LiOtBu-Promoted trans-Stereoselective and ß-Regioselective Hydroboration of Propargyl Alcohols.

A convenient and efficient trans-stereoselective and ß-regioselective hydroboration of propargyl alcohols was achieved simply with LiOtBu as the base and (Bpin)2 as the boron reagent in dimethyl sulfoxide at room temperature. Both terminal and internal propargyl alcohols with diverse structures and functional groups underwent the transformation smoothly to produce ß-Bpin-substituted (E)-allylic alcohols, of which the synthetic potentials were demonstrated by the downstream conversions of boronate, alkenyl, and hydroxyl groups.

Stereoselective Dehydroxyboration of Allylic Alcohols to Access (E)-Allylboronates by a Combination of C-OH Cleavage and Boron Transfer under Iron Catalysis.

Iron-catalyzed direct SN2' dehydroxyboration of allylic alcohols has been developed to access (E)-stereoselective allylboronates. Allylic alcohols with diverse structures and functional groups, especially derived from natural products, underwent smooth transformation. The six-membered ring transition state formed by allylic alcohols and iron-boron intermediate was indicated to be the key component involved in transfer of the boron group, activation of the C-OH bond, and control of the stereoselectivity.

Distinct Features of Gut Microbiota in High-Altitude Tibetan and Middle-Altitude Han Hypertensive Patients.

Indigenous animals show unique gut microbiota (GM) in the Tibetan plateau. However, it is unknown whether the hypertensive indigenous people in plateau also have the distinct gut bacteria, different from those living in plains. We sequenced the V3-V4 region of the gut bacteria 16S ribosomal RNA (rRNA) gene of feces samples among hypertensive patients (HPs) and healthy individuals (HIs) from 3 distinct altitudes: Tibetans from high altitude (3600-4500 m, n = 38 and 34), Hans from middle altitude (2260 m, n = 49 and 35), and Hans from low altitude (13 m, n = 34 and 35) and then analyzed the GM composition among hypertensive and healthy subgroups using the bioinformatics analysis, respectively. The GM of high-altitude Tibetan and middle-altitude Han HPs presented greater α- and ß-diversities, lower ratio of Firmicutes/Bacteroidetes (F/B), and higher abundance of beneficial Verrucomicrobia and Akkermansia than the low-altitudes HPs did. The GM of high-altitude Tibetan and middle-altitude HIs showed greater α-diversity and lower ratio of F/B than the low-altitudes HIs did. But, ß-diversity and abundance of Verrucomicrobia and Akkermansia among different subgroups of HIs did not show any differences. Conclusively, the high-altitude Tibetan and middle-altitude Han HPs have a distinct feature of GM, which may be important in their adaptation to hypertension in the plateau environments.

Epigallocatechin-3-gallate ameliorates lipopolysaccharide-induced acute lung injury by suppression of TLR4/NF-κB signaling activation.

Acute lung injury (ALI) is a serious clinical syndrome with a high rate of mortality. The activation of inflammation is well-recognized as a vital factor in the pathogenesis of lipopolysaccharide (LPS)-induced ALI. Therefore, suppression of the inflammatory response could be an ideal strategy to prevent ALI. Epigallocatechin-3-gallate (EGCG), mainly from green tea, has been shown to have an anti-inflammatory effect. The aim of the study was to explore whether EGCG alleviates inflammation in sepsis-related ALI. Male BALB/C mice were treated with EGCG (10 mg/kg) intraperitoneally (ip) 1 h before LPS injection (10 mg/kg, ip). The results showed that EGCG attenuated LPS-induced ALI as it decreased the changes in blood gases and reduced the histological lesions, wet-to-dry weight ratios, and myeloperoxidase (MPO) activity. In addition, EGCG significantly decreased the expression of pro-inflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and IL-6 in the lung, serum, and bronchoalveolar lavage fluid, and alleviated the expression of TLR-4, MyD88, TRIF, and p-p65 in the lung tissue. In addition, it increased the expression of IκB-α and had no influence on the expression of p65. Collectively, these results demonstrated the protective effects of EGCG against LPS-induced ALI in mice through its anti-inflammatory effect that may be attributed to the suppression of the activation of TLR 4-dependent NF-κB signaling pathways.

