Acid-promoted intra- and intermolecular [2+2] cycloaddition of indoles to aryl alkynes to access cyclobutene-fused indolines.

Herein, we have reported the first example of both intra- and intermolecular [2+2] cycloaddition of the electron-rich indoles and unactivated aryl alkynes promoted by the combination of Fe(NO3)3 and HNO3, which highlights efficient and selective access to several different types of functionalized cyclobutene-fused indolines from readily available starting materials with cheap catalysts and simple operations.

Alpha-glucosidase inhibitor 1-Deoxynojirimycin promotes beige remodeling of 3T3-L1 preadipocytes via activating AMPK.

Obesity is a serious health challenge in the world, and searching effective drugs to cure obesity is of great importance. 1-Deoxynojirimycin (DNJ) is extracted from mulberry leaves and acts as an α-glucosidase inhibitor to lower blood glucose. Recent studies demonstrated that it also has anti-obesity effect, but the mechanisms remain unknown. In our present study, we mainly examined the effects of DNJ on beige remodeling of 3T3-L1 preadipocytes. We observed that DNJ didn't affect the mRNA levels of fatty acid binding protein 4 (aP2), peroxisome proliferator-activated receptor γ (PPARγ), preadipocyte factor-1 (Pref-1) as well as the mitochondrial uncoupling protein 1 (UCP1), PR domain containing protein 16 (PRDM16), transmembrane protein 26 (TMEM26) in undifferentiated preadipocytes. But after inducing 3T3-L1 preadipocytes to differentiation with white or beige adipogenic medium, DNJ significantly reduced aP2, PPARγ and Pref-1 expressions, while up-regulated the expressions of UCP1, PRDM16 and TMEM26, accompanying with decreased lipid deposition. The ratio of p-AMPK/AMPK was up-regulated by DNJ (10 µM) treatment for 10 days, and the effects of DNJ on p-AMPK/AMPK, UCP1 and PRDM16 could be blocked by AMPK inhibitor Compound C. These results demonstrated that hypoglycemic agent DNJ could suppress the adipogenesis during the differentiation of white preadipocytes, and promote the switch of white preadipocytes to beige adipocytes via activating AMPK, which provided new mechanisms for explaining the benefits of DNJ on obesity-related disorders.

Vitexin compound 1, a novel extraction from a Chinese herb, suppresses melanoma cell growth through DNA damage by increasing ROS levels.

BACKGROUND: Vitex negundo L (Verbenaceae) is an aromatic shrub that is abundant in Asian countries. A series of compounds from Vitex negundo have been used in traditional Chinese medicine for the treatment of various diseases. Cutaneous melanoma is one of the most aggressive malignancies. A significant feature of melanoma is its resistance to traditional chemotherapy and radiotherapy; therefore, there is an urgent need to develop novel treatments for melanoma. METHODS: We first examined the effects of VB1 (vitexin compound 1) on cell viability by CCK-8 (cell counting kit) and Colony Formation Assay; And then, we analyzed the apoptosis and cell cycle by flow cytometry, verified apoptosis by Immunoblotting. The in vivo effect of VB1 was evaluated in xenograft mouse model. Potential mechanisms of VB1's antitumor effects were explored by RNA sequencing and the key differential expression genes were validated by real-time quantitative PCR. Finally, the intracellular reactive oxygen species (ROS) level was detected by flow cytometry, and the DNA damage was revealed by Immunofluorescence and Immunoblotting. RESULTS: In this study, we show that VB1, which is a compound purified from the seed of the Chinese herb Vitex negundo, blocks melanoma cells growth in vitro and in vivo, arrests the cell cycle in G2/M phase and induces apoptosis in melanoma cell lines, whereas the effects are not significantly observed in normal cells. To study the details of VB1, we analyzed the alteration of gene expression profiles after treatment with VB1 in melanoma cells. The findings showed that VB1 can affect various pathways, including p53, apoptosis and the cell cycle pathway, in a variety of melanoma cell lines. Furthermore, we confirmed that VB1 restored the P53 pathway protein level, and then we demonstrated that VB1 significantly induced the accumulation of ROS, which resulted in DNA damage in melanoma cell lines. Interestingly, our results showed that VB1 also increased the ROS levels in BRAFi (BRAF inhibitor)-resistant melanoma cells, leading to DNA cytotoxicity, which caused G2/M phase arrest and apoptosis. CONCLUSIONS: Taken together, our findings indicate that vitexin compound 1 might be a promising therapeutic Chinese medicine for melanoma treatment regardless of BRAFi resistance.

Design, synthesis, and biological evaluation of crenatoside analogues as novel influenza neuraminidase inhibitors.

Natural products, especially derived from TCMH, have been found to exert antiviral effects against influenza virus. Crenatoside, a phenylethanoid glycoside from Pogostemon cablin Benth, which has been shown as a novel effective NA inhibitor previously, is considered as the leading compound for our further SARs studies. This work presented design, synthesis of novel crenatoside analogues from readily available d-Glucose and l-rhamnose in a convergent manner. Furthermore, their biological activities and SARs were also investigated. Especially, compound 2 h showed impressive IC50 = 27.77 µg/mL against NAs, which is 3 folds more potent than the leading compound crenatoside (IC50 = 89.81 µg/mL). These results would promise their therapeutic potential for influenza disease.

Purified vitexin compound 1 induces apoptosis through activation of FOXO3a in hepatocellular carcinoma.

