Chemical constituents of Wikstroemia alternifolia and their neuroprotective activities.

Phytochemical investigation on the plant of Wikstroemia alternifolia led to the isolation of 26 compounds including two new ones, wikstralternifols A and B (1 and 7). Their structures including the absolute configuration were elucidated by spectroscopic data together with analysis of experimental and calculated ECD data. All compounds were isolated from this plant for the first time, and their main structural types were lignans, sesquiterpenoids, and flavonoids. In the sodium nitroprusside-induced rat pheochromocytoma PC-12 cell model, the neuroprotective activities of the selected sesquiterpenoids (1 and 4) and lignans (7 - 14) were screened at the concentration of 10 µM, and 7 - 14 displayed better activities than the positive control edaravone.

Prenylated dihydroflavones from the root barks of Morus alba.

Three new prenylated dihydroflavones, moralbaflavones A-C (1-3), together with four known ones (4a/4b, 5, and 6) were isolated from the root barks of Morus alba L. Their structures including the absolute configurations were determined by the analysis of HRMS, NMR, and ECD data. The neuroprotective properties of these prenylated dihydroflavones were screened at the concentration of 10 µM in the sodium nitroprusside-induced rat pheochromocytoma PC-12 cells, and the results showed moralbaflavone C (3) possessed significant neuroprotective activity, being more potent than the positive control edaravone.

Discovering a New Okadaic Acid Derivative, a Potent HIV Latency Reversing Agent from Prorocentrum lima PL11: Isolation, Structural Modification, and Mechanistic Study.

Marine toxins (MTs) are a group of structurally complex natural products with unique toxicological and pharmacological activities. In the present study, two common shellfish toxins, okadaic acid (OA) (1) and OA methyl ester (2), were isolated from the cultured microalgae strain Prorocentrum lima PL11. OA can significantly activate the latent HIV but has severe toxicity. To obtain more tolerable and potent latency reversing agents (LRAs), we conducted the structural modification of OA by esterification, yielding one known compound (3) and four new derivatives (4-7). Flow cytometry-based HIV latency reversal activity screening showed that compound 7 possessed a stronger activity (EC50 = 46 ± 13.5 nM) but was less cytotoxic than OA. The preliminary structure-activity relationships (SARs) indicated that the carboxyl group in OA was essential for activity, while the esterification of carboxyl or free hydroxyls were beneficial for reducing cytotoxicity. A mechanistic study revealed that compound 7 promotes the dissociation of P-TEFb from the 7SK snRNP complex to reactivate latent HIV-1. Our study provides significant clues for OA-based HIV LRA discovery.

Diversity of sesquiterpenoids from Stellera chamaejasme with neuroprotective effects.

Chromatographic fractionation of the 95% EtOH extract of the roots of Stellera chamaejasme yielded 20 sesquiterpenoids of four different types, guaiane-, carotane-, sesquicarane-, and alpiniane-types. Among them, sesquistrachanoids A-F were previously undescribed ones, whose structures including absolute configurations were elucidated by spectroscopic methods, the Mo2(OAc)4-induced ECD experiment, and analysis of experimental and calculated 1D NMR and ECD data. Sesquistrachanoid A is a 2,3-seco-guaiane-type sesquiterpenoid with a α-pyrone core and sesquistrachanoid B is the first example of 8,9-seco-guaiane-type sesquiterpenoid featured with an 1,8-δ-lactone core. Sesquistrachanoid C is a guaiane sesquiterpenoid characterized by a peroxide bridge between C-8 and C-10. All sesquiterpenoids were evaluated for their neuroprotective effects on cell damage induced by sodium nitroprusside in PC-12 cells. The bioassay results showed that six compounds at 10 µM could restore the cell viability, being comparable to that of the positive control edaravone. The mechanistic study on the most pronounced activity compound, stelleraguaianone B, demonstrated that it played a neuroprotective role by promoting the mRNA expression of antioxidant enzymes to reduce oxidative stress.

Homo/Hetero-Dimers of Aromatic Bisabolane Sesquiterpenoids with Neuroprotective Activity from the Fungus Aspergillus versicolor A18 from South China Sea

Chromatographic fractionation of the EtOH extracts of the marine-derived fungus Aspergillus versicolor A18 has led to the isolation of 11 homo/hetero-dimers of aromatic bisabolane sesquiterpenoids including eight diphenyl ether-coupled aromatic bisabolanes (1a/1b and 5−10) and three homodimers (2−4), together with their monomers including three aromatic bisabolanes (11−13) and two diphenyl ethers (14 and 15). Their structures and absolute configurations were elucidated by extensive spectroscopic analysis including HRESIMS, 1D/2D NMR, calculated ECD, and the optical rotatory data. Among the four new compounds, (+/−)-asperbisabol A (1a/1b), asperbisabol B (2), and asperbisabol C (3), the enantiomers 1a and 1b represent an unprecedented skeleton of diphenyl ether-coupled aromatic bisabolane sesquiterpenoids with a spiroketal core moiety. The neuroprotective effects of selected compounds against sodium nitroprusside (SNP)-induced injury were evaluated in PC12 cells by the MTT assay. Five compounds (1a, 6, and 8−10) showed remarkable neuroprotective activities at 10 µM, being more active than the positive control edaravone.