Epigallocatechin-3-gallate ameliorates lipopolysaccharide-induced acute lung injury by suppression of TLR4/NF-κB signaling activation

Acute lung injury (ALI) is a serious clinical syndrome with a high rate of mortality. The activation of inflammation is well-recognized as a vital factor in the pathogenesis of lipopolysaccharide (LPS)-induced ALI. Therefore, suppression of the inflammatory response could be an ideal strategy to prevent ALI. Epigallocatechin-3-gallate (EGCG), mainly from green tea, has been shown to have an anti-inflammatory effect. The aim of the study was to explore whether EGCG alleviates inflammation in sepsis-related ALI. Male BALB/C mice were treated with EGCG (10 mg/kg) intraperitoneally (ip) 1 h before LPS injection (10 mg/kg, ip). The results showed that EGCG attenuated LPS-induced ALI as it decreased the changes in blood gases and reduced the histological lesions, wet-to-dry weight ratios, and myeloperoxidase (MPO) activity. In addition, EGCG significantly decreased the expression of pro-inflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 in the lung, serum, and bronchoalveolar lavage fluid, and alleviated the expression of TLR-4, MyD88, TRIF, and p-p65 in the lung tissue. In addition, it increased the expression of IκB-α and had no influence on the expression of p65. Collectively, these results demonstrated the protective effects of EGCG against LPS-induced ALI in mice through its anti-inflammatory effect that may be attributed to the suppression of the activation of TLR 4-dependent NF-κB signaling pathways.

Synthesis and activity evaluation of the cyclic dipeptides arylidene N-alkoxydiketopiperazines.

A series of arylidene N-alkoxydiketopiperazines was designed and stereoselectively synthesized via oxime-ether formation and intramolecular acylation. Possible cyclization and acid-catalyzed rearrangement-fragmentation mechanisms were discussed. The crystal structure of the novel diketopiperazine further confirmed the rearrangement mechanism. Most compounds exhibited antitumor activity. Several compounds were more potent against caspase-3. Specifically, compounds 6e, 6g, and 6f inhibited caspase-3 at IC50 values lying within the low micromolar range and demonstrated good selectivity. The binding modes of alkoxydiketopiperazines in the active center of caspase-3 were also discussed based on the molecular docking results.

[Study on UHPLC fingerprint and determination of eight phenolic components of Tetrastigma hemsleyanum leaves].

A novel method combining ultra-high performance liquid chromatography (UHPLC) fingerprint and simultaneous quantitative analysis of eight phenolic components was developed and validated for quality evaluation of Tetrastigma hemsleyanum leaves. For fingerprint analysis, 15 peaks were selected as the common peaks to evaluate the similarities among 41 batches of T. hemsleyanum leaves collected from different regions. Additionally, simultaneous quantification of eight markers, including neochlorogenic acid, chlorogenic acid, cryptochlorogenic acid, isoorientin, orientin, vitexin-2-O-rhamnoside,vitexin and isovitexin, was performed and the obtained data demonstrated that our method has achieved desired linearity, precision and accuracy. Clustering statistical analysis was further application in T. hemsleyanum leaves from different regions. The results indicated that new approach conbine ultra-high performance liquid chromatography (UHPLC) fingerprint and simultaneous quantitative analysis of eight phenolic components was applicable in quality control of T. hemsleyanum leaves.

[Investigation on resource and quality assessment of Cibotii Rhizoma].

The study is aimed to understand the resource and the current situation of the use of Cibotii Rhizoma and provide the basis for protecting and utilization. The method of literature survey, field survey and quality assessment were applied in the study. The results showed that all the Cibotii Rhizoma came from wild resource and was mainly founded in Fujian, Guangxi, Guizhou, Yunnan, Guangdong, Hunan, Jiangxi, Sichuan, Chongqing, Zhejiang, etc. It contains over 5 000 000 kg in the area which total is about 7 000 hm2. The annual output is over 850 000 kg. At present, there is no cultivated resources. Based on the investigation and market sampling analysis from various regions, the results showed that the quality of the collected crude drugs conformed with the regulations of the Chinese pharmacopoeia. However the qualification rate of decoction pieces of Cibotii Rhizoma in market was only 56.4%. At present, the resource of Cibotii Rhizoma could meet the needs of medinal uses. It is important to protect the wild resource which is less and less because of the environmental factors. It also need to make a standard of processing method to ensure the safety, and solve quality problem of the decoction pieces.

Synthesis and biological evaluation of open-chain analogs of cyclic peptides as inhibitors of cellular Shp2 activity.

