Sulfonylation of Propargyl Alcohols with Sulfinamides for the Synthesis of Allenyl Sulfones.

A regio- and chemoselective sulfonylation of propargyl alcohols with sulfinamides in 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) was developed. It provided straightforward and mild access to multi-substituted allenyl sulfones by using sulfinamides as the sulfonyl sources. This transformation was promoted by HFIP and did not require any catalysts or oxidants, which allowed for the successful conversion of various tertiary and secondary propargyl alcohols into allenyl sulfones in high yields.

Alkynyl Borrowing: Silver-Catalyzed Amination of Secondary Propargylic Alcohols via C(sp3)-C(sp) Bond Cleavage.

The silver-catalyzed alkynyl borrowing amination of secondary propargyl alcohols via C(sp3)-C(sp) bond cleavage has been developed. This new strategy was based on the ß-alkynyl elimination of propargyl alcohols and alkynyl as the borrowing subject. This alkynyl borrowing amination featured high atom economy, wide functional group tolerance, and high efficiency.

In vivo hepatotoxicity screening of different extracts, components, and constituents of Polygoni Multiflori Thunb. in zebrafish (Danio rerio) larvae.

Polygonum multiflorum Thunb. (PM) is a traditional Chinese medicine, commonly used to treat a variety of diseases. However, the hepatotoxicity associated with PM hampers its clinical application and development. In this study, we refined the zebrafish hepatotoxicity model with regard to the following endpoints: liver size, liver gray value, and the area of yolk sac. The levels of alanine aminotransferase, aspartate transaminase, albumin, and microRNAs-122 were evaluated to verify the model. Subsequently, this model was used to screen different extracts, components, and constituents of PM, including 70 % EtOH extracts of PM, four fractions from macroporous resin (components A, B, C, and D), and 19 compounds from component D. We found that emodin, chrysophanol, emodin-8-O-ß-D-glucopyranoside, (cis)-emodin-emodin dianthrones, and (trans)-emodin-emodin dianthrones showed higher hepatotoxicity compared to other components in PM, whereas polyphenols showed lower hepatotoxicity. To the best of our knowledge, this study is the first to identify that dianthrones may account for the hepatotoxicity of PM. We believe that these findings will be helpful in regulating the hepatotoxicity of PM.

Cyano-borrowing: titanium-catalyzed direct amination of cyanohydrins with amines and enantioselective examples.

The direct amination of cyanohydrins with amines via a catalytic cyano-borrowing reaction was developed. The transformation features broad substrate scope, excellent functional group compatibility, and very mild and simple operations. Moreover, a titanium catalyst supported by quinine and (S)-BINOL ligands enabled an asymmetric cyano-borrowing reaction with moderate to high enantioselectivity.

Titanium-Catalyzed Cyano-Borrowing Reaction for the Direct Amination of Cyanohydrins with Ammonia.

α-Aminonitrile was an important building block in natural products and key intermedia in organic chemistry. Herein, the direct amination of cyanohydrins with the partner of ammonia to synthesis N-unprotected α-aminonitriles is developed. The reaction proceeds via titanium-catalyzed cyano-borrowing reaction, which features high atom economy and simple operation. A broad range of ketone or aldehyde cyanohydrins was tolerated with ammonia, and the N-unprotected α-aminonitriles were synthesis with moderate to high yields under mild reaction conditions.

Genotoxicity and Embryotoxicity Study of Bicyclol Methyl Ether, Main Impurity in Bicyclol.

OBJECTIVE: To assess the genotoxicity and embryotoxicity of bicyclol methyl ether (BME), the main impurity in bicyclol. METHODS: Five concentrations of BME (0.5, 5, 50, 500 and 5000 µg/plate) were used in the Ames test to detect gene mutation. In the chromosome aberration test, Chinese hamster lung cells were used to detect chromosomal aberration of BME (15, 30, 60, 120 µg/mL) with or without S9 mixture. Embryotoxicity test was also conducted to determine any embryotoxicity of BME (7.5, 22.5, 67.5 µg/L) using zebrafish embryos. RESULTS: No significant differences were observed in the Ames test and the chromosome aberration test in the BME groups compared with the vehicle control group. The zebrafish embryos toxicity test also showed no embryo development toxicity of BME, including hatching rate, body length, pericardial area and yolk sac area. CONCLUSIONS: Bicyclol methyl ether has no genotoxicity in vitro and embryotoxicity in zebrafish embryos, and the impurity in bicyclol is qualified.

