A new canthinone glycoside isolated from the root barks of Ailanthus altissima with NO inhibitory activity.

One new canthinone glycoside (1), together with six known compounds (2-7) including three lignans (2-4), two coumarins (5-6) and one phenol (7) was isolated from the root barks of Ailanthus altissima. The structure of new compound 1 was established by the interpretation of UV, IR, MS and NMR data, while its absolute configuration was determined by acid hydrolysis and GIAO NMR calculations with DP4+ probability analysis. The inhibitory effects of all compounds on Nitric oxide (NO) production were investigated in lipopolysaccharide (LPS)-induced RAW 264.7 cells. Results showed that compounds 2 and 5 displayed NO production inhibitory activity with IC50 values of 30.1 and 15.3 µM, respectively.

Sesquiterpene from Artemisia argyi seed extracts: A new anti-acute peritonitis agent that suppresses the MAPK pathway and promotes autophagy.

To find novel anti-inflammatory drugs, we screened anti-inflammatory compounds from 18 different types of Artemisia argyi seed extracts. The in vitro and in vivo anti-inflammatory activities of the screened compounds and their mechanisms were characterized. We first detected the cytotoxic effect of the compounds on RAW264.7 cells and the inhibitory effect on LPS-induced NO release. It was found that sesquiterpenoids CA-2 and CA-4 had low cytotoxic and strong NO inhibitory activity with an IC50 of 4.22 ± 0.61 µM and 2.98 ± 0.23 µM for NO inhibition, respectively. Therefore, compound CA-4 was studied in depth. We found that compound CA-4 inhibited LPS-induced pro-inflammatory factor production and M1 macrophage differentiation in RAW264.7 cells. Additionally, CA-4 inhibited the expression of p-ERK1/2, p-JNK, iNOS, and COX-2 by blocking the MAPK signaling pathway. CA-4 also promoted the expression of autophagy-related proteins such as LC3 II and Beclin-1 by inhibiting activation of the PI3K/AKT/mTOR signaling pathway, and promoted the generation of autophagosomes. Finally, CA-4 significantly inhibited the degree of inflammation in mice with acute peritonitis, showing good anti-inflammatory activity in vivo. Consequently, compound CA-4 may be a promising drug for the treatment of acute inflammatory diseases and provide new ideas for the synthesis of novel anti-inflammatory compounds.

2,3-Seco and 3-nor guaianolides fromAchillea alpina with antidiabetic activity.

In this study, we presented the isolation and characterization of eight novel seco-guaianolide sesquiterpenoids (1-8) and two known guaianolide derivatives (9 and 10), from the aerial part of Achillea alpina L.. Compounds 1-3 were identified as guaianolides bearing an oxygen insertion at the 2, 3 position, while compounds 4-8 belonged to a group of special 3-nor guaianolide sesquiterpenoids. The structural elucidation of 1-8, including their absolute configurations, were accomplished by a combination of spectroscopic data analysis and quantum electronic circular dichroism (ECD) calculations. To evaluate the potential antidiabetic activity of compounds 1-10, we investigated their effects on glucose consumption in palmitic acid (PA)-mediated HepG2-insulin resistance (IR) cells. Among the tested compounds, compound 7 demonstrated the most pronounced ability to reverse IR. Moreover, a mechanistic investigation revealed that compound 7 exerted its antidiabetic effect by reducing the production of the pro-inflammatory cytokine IL-1ß, which was achieved through the suppression of the NLRP3 pathway.

Structurally Diverse Phenolic Amides from the Fruits of Lycium barbarum with Potent α-Glucosidase, Dipeptidyl Peptidase-4 Inhibitory, and PPAR-γ Agonistic Activities.

