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.

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.

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.

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.

1,10-seco guaianolide-type sesquiterpenoids from Chrysanthemum indicum.

ABSTACTA chemical investigation of the whole plant of traditional Chinese medicine, Chrysanthemum indicum L., led to the discovery of six guaianolide-type sesquiterpenoids 1-6 with a 1,10-splited skeleton. The structure of the new compound 1 was established by extensive analysis of UV, IR, MS, NMR and ECD data. Compounds 3-6 are mutually stereoisomers with four chiral centers and their absolute configurations were determined by comparison of ECD spectra. The anti-inflammatory effects of these isolates on lipopolysaccharide (LPS)-induced nitric oxide (NO) were investigated in RAW 264.7 cells. Results showed that most of the compounds displayed NO production inhibitory activities with IC50 values ranged from 3.54 to 8.17 µM.

Chrysanthemulide A induces apoptosis through DR5 upregulation via JNK-mediated autophagosome accumulation in human osteosarcoma cells.

Osteosarcoma is the most frequent malignant primary bone tumor, and it generally develops a multidrug resistance. Chrysanthemulide A (CA) is a sesquiterpenoid from the herb Chrysanthemum indicum that has demonstrated a great anti-osteosarcoma potential. In this study, CA-induced apoptotic cell death resulted in the activation of the caspase-8-mediated caspase cascade, as evidenced by the cleavage of the substrate protein Bid and the caspase-8 inhibitor Z-VAD-FMK. The CA treatment upregulated the expression of death receptor 5 (DR5) in both whole cells and the cell membrane. Blocking DR5 expression by the small interfering RNA (siRNA) treatment decreased the caspase-8-mediated caspase cascade and efficiently attenuated CA-induced apoptosis, suggesting the critical role of DR5 in CA-induced apoptotic cell death. CA-induced upregulation of the DR5 protein was accompanied by the accumulation of LC3B-II, indicating the formation of autophagosomes. Importantly, DR5 upregulation was mediated by transcriptionally controlled autophagosome accumulation, as blockade of autophagosomes by LC3B or ATG-5 siRNA substantially decreased DR5 upregulation. Furthermore, CA activated the c-Jun N-terminal kinase (JNK) signaling pathway, and treatment with JNK siRNAs or inhibitor SP600125 significantly attenuated CA-mediated autophagosome accumulation and DR5-mediated cell apoptosis. Finally, CA sensitized the osteosarcoma cells to the DR5 ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptotic cell death. Above all, these results suggest that CA induces apoptosis through upregulating DR5 via JNK-mediated autophagosome accumulation and that combined treatment with CA and TRAIL might be a promising therapy for osteosarcoma.

Isolation, Chiral-Phase Resolution, and Determination of the Absolute Configurations of a Complete Series of Stereoisomers of a Rearranged Acetophenone with Three Stereocenters.

A synthesis-inspired chemical investigation of the leaves of Melicope ptelefolia led to the isolation of evodialones A-D (1-4), four rearranged acetophenone stereoisomers possessing a prenylated acylcyclopentenone skeleton with three stereogenic carbons. Evodialones C and D (3 and 4) are new minor constituents. The chiral-phase HPLC resolution gave (+)-1-4 and (-)-1-4, eight enantiomers forming a complete stereoisomer library. Their absolute configurations were elucidated via extensive spectroscopic data and a modified Mosher's method. The relationship between the chiral structures and their NMR and ECD data is discussed. Compounds (±)-1, -2, and -4 have significant protective effects on high-glucose-induced oxidative stress in human vein endothelial cells.

Artemisianins A-D, new stereoisomers of seco-guaianolide involved heterodimeric [4+2] adducts from Artemisia argyi induce apoptosis via enhancement of endoplasmic reticulum stress.

Artemisianins A-D (1-4), four stereoisomers of sesquiterpenoid dimers, forming via [4+2] cycloaddition from a 1, 10-seco-guaianolide dienophile and a guaianolide diene, along with two biosynthetically related precurors 5 and 6, were isolated from the famous traditional Chinese medicine Artemisia argyi. The structures of 1-4, including their absolute configurations, were elucidated by extensive spectroscopic data and ECD/TDDFT calculation analysis. Compounds 1-4 exhibited cytotoxicity with IC50 values ranging from 7.2 to 23.3 µM. The accumulation of Ca2+ in cytoplasm and enlarged endoplasmic reticulum (ER) indicated that 1 mediated HT-29 cancer cell apoptosis through improvement of ER-stress, which was further proved by unfolded protein response (UPR) pathway on basis of the upregulation of IRE1α, p-PERK, ATF6, and CHOP.

Highly Oxidized Guaianolide Sesquiterpenoids with Potential Anti-inflammatory Activity from Chrysanthemum indicum.

Ten new highly oxidized monomeric (1-8) and dimeric guaianolides (9 and 10), along with two known guaianolide derivatives (11 and 12), were isolated from the aerial parts of Chrysanthemum indicum using a bioassay-guided fractionation procedure. The new compounds were characterized by the basic analysis of the spectroscopic data obtained, and the absolute configurations were determined by both empirical approaches and ECD calculations. Inhibitory effects of 1-12 on nitric oxide production were investigated in lipopolysaccaride (LPS)-mediated RAW 264.7 cells, and most of them (1-8 and 11) displayed IC50 values in the range 1.4-9.7 µM. Moreover, a mechanistic study revealed that the potential anti-inflammatory activity of compound 1 appears to be mediated via suppression of an LPS-induced NF-κB pathway and down-regulation of MAPK activation.

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.

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.

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.

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.

Correction: Neuroinflammatory inhibitors from Gardneria nutans Siebold & Zuccarini.

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

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.

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.