Acute toxicity screening of different extractions, components and constituents of Polygonum multiflorum Thunb. on zebrafish (Danio rerio) embryos in vivo.

Polygonum multiflorum Thunb. has been used widely in East Asia in treatment of diseases associated with aging. However, there are many reports referred to the toxicity of P. multiflorum, especially for liver adverse reactions. The toxicity of it is caused by over dosage or by the herb itself remains unclear. The aim of this study was to study the toxicity of different extractions, components and constituents of P. multiflorum, which were assessed in zebrafish embryos. Firstly, the difference of extracting solvent to the toxicity of P. multiflorum was researched to probe the influence of usages to the safety of P. multiflorum. The toxicity of 70% EtOH extract is considerably higher than that of other extracts. Secondly, 70% EtOH extract was subjected to macroporous resin (DM-8) eluting with a gradient of water and EtOH (H2O, 25% EtOH, 40% EtOH and 95% EtOH) to give four components (A-D). The toxicity of the component (D) showed higher than the other components (A-C). Thus, the component (D) was taken more attentions to research. Lastly, study on the chemical constituents of the component (D), 27 compounds, including 7 anthraquinones (1-7), 8 stilbenes (8-15), 7 anthrones (16-22), 3 cinnamic acid amides (23-25), 2 naphthols (26-27) were isolated and assessed in zebrafish embryos. Compounds 1-3, 16-22 and 26-27 showed severe toxicity against the zebrafish embryos while other compounds, such as stilbenes, showed no obvious toxicity.

Time-response characteristic and potential biomarker identification of heavy metal induced toxicity in zebrafish.

The present work aims to explore the time-response (from 24 h to 96 h) characteristic and identify early potential sensitive biomarkers of copper (Cu) (as copper chloride dihydrate), cadmium (Cd) (as cadmium acetate), lead (Pb) (as lead nitrate) and chromium (Cr) (as potassium dichromate) exposure in adult zebrafish, focusing on reactive oxygen species (ROS), SOD activity, lipid peroxidation and gene expression related to oxidative stress and inflammatory response. Furthermore, the survival rate decreased apparently by a concentration-dependent manner after Cu, Cr, Cd and Pb exposure, and we selected non-lethal concentrations 0.05 mg/L for Cu, 15 mg/L for Cr, 3 mg/L for Cd and 93.75µg/L for Pb to test the effect on the following biological indicators. Under non-lethal concentration, the four heavy metals have no apparent histological change in adult zebrafish gills. Similar trends in ROS production, MDA level and SOD activity were up-regulated by the four heavy metals, while MDA level responded more sensitive to Pb by time-dependent manner than the other three heavy metals. In addition, mRNA levels related to antioxidant system (SOD1, SOD2 and Nrf2) were up-regulated by non-lethal concentration Cu, Cr, Cd and Pb exposure. MDA level and SOD1 gene have a more delayed response to heavy metals. Genes related to immunotoxicity were increased significantly after heavy metals exposure at non-lethal concentrations. TNF-α and IL-1ß gene have similar sensibility to the four heavy metals, while IL-8 gene was more responsive to Cr, Cd and Pb exposure at 48 h groups and IFN-γ gene showed more sensitivity to Cu at 48 h groups than the other heavy metals. In conclusion, the present works have suggested that the IFN-γ gene may applied as early sensitive biomarker to identify Cu-induced toxicity, while MDA content and IL-8 gene may use as early sensitive biomarkers for evaluating the risk of Pb exposure. Moreover, IL-8 and IFN-γ gene were more responsive to heavy metals, which may become early sensitive and potential biomarkers for evaluating inflammatory response induced by heavy metals. This work reinforces the concept of the usefulness of gene expression assays in the evaluation of chemicals effects and helps to establish a background data as well as contributes to evaluate early environmental risk for chemicals, even predicting toxicity.

Sensitive biomarkers identification for differentiating Cd and Pb induced toxicity on zebrafish embryos.