A new tigliane-type diterpenoid from Euphorbia tirucalli.

Five tigliane (1-5) and one ingenane (6) diterpenoids were isolated from the ethanol extract of Euphorbia tirucalli. The structures of these compounds were identified based on analysis of their spectroscopic data. Among them, compound 12-O-(2E,4E,6E,8E-tetradecatetraenoyl)-13-O-isobutyroyl-4ß-deoxyphorbol (1) was a new tigliane. The Rho123 effluxion assay showed that tiglianes with a trans-fused 5/7 ring system such as compounds 1, 2, and 4 had potent inhibitory activity against P-glycoprotein in HepG2/ADR cells.

(+)-Isobicyclogermacrenal and spathulenol from Aristolochia yunnanensis alleviate cardiac fibrosis by inhibiting transforming growth factor ß/small mother against decapentaplegic signaling pathway.

Cardiac fibrosis contributes to both systolic and diastolic dysfunction in many cardiac pathophysiologic conditions. Antifibrotic therapies are likely to be a crucial strategy in curbing many fibrosis-related cardiac diseases. In our previous study, an ethyl acetate extract of a traditional Chinese medicine Aristolochia yunnanensis Franch. was found to have a therapeutic effect on myocardial fibrosis in vitro and in vivo. However, the exact chemicals and their mechanisms responsible for the activity of the crude extract have not been illustrated yet. In the current study, 10 sesquiterpenoids (1-10) were isolated from the active extract, and their antifibrotic effects were systematically evaluated in transforming growth factor ß 1 (TGFß1)-stimulated cardiac fibroblasts and NIH3T3 fibrosis models. (+)-Isobicyclogermacrenal (1) and spathulenol (2) were identified as the main active components, being more potent than the well-known natural antifibrotic agent oxymatrine. Compounds 1 and 2 could inhibit the TGFß1-induced cardiac fibroblasts proliferation and suppress the expression of the fibrosis biomarkers fibronectin and α-smooth muscle actin via down-regulation of their mRNA levels. The mechanism study revealed that 1 and 2 could inhibit the phosphorylation of TGFß type I receptor, leading to the decrease of the phosphorylation levels of downstream Smad2/3, then consequently blocking the nuclear translocation of Smad2/3 in the TGFß/Smad signaling pathway. These findings suggest that 1 and 2 may serve as promising natural leads for the development of anticardiac fibrosis drugs.

Anti-inflammatory Ingenane Diterpenoids from the Roots of Euphorbia kansui.

Bioassay-guided fractionation of the ethanolic extract of the roots of Euphorbia kansui led to the isolation of two new ingenane diterpenoids, euphorkans A (1: ) and B (2: ), together with 16 known analogues (3:  - 18: ). Their structures were determined by combined spectral and chemical methods. All the isolates were evaluated for their inhibitory effects on lipopolysaccharide-induced nitric oxide production in RAW264.7 macrophage cells. Compounds 1:  - 6: and 10:  - 13: exhibited pronounced inhibitory activity with IC50 values in the range of 2.78 - 10.6 µM, and were more potent than the positive control, quercetin (IC50 = 15.8 µM). Compounds 1: and 5: were selected for further assays toward the key inflammation mediators TNF-α and IL-6, and showed a significant inhibition in a dose-dependent manner. The preliminary mechanistic study revealed that 1: and 5: inhibited NF-κB activity, which may exert a role in their anti-inflammatory activity.

A new selaginellin derivative and a new triarylbenzophenone analog from the whole plant of Selaginella pulvinata.

Five selaginellin derivatives (1 and 3-6) including a new one, selaginellin T (1), and a new triarylbenzophenone analog, selagibenzophenone A (2), were isolated from the whole plants of Selaginella pulvinata. Their structures were determined by 1D- and 2D-NMR and HR-ESI-MS data. Selagibenzophenone A (2) is the first example of naturally occurring triarylbenzophenone. The results of the phosphodiesterase-4 (PDE4) inhibitory screening assays showed that compounds 1-6 exhibited potent activities with the IC50 values in the range of 1.04-9.35 µM.