A total of nine new phenolic amides (1-9), including four pairs of enantiomeric mixtures (3-5 and 8), along with ten known analogues (10-19) were identified from the fruits of Lycium barbarum using bioassay-guided chromatographic fractionation. Their structures were elucidated by comprehensive spectroscopic and spectrometric analyses, chiral HPLC analyses, and quantum NMR, and electronic circular dichroism calculations. Compounds 5-7 are the first example of feruloyl tyramine dimers fused through a cyclobutane ring. The activity results indicated that compounds 1, 11, and 13-17 exhibited remarkable inhibition against α-glucosidase with IC50 of 1.11-33.53 µM, 5-150 times stronger than acarbose (IC50 = 169.78 µM). Meanwhile, compounds 4a, 4b, 5a, 5b, 13, and 14 exerted moderate agonistic activities for peroxisome proliferator-activated receptor (PPAR-γ), with EC50 values of 10.09-44.26 µM. Especially,compound 14 also presented inhibitory activity on dipeptidyl peptidase-4 (DPPIV), with an IC50 value of 47.13 µM. Furthermore, the banding manner of compounds 14 and 17 with the active site of α-glucosidase, DPPIV, and PPAR-γ was explored by employing molecular docking analysis.

Monomeric and dimeric guaianolide sesquiterpenoids with hypoglycemic activity from Achillea alpina.

Three new monomeric (1-3) and two newdimeric guaianolides (4 and 5), along with three known analogues (6-8) were isolated from the aerial part of Achillea alpina L. Compounds 1-3 were three novel 1,10-seco-guaianolides, while 4 and 5 were two novel 1,10-seco-guaianolides involved heterodimeric [4 + 2] adducts. The new structures were elucidated by analysis of spectroscopic data and quantum chemical calculations. All isolates were evaluated for their hypoglycemic activity with a glucose consumption model in palmitic acid (PA)-induced HepG2-insulin resistance (IR) cells, and compound 1 showed the most promising activity. A mechanistic study revealed that compound 1 appeared to mediate hypoglycemic activity via inhibition of the ROS/TXNIP/NLRP3/caspase-1 pathway.

Dysosmaflavonoid A-F, new flavonols with potent DPPH radical scavenging activity from Dysosma versipellis.

Six new flavonols, including four glucosylated flavonols (dysosmaflavonoid A-D), one phenylpropanoid-substituted flavonol (dysosmaflavonoid E), and one phenyl-substituted flavonol (dysosmaflavonoid F), together with five known analogues, were isolated from the roots and rhizomes of Dysosma versipellis. Their structures were elucidated by comprehensive analysis of their NMR, IR, UV, HRESIMS, and HPLC data. The antioxidant activities of all isolated compounds were examined by 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay. Compounds 2, 3, 5-8, and 12 exhibited significant DPPH scavenging capacity with IC50 values of 33.95, 39.02, 31.17, 32.79, 31.85, 30.48, and 23.75 µM, respectively, in comparison with Trolox (IC50, 15.80 µM). Compound 12 displayed more potent DPPH radical scavenging activity than prenylated and (or) glucosided derivatives (2-4, or 10). The preliminary structure-activity relationship showed that the catechol structure in flavonol is essential for DPPH radical scavenging effect.

LSD1 inhibitors from the roots of Pueraria lobata.

One new 6a,11a-dehydropterocarpan derivative, 6-O-methyl-anhydrotuberosin (1), one new 6a-hydroxypterocarpan, (6aR,11aR,11bR)-hydroxytuberosone (7), and seven known compounds including two 6a,11a-dehydropterocarpans (2 and 4), two coumestans (3 and 5), one isoflavonoid (6) and two other phenolic compounds (8 and 9) were isolated from the roots of Pueraria lobata. The structures of the isolated compounds were elucidated with spectroscopic and spectrometric methods (1 D and 2DNMR, HRESIMS). Compounds 1, 2, 4-5 showed potent LSD1 inhibitory activities with IC50 values ranging from 1.73 to 4.99 µM. Furthermore, compound 2 showed potent cytotoxicity against gastric cancer cell lines MGC-803 and BGC-823, and lung cancer cell lines H1299 and H460.