A series of open-chain analogs of cyclic peptides was designed and synthesized using sansalvamide A as a model compound. All compounds exhibited low antitumor activity. Furthermore, the evaluation of their inhibitory potency toward IMPDH, SHP2, ACHE, proteasome, MAGL, and cathepsin B showed that all of the compounds were potent against protein tyrosine phosphatase Shp2. Specifically, compounds 1a, 1d, 2b, and 2f were found to inhibit SHP2 with IC50 values in the low micromolar range and good selectivity. Based on the molecular docking results, the binding modes of the chain cyclic peptides in the active center of SHP2 were discussed.

[Separation and Quantitative Determination of Four Flavonoids in Tetrastigma hemsleyanum].

OBJECTIVE: To develop a method for separation and quantitative determination of four flavonoids in Tetrastigma hemsleyanum. METHODS: The Separation was performed on a Waters Preparative scale LC-MS autopurification system. Several spectral analyses, such as NMR,HR-MS and UV were used to identify the chemical structures. Quantitative assay was performed on a UHPLC Phenomenex Kinetex C18 column (100 mm x 4.6 mm, 2.6 µm) with the mobile phase consisting of acetonitrile( B) and water containing 0. 1% formic acid (A) in a gradient mode at a flow rate of 0.4 mL/min. The column temperature was at 30 °C and the optimum detection wavelength of DAD was set at 350 nm. RESULTS: Four flavonoids were isolated from the root of Tetrastigma hemsleyanum, which were identified as rutin, isoquercitrin, kaempferol-3-O-rutinoside and astragalin. As to quantitative analysis, a good separation of four flavonoids with in 17.5 min, the linear range of rutin, isoquercitrin, kaempferol-3-O-rutinoside and astragalin was 0.283-11.32 µg/mL (r1 = 0.9998), 0.311-12.44 µg/mL (r2 = 0.9994), 0.277-11.08 µg/mL (r3 = 0.9995) and 0.103-2.06 µg/mL (r4 = 0.9990), respectively. The average recovery (n = 6) was 99.75% (RSD = 2.15%), 98.73% (RSD = 2.58%) ,98. 03% (RSD = 2.23%), and 97.62% (RSD = 1.95%), respectively. CONCLUSION: Four flavonoids are isolated from the root of Tetrastigma hemsleyanum for the first time, and the UHPLC method is simple, rapid and accurate, which can be used for quantitative analysis of multi-component of Tetrastigma hemsleyanum and provide a novel approach for evaluation of the quality of Tetrastigma hemsleyanum comprehensively.

[Rapid simultaneous determination of ten major flavonoids in Tetrastigma hemsleyanum by UPLC-MS/MS].

In this study, a rapid and sensitive analytical method was developed for the determination of 10 major compounds (procyanidin B1, catechin, procyanidin B2, rutin, isoquercitrin, kaempferol-3-O-rutinoside, astragalin, quercitrin, quercetin, and kaempferol) in Tetrastigma hemsleyanum by using ultra-performance liquid chromatography coupled with triple-quadrupole tandem mass spectrometry (UPLC-MS/MS) in multiple-reaction monitoring (MRM) mode. UPLC-MS/MS assay with negative ion mode was performed on a Waters CORTECS C18 (2.1 mm x 100 mm, 1.6 µm) with the mobile phase consisting of acetonitrile (A) and 0.1% aqueous formic acid (B) in gradient elution at a flow rate of 0.25 mL · min(-1) and the column temperature was set at 45 °C. Under the optimized chromatographic conditions, good separation for 10 target compounds were obtained including chiral isomer procyanidins B1 and B2 were completely separated within 8.5 min. Satisfactory linearity was achieved with wide linear range and fine determination coefficient (r > 0.996 6), the overall recoveries were ranged from 95.44%-110.40% with the RSD ranging from 2.37%-8.69%. It is the first report about simultaneous analysis of 10 major flavonoids components in Tetrastigma hemsleyanum by using UPLC-MS/MS method, which affords highly sensitive, specific, speedy and efficient method for quality control of Tetrastigma hemsleyanum

[Qualitative and quantitative analysis of major constituents in Tetrastigma hemsleyanum by HPLC-Q-TOF-MS and UPLC-QqQ-MS].