Cadmium (Cd) and lead (Pb) are naturally existing heavy metals that pose significant health risks. The present study aims to identify sensitive biomarkers for differentiating the toxicities induced by Cd and Pb and for providing clues for the early prediction of toxicity and environmental risk assessment. Indicators related to oxidative stress and inflammatory responses in zebrafish treated with Cd and Pb over time (from 24hpf to 96hpf) were compared. Furthermore, endpoints such as embryo lethality and teratogenicity were detected. Then, several related genes involved in oxidative stress and inflammatory responses characterizing both Cd and Pb exposure, along with key molecules in the MAPKs pathway, were compared at the mRNA level, allowing the selection of the most sensitive and informative biomarkers. Significant increases in reactive oxygen species (ROS) production were observed in zebrafish exposed to Cd and Pb. Cd and Pb exposure induced developmental toxicity, influencing survival rate, hatching rate, larval growth, and heart rate and causing abnormal embryonic development. Similar trends in SOD1 and SOD2 gene expression were induced by Cd and Pb, while nuclear factor erythroid-2 related factor 2 (Nrf2) gene expression responded differently to each metal. In addition, Cd and Pb induced a delayed activation of the CAT and HO-1 genes, with no apparent change in the 24hpf and 48hpf groups. Genes related to immunotoxicity were activated significantly in a time-dependent manner, and these genes exhibited different sensitivities to Cd and Pb. MAPKs pathway genes were also activated in a time-dependent manner, and the expression of these genes showed different effects under Cd and Pb treatment. In summary, the present works have identified some potential sensitive biomarkers. The Nrf2 gene is a potential biomarker to differentiate Pb-induced toxicity from that of Cd, and the IFN-γ gene may be used as a sensitive biomarker for evaluating the risk of Pb contamination. We found that the timeline of MAPKs pathway activation helped to differentiate these two metals toxicities. Furthermore, Pb induced the early activation of ERK2/3 and JNK1, while p38 MAPKs showed delayed activation with no apparent change in the 24hpf group. Cd induced an early activation of ERK2 and a delayed activation of p38a, p38b, ERK3 and JNK1, indicating that the JNK1 pathway is sensitive to Pb exposure, while the p38 pathway may be susceptible to Cd. This work contributes to sensitive biomarker identification and early environmental risk evaluation for chemicals as well as toxicity prediction.

Anti-Psoriasis Effects and Mechanisms of Α-(8-Quinolinoxy) Zinc Phthalocyanine-Mediated Photodynamic Therapy.

BACKGROUND/AIMS: The aim of this study was to determine the anti-psoriasis effects of α-(8-quinolinoxy) zinc phthalocyanine (ZnPc-F7)-mediated photodynamic therapy (PDT) and to reveal its mechanisms. METHODS: HaCaT cells were used to observe the influence of ZnPc-F7-PDT on cell proliferation in vitro. The in vivo anti-psoriasis effects of ZnPc-F7-PDT were evaluated using a mouse vagina model, a propranolol-induced cavy psoriasis model and an imiquimod (IMQ)-induced nude mouse psoriasis model. Flow cytometry was carried out to determine T lymphocyte levels. Western blotting was performed to determine protein expression, and a reverse transcription-polymerase chain reaction test was performed to determine mRNA expression. RESULTS: The results showed that ZnPc-F7-PDT significantly inhibited the proliferation of HaCaT cells in vitro; when the light doses were fixed, changing the irradiation time or output power had little influence on the inhibition rate. ZnPc-F7-PDT significantly inhibited the hyperproliferation of mouse vaginal epithelium induced by diethylstilbestrol and improved propranolol- and IMQ-induced psoriasis-like symptoms. ZnPc-F7-PDT inhibited IMQ-induced splenomegaly and T lymphocyte abnormalities. ZnPc-F7-PDT did not appear to change T lymphocytes in the mouse vagina model. ZnPc-F7-PDT down-regulated the expression of proliferating cell nuclear antigen (PCNA), B-cell lymphoma-2 (Bcl-2), interleukin (IL)-17A mRNA and IL-17F mRNA, and up-regulated the expression of Bax. CONCLUSION: In conclusion, ZnPc-F7-PDT exhibited therapeutic effects in psoriasis both in vitro and in vivo and is a potential approach in the treatment of psoriasis. Potential mechanisms of these effects included the inhibition of hyperproliferation; regulation of PCNA, Bcl-2, Bax, IL-17A mRNA and IL-17F mRNA expression; and immune regulation.