Two new guaianolide-type sesquiterpenoids with NO inhibitory activity from Chrysanthemum indicum.

Two new guaianolide-type sesquiterpenoids chrysanthemulides K and L (1 and 2), together with six known analogues (3-8), were isolated from an CH2Cl2 extract of the aerial parts of Chrysanthemum indicum. The structures of new compounds 1 and 2 were established by extensive spectroscopic analysis, including UV, IR, MS, NMR and computational electronic circular dichroism (ECD) methods. Inhibitory effects of all compounds on nitric oxide production were investigated in lipopolysaccharide (LPS)-induced RAW 264.7 cells. Results showed that compounds 1-8 displayed NO production inhibitory activity with IC50 values ranged from 3.5 to 34.3 µM.

Germacranolide- and guaianolide-type sesquiterpenoids from Achillea alpina L. reduce insulin resistance in palmitic acid-treated HepG2 cells via inhibition of the NLRP3 inflammasome pathway.

Chemical investigation on the aerial part of Achillea alpina L. led to the isolation of twenty sesquiterpenoids. The structures of the undescribed achigermalides A-H were determined by extensive spectroscopic analysis, including NMR, HRESIMS, UV and IR, and their absolute configurations were established by computational electronic circular dichroism (ECD) method. The X-ray crystal structure for 8α-angeloxy-1ß,2ß:4ß,5ß-diepoxy-10ß-hydroxy-6ßH,7αH,11ßH-12,6α-guaianolide was reported for the first time. Glucose consumption was analyzed to investigate the effect of all compounds on palmitic acid (PA)-mediated insulin resistance (IR) in HepG2 cells, and achigermalides D-F, desacetylherbohde A, and 4E,10E-3-(2-methylbutyroyloxy)-germacra-4,10(1)-diene-12,6α-olide appreciably enhanced the glucose consumption at low concentrations of 1.56-6.25 µM. Moreover, achigermalide D decreased the expression of IL-1ß and the generation of reactive oxygen species (ROS), and also down-regulated the protein levels of TXNIP, NLRP3, caspase-1 and NF-κB in the Western blot analysis, suggesting achigermalide D mediated IR via the suppression of NLRP3 inflammasome pathway.

Hypeisoxazole A, a Racemic Pair of Tetrahydroisoxazole-Fused Benzylisoquinoline Alkaloids from Hypecoum erectum and Structural Revision of Hypecoleptopine.

(±)-Hypeisoxazole A (1), a racemic pair of rearranged benzylisoquinoline alkaloids possessing an unprecedented diindeno[2,1-c:2',1'-d] isoxazole scaffold, was isolated from the medicinal herb Hypecoum erectum, along with hypecoleptopine (2), whose structure is now revised as a novel spiro-benzylisoquinoline alkaloid with a 6/6/5/6/6 skeleton. Their structures were determined by comprehensive spectroscopic and spectrometric analyses, X-ray diffraction, and computational studies. Racemic mixture of 2 and its pure enantiomers modulated neuronal excitability activity.

Cytotoxic Polyhydroxylated Oleanane Triterpenoids from Cissampelos pareira var. hirsuta.

Three new polyhydroxylated oleanane triterpenoids, cissatriterpenoid A-C (1-3), along with one known analogue (4), were isolated from the whole plant of Cissampelos pareira var. hirsuta. Their chemical structures were elucidated by extensive spectroscopic data (IR, HR-ESI-MS, 1H-NMR, 13C-NMR, DEPT, 1H-1H COSY, HSQC, HMBC, NOESY) and the microhydrolysis method. The isolation of compounds 1-4 represents the first report of polyhydroxylated oleanane triterpenoids from the family Menispermaceae. All isolated compounds were evaluated for their cytotoxicity against five human cancer cell lines, and the inhibitory activity against NO release in LPS-induced RAW 264.7 cells. Compound 3 showed the most potent cytotoxic activities against the A549, SMMC-7721, MCF-7, and SW480 cell lines, with IC50 values of 17.55, 34.74, 19.77, and 30.39 µM, respectively, whereas three remaining ones were found to be inactive. The preliminary structure-activity relationship analysis indicated that the γ-lactone ring at C-22 and C-29, and the olefinic bond at C-12 and C-13 were structurally required for the cytotoxicity of polyhydroxylated oleanane triterpenoids against these four cell lines. Based on lipid-water partition coefficients, compound 3 is less lipophilic than 1 and 4, which agrees with their cytotoxic activities. This confirms the potential of C. pareira var. hirsuta in the tumor treatment.

