Lathyrane diterpenoids with multidrug resistance reversal activity from the tubers of Euphorbia antiquorum.

Nine previously unreported lathyrane diterpenoids named euphorantesters A-I, along with 16 known analogues, have been separated from the tubers of Euphorbia antiquorum. Their structures were established by means of spectroscopic analyses, time-dependent density functional theory based electronic circular dichroism calculation and single crystal X-ray crystallography. Their reversal ability against P-glycoprotein-mediated multidrug resistance (MDR) in MCF-7/ADR cell line was then evaluated, and 15 ones exhibited moderate MDR reversal activity with reversal fold falling in the range of 1.12-13.15. The most active euphorantester B could effectively increase the sensitivity of MCF-7/ADR cell to adriamycin comparably to the reference drug verapamil.

Grifolin Induces Cell Death of Human Lung Cancer A549 Cell Line via Inhibiting KRAS-Mediated Multiple Signaling Pathways.

In the current work, grifolin was obtained from the twigs and leaves of Daphne genkwa for the first time and displayed significant growth inhibition against human lung carcinoma A549 cells. Subsequent in vitro antitumor evaluation revealed that grifolin could induce remarkable cell apoptosis and G0/G1 phase arrest, as well as block cell migration and invasion. In addition, grifolin also disrupted cellular energy metabolism by inducing reactive oxygen species, reducing adenosine triphosphate and mitochondrial membrane potential, and damaging DNA synthesis. Further RNA-seq analysis demonstrated that treatment of grifolin on A549 cells led to gene enrichment in MAPK, PI3K/Akt and NF-κB signaling pathways, all of which were inhibited by grifolin according to immunoblotting experiments. Further mechanistical studies disclosed that the expression of a key upstream protein KRAS was also blocked, and the cell death triggered by grifolin could be rescued by a RAS activator ML-099. Moreover, pretreatment of ML-099 on A549 cells could reverse the grifolin-induced downregulation of key proteins in the three aforementioned pathways. These findings indicate that grifolin could induce cell death in A549 cell line by inhibiting KRAS-mediated multiple signaling pathways.

Bioactive monoterpenoids and acetophenones from the aerial parts of Eupatorium fortunei.

Thirty-nine thymol and acetophenone derivatives, including eight pairs of enantiomers, were isolated from the aerial parts of Eupatorium fortunei. Their structures were assigned by detailed analyses of spectroscopic data and NMR calculations based on density functional theory, with 18 ones (1a/1b-14) being previously undescribed compounds. While the absolute configurations of 1a/1b, 2a/2b, 4, 6a/6b, 7, 11a/11b and 15a/15b-18a/18b were established by calculations of electronic circular dichroism data, that of 14 was determined by modified Mosher's method. Compounds 1a/1b and 2a/2b represent a previously unreported type of monoterpenoid dimers via an amide linkage, and compound 3 is a monoterpene-phenylpropanoid hybrid connected through an ester bond. Among the known molecules, the formerly mis-assigned structures of 15a/15b and 22 were revised, and pure natural enantiomers of 16a/16b-18a/18b were reported for the first time. Selective compounds showed antiradical and NO production inhibitory activities in the preliminary biological screening. Compound 31 was further demonstrated to alleviate oxidative stress by activating Nrf2 signaling pathway.

Structurally Diverse Sesquiterpenoids with NO Production and α-Glucosidase Inhibitory Activities from the Fruits of Schisandra chinensis.

Chemical fractionation of the AcOEt partition, generated from the EtOH extract of the fruits of Schisandra chinensis, afforded a series of sesquiterpenyl constituents including two new cadinanes, a new eudesmane, two new widdranes (a handling artefact and a new natural product), a new bisabolane and two new natural cuparane enantiomers, along with 15 known structurally related analogs. Structures of the new compounds were unambiguously characterized by interpretation of detailed spectroscopic data including ESI-MS and 1D/2D NMR, with their absolute configurations being established by electronic circular dichroism (ECD) calculation and induced ECD experiment. The inhibitory effects of all the isolates against α-glucosidase and lipopolysaccharide (LPS) induced nitric oxide (NO) production in murine RAW264.7 macrophages, as well as their antibacterial and cytotoxic potential, were evaluated, with selective compounds showing moderate α-glucosidase and NO inhibitory activity. Notably, canangaterpene III exhibited the most significant NO inhibitory effect with an IC50 value of 31.50±1.49 µM.

