Discovery, Structure Correction, and Biosynthesis of Actinopyrones, Cytotoxic Polyketides from the Deep-Sea Hydrothermal-Vent-Derived Streptomyces sp. SCSIO ZS0520.

Three new actinopyrone derivatives, actinopyrones E-G (1, 3, and 4), together with three known analogues, PM050463 (2), actinopyrone D (5), and PM050511 (6), were isolated from Streptomyces sp. SCSIO ZS0520 derived from a deep-sea hydrothermal vent. Their structures, complete with absolute configurations, were elucidated using extensive spectroscopic analyses combined with Mosher's method, ECD calculations, and bioinformatics analyses. These findings corrected the absolute configurations of previously reported actinopyrone analogues 2, 5, and 6 at C-3, C-9, and C-10. Notably, compound 6 displayed notable cytotoxicity against six human cell lines with IC50 values of 0.26-2.22 µM. A likely biosynthetic pathway and annotations of protein function are proposed on the basis of bioinformatics analyses. Genes coding for methyltransferase and glycosyltransferase tailoring chemistries needed to generate final structures were notably absent from the biosynthetic gene cluster. Taken together, these results enable further bioengineering of the actinopyrones and related congeners as potential antitumor agents.

Dracomolphin A-E, new lignans from Dracocephalum moldavica.

Eight new lignans, dracomolphin A-E (1-8), together with eight known lignans (9-16) were isolated from the aerial part of Dracocephalum moldavica. The structures of the isolated compounds were established based on NMR and HRESIMS data. Dracomolphin A (1-4) was elucidated as a lignan possessed a 5-membered ketal ring formed between C-8' and C-3, C-4. The two stereogenic centers rendered dracomolphin A as a mixture of two diastereomeric pairs of enantiomers (1-4). All of the four isomers were separated successfully by using chiral HPLC and their stereochemical features were determined by CD spectra. Bioactivity screening revealed that compounds 1-4, 6, 7, 12, 15 and 16 were potential Nrf2 transcriptional activators. Dracomolphin E (8) reduced cell viability of lung cancer NCI-H292 cells associated with apoptosis.

Morusin induces apoptosis and autophagy via JNK, ERK and PI3K/Akt signaling in human lung carcinoma cells.

Due to drug resistance and side effects, the development of novel therapeutics for the treatment of lung cancer is still in an urgent need. Morusin, a naturally occurring prenylated flavonoid isolated from the root bark of Morus alba, has been reported to be a promising candidate for cancer treatment including lung cancer. This study aimed to validate the anti-cancer effects of morusin in human non-small cell lung cancer (NSCLC) cell lines A549 and NCI-H292. The results indicated that morusin had growth inhibitory, pro-apoptotic and pro-autophagic effects on A549 and NCI-H292 cells. The induction of apoptosis was characterized by chromatin condensation and PARP cleavage. Mitochondrial membrane potential (MMP) loss, cytochrome c release, Bax/Bcl-2 dysregulation, and caspase-3 cleavage were also observed, indicating a mitochondria-dependent apoptosis was induced by morusin. A pro-autophagic effect was demonstrated by the increased level of LC3-Ⅱ and decreased level of SQSTM1/p62. Furthermore, morusin inhibited PI3K/Akt signaling and activated JNK, ERK pathways as indicated by the alteration in the ratio of phosphorylation level over total protein expression level. A PI3K/Akt inhibitor (LY294002), a JNK inhibitor (SP600125) and a MEK/ERK inhibitor (U0126) contributed to the determination that these pathways were involved in both apoptosis and autophagy induced by morusin. Moreover, morusin treatment strikingly enhanced intracellular ROS level, an ROS scavenger NAC blocked cell death and changes of Akt, JNK and ERK induced by morusin.

Bruceine D induces lung cancer cell apoptosis and autophagy via the ROS/MAPK signaling pathway in vitro and in vivo.

Worldwide, lung cancer remains a leading cause of cancer mortality. Bruceine D (BD) has been shown to induce pancreatic cancer cell death via several different mechanisms. In this study, we demonstrated that BD inhibited lung cancer cell proliferation. Apoptosis and autophagy were the most important mechanisms involved in BD-induced lung cancer cell death, and complete autophagic flux was observed in A549 and NCI-H292 cells. In addition, BD significantly improved intracellular reactive oxygen species (ROS) levels. BD-mediated cell apoptosis and autophagy were almost inhibited in cells pretreated with N-acetylcysteine (NAC), an ROS scavenger. Furthermore, MAPK signaling pathway activation contributed to BD-induced cell proliferation inhibition and NAC could eliminate p-ERK and p-JNK upregulation. Finally, an in vivo study indicated that BD inhibited the growth of lung cancer xenografts. Overall, BD is a promising candidate for the treatment of lung cancer owing to its multiple mechanisms and low toxicity.

Flavonoids from the leaves of Epimedium Koreanum Nakai and their potential cytotoxic activities.

Phytochemical studies on the leaves of Epimedium koreanum Nakai have resulted in the discovery of two new flavonol glycosides, koreanoside F (1) and koreanoside G (2), along with six known flavonoids. Their structures were elucidated on the basis of HRESIMS, UV, IR, 1 D NMR and 2 D NMR data. Absolute configurations of 1 and 2 was further determined by 13C-NMR spectra with gate decoupling (GD). All of the compounds were evaluated for cytotoxic activities by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazoliumbromide (MTT) assay. The results indicated that compounds 3, 5, 6, 7 and 8 inhibited the proliferation of A549 and NCI-292 cells with IC50 values of 5.7-23.5 µM. Real-time monitoring in three kinds of lung cancer cells and a kind of human bronchial epithelial cells treated with compound 6 was also assessed.