Iridoid glycosides isolated from Nardostachys chinensis batal with NO production inhibitory activity.

Investigation into the chemical diversity of Nardostachys chinensis Batal led to the discovery of three new (1-3) and one known (4) iridoid glycosides. Their structures were established through spectroscopic methods including 1 D and 2 D NMR experiments and HRESIMS analysis. Inhibitory effects of 1-4 on nitric oxide production were investigated in lipopolysaccaride (LPS)-mediated RAW 264.7 cells, and they displayed IC50 values in the range 7.8-15.2 µM.

Iso-seco-tanapartholide activates Nrf2 signaling pathway through Keap1 modification and oligomerization to exert anti-inflammatory effects.

Covalent modification of Keap1 results in reducing ubiquitination and the accumulation of Nrf2, which subsequently initiates the transcription of cellular anti-oxidant and anti-inflammatory genes. Iso-seco-tanapartholide (IST), a sesquiterpene isolated from the traditional Chinese medicine Artemisia argyi, had been reported to possess NF-κB inhibitory activity. However, its deep anti-inflammatory effects and direct target have never been reported. Here we show that IST activated Nrf2 and increased its target gene expression. In particular, LPS-caused inflammation in vitro and in vivo was mitigated by IST-induced Nrf2 activation but aggravated by Nrf2 inhibition. Mechanically, IST targeted Keap1 proteins via alkylating its cysteine residues 151, 273, 288, and so on. Subsequently, the modifying agent IST was displaced by intermolecular sulfhydryl disulfide interchange to lead to a disulfide dimer of Keap1. The resulting conformational change of Keap1 liberated Nrf2 from sequestration and allowed it translocation to the nucleus to activate the transcriptional program. Further studies demonstrated that Keap1 dimer formation contributed to the anti-inflammatory effects of IST. Taken together, our findings reveal a new mechanism for Nrf2 activation and provide a potential lead compound to treat inflammatory diseases through targeting Keap1.

Penispidins A-C, Aromatic Sesquiterpenoids from Penicillium virgatum and Their Inhibitory Effects on Hepatic Lipid Accumulation.

Penispidins A-C (1-3), new aromatic sesquiterpenoids with two classes of rare carbon skeletons, were isolated from the endophytic fungus Penicillium virgatum HL-110. 1 represents the first example of a dunniane-type aromatic sesquiterpenoid, possessing a novel 4/6/6 tricyclic system, while (±)-2 and 3 have a 7,12-cyclized bisabolene skeleton, featuring a 3,4-benzo-fused 2-oxabicyclo[3.3.1]nonane central framework. Their structures were elucidated on the basis of spectroscopic methods, single-crystal X-ray diffraction, and ECD calculations. 1 inhibited hepatic lipid accumulation in HepG2 cells.

Lycibarbarines A-C, Three Tetrahydroquinoline Alkaloids Possessing a Spiro-Heterocycle Moiety from the Fruits of Lycium barbarum.

Three tetrahydroquinoline alkaloids, lycibarbarines A-C (1-3), possessing a unique tetracyclic tetrahydroquinoline-oxazine-ketohexoside fused motif, were isolated from the fruits of Lycium barbarum. Their structures were determined by spectroscopic analysis and quantum-chemical calculations. Compounds 1 and 3 exhibited neuroprotective activity when evaluated for corticosterone-induced injury by reducing the apoptosis of PC12 cells through the inhibition of caspase-3 and caspase-9.

