Homocoupling of benzyl pyridyl ethers via visible light-mediated deoxygenation.

The photocatalytic coupling of ethers is uncommon because of the challenges in breaking C-O bonds and low selectivity. Herein, we report a visible light-mediated deoxygenation homocoupling of benzyl pyridyl ethers via their pyridium salts. This approach enables C(sp3)-O bond homolysis under mild conditions. Mechanistic experiments support the radical nature of the reaction. This method is highly compatible with electron-withdrawing groups and has potential applications for drug precursor synthesis.

Thymidylate synthase promotes esophageal squamous cell carcinoma growth by relieving oxidative stress through activating nuclear factor erythroid 2-related factor 2 expression.

BACKGROUND: Thymidylate synthase (TYMS) is involved in the malignant process of multiple cancers, and has gained much attention as a cancer treatment target. However, the mechanism in carcinogenesis of esophageal squamous cell cancer (ESCC) is little reported. The present study was to clear the biological roles and carcinogenic mechanism of TYMS in ESCC, and explored the possibility to use TYMS as a tumor marker in diagnosis and a drug target for the treatment of ESCC. METHODS: Stably TYMS-overexpression cells established by lentivirus transduction were used for the analysis of cell proliferation. RNA sequencing was performed to explore the possible carcinogenic mechanisms. RESULTS: GEPIA databases analysis showed that TYMS expression in esophageal cancer tissues was higher than that in normal tissues. The MTT assay, colony formation assay, and nude mouse subcutaneous tumor model found that the overexpression of TYMS increased cell proliferation. Transcriptome sequencing analysis revealed that the promoted cell proliferation in TYMS-overexpression ESCC cells were mediated through activating genes expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and Nrf2 dependent antioxidant enzymes to relieve oxidative stress, which was confirmed by increased glutathione (GSH), glutathione peroxidase (GPX) activities, and reduced reactive oxygen species. Nrf2 active inhibitors (ML385) used in TYMS-overexpression cells inhibited the expression of Nrf2-dependent antioxidant enzyme genes, thereby increasing oxidative stress and blocking cell proliferation. CONCLUSION: Our study indicated a novel and effective regulatory capacity of TYMS in the cell proliferation of ESCC by relieving oxidative stress through activating expression of Nrf2 and Nrf2-dependent antioxidant enzymes genes. These properties make TYMS and Nrf2 as appealing targets for ESCC clinical chemotherapy.

Visible Light-Induced Deoxygenation and Allylation/Vinylation of Pyridyl Ethers.

The generation of alkyl radicals by deoxygenation of unactivated ethers under visible light catalysis is a hitherto unmet challenge. Herein, we report a visible light-induced deoxygenation of pyridyl ethers via formation of their pyridinium salts. The generated benzylic radicals further react with allyl/alkenyl sulfones to provide a series of coupling products in good to moderate yields. This process is proposed to undergo a reductive quenching cycle, which was elucidated by chemical, optical, and electrical experiments.

Improving Water-Absorption and Mechanical Strength: Lyotropic Liquid Crystalline-Based Spray Dressings as a Candidate Wound Management System.

A spray dressing based on lyotropic liquid crystalline (LLC) with adjustable crystalline lattices was investigated in this study. It possesses water-triggering phase transition property and ease of spraying on wound, as well as stable drug encapsulation and controllable drug release. When it comes to wound with exudate, adequate water absorption and sustainable mechanical strength after water absorption was important for a good dressing, while most of the normal LLC dressings were still unable to meet such standards. Herein, a type of hyaluronic acid (HA)-incorporated LLC-based spray dressing (HLCSD) was developed to overcome the above limitations. After comparing HAs with different molecular weights (MWs) and concentrations, 3% HA with MW of 800~1000 kD was chosen as an ideal amount of excipients to add into the HLCSD. The water absorption of HLCSD precursor increased by 150% with the appearance of enlarged water channels. The complex modulus of HLCSD gel also increased from 1 to 100 kPa, which suggested lasting wound coverage and good patient compliance when used clinically. The spraying and phase transition properties of HLCSD was studied and showed acceptable changes. Moreover, good safety comparable with the commercial product Purilon® was also demonstrated in an in vivo acute skin irritation test. Thus, the improved HLCSD was a promising dressing for exudation wound treatment.