We previously reported that purified vitexin compound 1 (VB1, a neolignan from the seed of Chinese herb Vitex negundo) exhibited antitumor activity in cancer cell lines and xenograft models. In the present study, we examined the molecular mechanisms by which activation of the FOXO3a transcription factor mediated VB1-induced apoptosis in hepatocellular carcinoma (HCC) cells. The effects of VB1 on the proliferation of HCC cell lines HepG2, Hep3B, Huh-7 and human embryo liver L-02 cells were investigated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Apoptotic death in HepG2 cells was examined using an enzyme-linked immunosorbent assay (ELISA) detection kit, flow cytometry after propidium iodide (PI) staining, and by DNA agarose gel electrophoresis. Caspase activity was measured using ELISA. The AKT/FOXO3a and ERK/FOXO3a pathways were analyzed using western blotting. VB1 inhibited human HCC cell proliferation in a concentration-dependent manner and increased the percentage of sub-G1 population HepG2 cells. Histone/DNA fragmentation and active caspase-3, -8 and -9 levels increased in a concentration-dependent manner and a DNA ladder was formed. The phosphorylation of AKT and ERK1/2 were inhibited and FOXO3a transcription factor was activated, resulting in apoptotic death. Knockdown of AKT1 by small interfering RNA (siRNA) and the MEK1/2 inhibitor, PD98059, enhanced VB1-induced apoptosis and FOXO3a transcriptional activity. Suppression of FOXO3a expression by siRNA inhibited VB1-induced apoptosis. VB1 induced expression of Bim, TRAIL, DR4 and DR5. Activation of the FOXO3a transcription factor appears to mediate pro-apoptotic effects of VB1 by inhibiting the AKT and ERK pathways.

Two acylated flavonoid glycosides from the leaves of Quercus dentata.

Two new acylated flavonoid glycosides have been isolated from the leaves of Quercus dentata Thunb. On the basis of chemical and spectral data, the structures of the compounds have been elucidated as kaempferol 3-O-(2", 4"-diacetyl-3"-cis-p-coumaroyl-6"-trans-p-coumaroyl)-beta-D-glucopyranoside (1), and kaempferol 3-O-(2"-trans-p-coumaroyl-3", 4"-diacetyl-6"-cisp-coumaroyl)-beta-D-glucopyranoside (2).

[Studies on flavonoid glycosides of Sarcandra glabra].

OBJECTIVE: To in vestigate the chemical constituents of Sarcandra glabra and obtain a more comprehensive understanding on its effective components. METHOD: The constituents were isolated by various column chromatographic method and their structures were elucidated by physico-chemical properties and spectroscopic analysis. RESULT: Five flavonoid glycosides were isolated and identified as kaempferol-3-O-beta-D-glucuronide (1), quercetin-3-O-alpha-D-glucuronide (2), quercetin-3-O-beta-D-glucuronopyranoside methyl ester (3), 5, 7, 4'-trihydroxy-8-C-beta-D-glucopyranosyl flavanone (4), neoastilbin (5), 5-O-caffeoylquinic acid methyl ester (6), 3, 4-dihydroxybenzoic acid (7), isofraxidin (8). CONCLUSION: Compounds 1-6 were isolated from the genus Sarcandra for the first time. The glucuroide compounds compounds 1-3, were first isolated from the genus Sarcandra.

[Studies on constituents of Oldenlandia diffusa].

OBJECTIVE: To investigate the chemical constituents of Oldenlandia diffusa. METHOD: The column chromatography with polyamide Sephadex LH -20, silica gel as packing materials and HPLC, were used to separate and purify the chemical components. The structures were elucidated on the basis of physicochemical properties and spectral data. RESULT: Nine compounds were isolated and identified as 2, 6-dihydroxy-1-methoxy-3-methylanthraquinone (1), 2-hydroxy-1-methoxy-3-methylanthraquinone (2), 2-hydroxy-3-methylanthraquinone (3), quercetin-3-O-[2-O-(6-O-E-sinapoyl)-beta-D-glucopyranosyl]-beta-glucopyranoside (4), quercetin-3-O-[2-O-(6-O-E-feruloyl)-beta-D-glucopyranosyl]-beta-glucopyranoside (5), kaempferol-3-O-[2-O-(6-O-E-feruloyl)-beta-D-glucopyranosyl]-beta-galactopyranoside (6), quercetin-3-O-(2-O-beta-D-glucop-yranosyl)-beta-D-glucopyranoside (7), rutin (8) and quercertin (9). CONCLUSION: Compounds 1 and 8 were obtained from this plant for the first time, and compound 1 was a new compound.

[Water-soluble chemical constituents of Swertia davidi Franch].

AIM: To study the active constituents of Swertia davidi Franch. METHODS: Column chromatographies on silica gel, Sephadex LH-20 and Diaion-201 et al. were used to isolate and purify the chemical components. Their structures were identified by UV, IR, MS, NMR and 2D-NMR. RESULTS: These compounds were elucidated as 8-O-beta-D-glucopyranosyl-1, 3, 5-trihydroxyxanthone (I), 5-O-beta-D-glucopyranosyl-1, 8-dihydroxy-3-methoxyxanthone (II), 5-O-beta-D-glucopyranosyl-1, 3, 8-trihydroxyxanthone (III) and swertamarin (IV). CONCLUSION: Compound III is a new xanthone glucoside. The other compounds were isolated from this plant for the first time.