Correction: Neuroinflammatory inhibitors from Gardneria nutans Siebold & Zuccarini.

[This corrects the article DOI: 10.1039/D1RA05204G.].

Two new flavonoid glucosides from the fruits of Sinopodophyllum hexandrum.

Two new flavonoid glucosides, sinoflavonoidgs A (1) and B (2), along with three known analogues 3-5, were isolated from the fruits of Sinopodophyllum hexandrum. Their structures were established on the basis of extensive spectroscopic (UV, IR, HR-ESI-MS, 1H-NMR, 13C-NMR, HSQC, HMBC) and chromatographic (HPLC) analysis. The isolation of compounds 1-2 represents the first report of ring B-glucosided flavonoids from the genus Sinopodophyllum. The cytotoxic activities of all isolated compounds were evaluated in comparison with etoposide against four cell lines (MCF-7, HepG2, HeLa, KB). The antioxidant activities of all isolated compounds were examined by DPPH free radical-scavenging assay. The preliminary structure-activity relationships showed that the glycosilation of 3-methoxyquercetin at C-3' resulted in a greater decrease of cytotoxic and antioxidant activity.

Sesquiterpenoids from Artemisia argyi and their NO production inhibitory activity in RAW264.7 cells.

Investigation into the chemical diversity of Artemisia argyi led to the discovery of two new (1, 4) and four known (2-3, 5-6) sesquiterpenoids. The new structures were determined via extensive spectroscopic data, including IR, UV, MS, and NMR, and the absolute configurations of these compounds were elucidated by calculated ECD method. All isolates were tested for their inhibitory activity against NO production in RAW 264.7 macrophages, and the isolated sesquiterpenoids exhibited NO production inhibitory activity with IC50 values ranging from 1.91 to 36.52 µM.

Neuroinflammatory inhibitors from Gardneria nutans Siebold & Zuccarini.

Two new monoterpene indole alkaloid glycosides nutanoside A-B (1-2), two new phenolic glycoside esters nutanester A-B (6-7), together with five known compounds (3-5, 8-9) were isolated from the ethanol extract of Gardneria nutans Siebold & Zuccarini. Their structures were established on the basis of extensive spectroscopic analysis and TDDFT/ECD calculations. Compounds 1 and 2 are two rare monoterpene indole alkaloids with the glucosyl moiety located at C-12 and represent the first two examples of enantiomer of ajmaline type monoterpene indole alkaloids. Compounds 3, 4 and 6 displayed significant inhibitory effects on NO production in over-activated BV2 microglial cells, with the IC50 values of 2.29, 6.36, and 8.78 µM, respectively. Compounds 1, 5, 7 could significantly inhibit the mRNA expression of inflammatory factors TNF-α and IL-6 induced by LPS in BV2 microglial cells at the effective concentration. Moreover, compound 3 exhibited stronger cytotoxicities against U87 and HCT116 cell lines than taxol with IC50 values of 10.58 and 14.60 µM, respectively.

Structure and absolute configuration assignments of ochracines F-L, chamigrane and cadinane sesquiterpenes from the basidiomycete Steccherinum ochraceum HFG119.

Ochracines F-L (1-7), seven previously undescribed chamigrane and cadinane sesquiterpenoids, together with four known chamigranes were isolated from cultures of the wood-decaying fungus Steccherinum ochraceum HFG119. Ochracines F-L were structurally characterized by extensive analysis of HRMS and NMR spectroscopic data. The relative configurations were assigned through a combination of NOE correlations and J-based configuration analysis (JBCA), while the absolute configurations were determined by X-ray single-crystal diffraction, and calculated methods (ECD, [α], 13C NMR). All the new isolates were evaluated for their cytotoxicity against five human cancer cell lines HL-60, SMMC-7721, A549, MCF-7, and SW-480, and inhibitory activity on NO production in RAW 264.7 macrophages.