Characterizing glycosyltransferases by a combination of sequencing platforms applied to the leaf tissues of Stevia rebaudiana.

BACKGROUND: Stevia rebaudiana (Bertoni) is considered one of the most valuable plants because of the steviol glycosides (SGs) that can be extracted from its leaves. Glycosyltransferases (GTs), which can transfer sugar moieties from activated sugar donors onto saccharide and nonsaccharide acceptors, are widely distributed in the genome of S. rebaudiana and play important roles in the synthesis of steviol glycosides. RESULTS: Six stevia genotypes with significantly different concentrations of SGs were obtained by induction through various mutagenic methods, and the contents of seven glycosides (stevioboside, Reb B, ST, Reb A, Reb F, Reb D and Reb M) in their leaves were considerably different. Then, NGS and single-molecule real-time (SMRT) sequencing were combined to analyse leaf tissue from these six different genotypes to generate a full-length transcriptome of S. rebaudiana. Two phylogenetic trees of glycosyltransferases (SrUGTs) were constructed by the neighbour-joining method and successfully predicted the functions of SrUGTs involved in SG biosynthesis. With further insight into glycosyltransferases (SrUGTs) involved in SG biosynthesis, the weighted gene co-expression network analysis (WGCNA) method was used to characterize the relationships between SrUGTs and SGs, and forty-four potential SrUGTs were finally obtained, including SrUGT85C2, SrUGT74G1, SrUGT76G1 and SrUGT91D2, which have already been reported to be involved in the glucosylation of steviol glycosides, illustrating the reliability of our results. CONCLUSION: Combined with the results obtained by previous studies and those of this work, we systematically characterized glycosyltransferases in S. rebaudiana and forty-four candidate SrUGTs involved in the glycosylation of steviol glucosides were obtained. Moreover, the full-length transcriptome obtained in this study will provide valuable support for further research investigating S. rebaudiana.

Linker Immolation Determines Cell Killing Activity of Disulfide-Linked Pyrrolobenzodiazepine Antibody-Drug Conjugates.

Disulfide bonds could be valuable linkers for a variety of therapeutic applications requiring tunable cleavage between two parts of a molecule (e.g., antibody-drug conjugates). The in vitro linker immolation of ß-mercaptoethyl-carbamate disulfides and DNA alkylation properties of associated payloads were investigated to understand the determinant of cell killing potency of anti-CD22 linked pyrrolobenzodiazepine (PBD-dimer) conjugates. Efficient immolation and release of a PBD-dimer with strong DNA alkylation properties were observed following disulfide cleavage of methyl- and cyclobutyl-substituted disulfide linkers. However, the analogous cyclopropyl-containing linker did not immolate, and the associated thiol-containing product was a poor DNA alkylator. As predicted from these in vitro assessments, the related anti-CD22 ADCs showed different target-dependent cell killing activities in WSU-DLCL2 and BJAB cell lines. These results demonstrate how the in vitro immolation models can be used to help design efficacious ADCs.

Water-soluble fluorescent probes based on dendronized polyfluorenes for cell imaging.

Novel water-soluble dendronized fluorescent polyfluorenes (DFPFs) are prepared from hydrophilic monomers and hydrophobic comonomers. Incomplete energy transfer is found to result in a two-color emission of the DFPFs at around 410 and 650 nm. The incomplete energy transfer can be attributed to the poor compatibility between the fluorene and benzothiadiazole units. Polyethylene oxide (PEO) encapsulation of the DFPFs shows over 90% cell viability, indicating good biocompatibility. These DFPFs show differential cellular uptake. P1 with fewer PEO chains exhibits limited cellular membrane uptake and low brightness in cells. By contrast, P3 with more PEO chains is efficiently internalized by cells and accumulated in the cytoplasm. A strong fluorescence from whole cells is also observed.