A qualitative analytical method of liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry (HPLC-Q-TOF-MS) was developed for identification of multi-constituents and an analytical method was developed for simultaneously determining 4 major compounds (rutin, isoquercitrin, kaempferol-3-0-rutinoside, and astragalin) in Tetrastigma hemsleyanum Diels et Gilg. The HPLC-Q-TOF-MS assay was performed on a Welch Ultimate XB-C18 column (4.6 mm x 150 mm, 5 microm) with the mobile phase consisting of acetonitrile (A) and water containing 0.1% Formic acid (B) in gradient mode at a flow rate of 0.8 mL x min(-1). The column temperature was at 30 degrees C, and negative ion mode was used for TOF-MS. The UPLC-QqQ-MS assay was performed on a Waters CORTECS C18 (2.1 mm x 100 mm, 1.6 microm) with the mobile phase consisting of acetonitrile (A) and water containing 0.1% formic acid (B) in gradient mode at a flow rate of 0.25 mL x min(-1). The column temperature was at 45 degrees C, and MRM mode was used for QqQ-MS. Based on the retention time and MS spectra, 24 compounds were identified or tentatively characterized by comparing with reference substances or literatures. For quantitative the linear range of 4 detected compounds were good (r > 0.9966), and the overall recoveries ranged from 98.27% to 101.58%, with the RSD ranging from 3.15% to 5.88%. The results indicated that new approach conbined HPLC-Q-TOF-MS and UPLC-QqQ-MS was applicable in qualitative and quantitative quality control of Tetrastigma hemsleyanum.

[Antitumor activities of kushen flavonoids in vivo and in vitro].

OBJECTIVE: To explore the antitumor activities of kushen (Sophora flavescens) flavonoids (KS-Fs) in vivo and in vitro. METHODS: Cell proliferation was assayed by using methyl thiazolyl tetrazolium (MTT) method. H22 hepatocellular carcinoma and S180 sarcoma were induced in ICR mice. Lewis lung carcinoma was induced in C57BL/6 mice. H460 and Eca-109 tumor were induced in Balb/c nude mice by injecting 5x10(5) or 5x10(6) tumor cells in the right flank, respectively. RESULTS: KS-Fs could inhibit the growth of a variety of human tumor cell lines (A549, SPC-A-1, NCI-H460, etc.) in vitro. The antitumor efficacies were confirmed in the mice models of H22, S180 and Lewis lung tumors and the nude mice models of human H460 and Eca-109 xenografted tumors. The oral or intravenous maximum tolerated dose of KS-Fs was more than 2.8 g/kg or 750 mg/kg respectively, far more than the oral medial lethal dose of kushen alkaloids (< or = 1.18 g/kg). No adverse reactions were observed. CONCLUSION: These results suggest that KS-Fs or kurarinone may be developed as a novel antitumor agent.

Comparison of efficacy and toxicity profile between intraperitoneal and intravenous topotecan in human ovarian cancer xenografts.

OBJECTIVE: To compare the therapeutic and toxic profile of topotecan given intraperitoneally with intravenously in human ovarian cancer xenografted into athymic nude mice. METHOD: Eighty female Balb-c/nu-nu mice were randomized assigned into eight groups (n=10). Xenografts resulted from intramesentery injection of cultured human ovarian cancer cells SKOV3 in athymic mice. Onset of intraperitoneal treatment with either topotecan or cisplatin (7.5 mg/kg) was on day 7. Animals scheduled for topotecan i.p. received intraperitoneal application of topotecan (1.5 mg/kg x 2, 3.0 mg/kg x 2, 6.0 mg/kg x 2 or 10.0 mg/kg x 1). Animals scheduled for topotecan i.v. received intravenous administration of topotecan (6.0 mg/kg x 2 or 10.0 mg/kg x 1). Two weeks after drug application animals were killed. Tumor growth inhibition were assessed and compared with untreated mice and cisplatin intraperitoneally administered mice. Acute toxicity was determined by loss of body weight. Cell cycle division and apoptosis after drug administration was determined by flow cytometric analysis. RESULTS: In a panel of ten tumour xenografts, intraperitoneal topotecan was significantly more effective than intravenous administration. The toxicity profile suggested a better tolerability in terms of weight loss after intraperitoneal administration than cisplatin control. Topotecan 10.0 mg/kg i.p. per day (1 day) schedule was an optimal treatment for ovarian cancer and well tolerated by mice with no signs of acute toxicity. Topotecan and cisplatin induce cells G0-G1 arrest and apparent apoptosis. No significant difference among mice treated with topotecan intraperitoneally or intravenously or cisplatin was observed in term of apoptosis and cell cycle perturbation. CONCLUSION: The results may have implications for the future design of clinical studies on intraperitoneal application of topotecan. It suggests that apoptosis and cell cycle perturbation play an limited role in the mechanism of topotecan administration.