IC50 values around 20 mM, which was similar to cisplatin and potential to be used as tumour drugs.