Meroterpenoids from Daphne genkwa shows promising in vitro antitumor activity via inhibiting PI3K/Akt/mTOR signaling pathway in A549 cells.

Phytochemical investigation into the leaves and branches of Daphne genkwa afforded 25 meroterpenoids (1-16) including nine pairs of enantiomers (1a/1b-8a/8b and 12a/12b), among which 20 compounds have been reported in the present work for the first time. The structures with absolute configurations of the new molecules (excluding 10-13) were established via comprehensive spectroscopic analyses especially electronic circular dichroism (ECD) and Mosher's methods. A preliminary in vitro cell viability assay revealed remarkable cytotoxicities of selective compounds against A549 (lung), Hela (cervical), MDA-MB231 (breast) and MCF-7 (breast) cancer cells, and compound 8a showed the best inhibitory activity with IC50 values in the range of 3.12-4.67 µM toward the four cell lines. Subsequent in vitro antitumor evaluation of 8a disclosed that it could inhibit the proliferation and metastasis, as well as induce significant apoptosis and cycle arrest, of A549 cells. Further mechanistic investigations revealed that 8a could exert its antitumor activity via inhibiting the PI3K/Akt/mTOR signaling pathway.

Identification of Small-Molecule Bioactive Constituents from the Leaves of Vaccinium bracteatum Confirms It as a Potential Functional Food with Health Benefits.

The health benefits of Vaccinium bracteatum are well recorded in ancient Chinese medical books and were also demonstrated by modern researches. However, the relationship between its beneficial functions and specific chemical constituents has not been fully characterized. This study investigated the bioactive small-molecule constituents in the leaves of V. bracteatum, which afforded 32 compounds including ten new ones (1-9) and ten pairs of enantiomers (9-18). Their structures with absolute configurations were elucidated by spectroscopic methods, especially nuclear magnetic resonance (NMR) and electronic circular dichroism (ECD) analyses, with 1-4 bearing a novel revolving-door shaped scaffold. While half-compounds exhibited decent antioxidant activity by scavenging 2,2-diphenyl-1-picrylhydrazyl (DPPH) radicals, all except 19 and 20 exerted significant capturing activity against diammonium 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonate) (ABTS) radicals. In addition, the new iridoids 1, 5, 6, and 7 exerted apparent neuroprotective activity toward PC12 cells, with 1 being comparable to the positive control, and selective compounds also displayed anti-diabetic and anti-inflammatory properties by inhibiting α-glucosidase and NO production, respectively. The current work revealed that the bioactive small-molecule constituents could be closely related to the functional food property of the title species.

Clerodane furanoditerpenoids from the stems of Tinospora sinensis.

One new clerodane-type furanoditerpenoid tinosinoid A (1) and nine new nor-clerodane analogs tinosinoids B-J (2-10) have been isolated from the stems of Tinospora sinensis. The structures of the new compounds with absolute configurations have been elucidated by spectroscopic means, including MS, NMR and ECD techniques, as well as chemical correlation. Compound 1 is a rare sulfur-containing clerodane diterpenoid incorporating a 2-mercaptoethanol unit via a thioether bond, while compounds 4/5 and 9 represent two pairs of unusual equilibrium regioisomers through an interesting intramolecular transesterification. Our bioassays established that 1 and 8 displayed moderate antiproliferative effects against two human tumor cell lines, and 9 and 10 showed significant α-glucosidase inhibitory activities. A kinetics study revealed that compound 10 was a noncompetitive α-glucosidase inhibitor, and its possible binding mode to the enzyme was further probed by molecular docking experiments.

Schipropins A-J, structurally diverse triterpenoids from Schisandra propinqua.

Schipropins A-J, a series of undescribed lanostane and cycloartane-type triterpenoids, were isolated from the stems and leaves of Schisandra propinqua. Their structures, most of which were characterized by C-3/C-4 cleavage, were elucidated by extensive spectroscopic analyses. Noteworthily, the absolute configurations of schipropins A, D-G, and I were determined by single-crystal X-ray diffraction. Furthermore, schipropins E and G were found to possess moderate NO production inhibitory activity.