Ruthenium-Catalyzed Ligand-Enabled Regiodivergent Difluoroallylation of Aryl C-H Bonds.

The gem-difluoroallyl group is a sought-after structural motif commonly found in pharmaceutical compounds. Despite its appeal, achieving a controlled synthesis of both α,α- and γ,γ-difluoroallylated compounds has proven to be a challenging task. This study presents a new approach to difluoroallylation, which utilizes a regiodivergent C-H bond reaction catalyzed by ruthenium catalysis. This method enables the meta and ortho C-H α,α- and ortho C-H γ,γ-difluoroallylation of arenes using 3-bromo-3,3-difluoropropenes.

A homodimeric IL-15 superagonist F4RLI with easy preparation, improved half-life, and potent antitumor activities.

Interleukin-15 (IL-15) is a promising candidate for cancer immunotherapy due to its potent immune-activating effects. There are several IL-15 molecules currently in clinical trials but facing shortages of poor half-life, circulation instability, or complicated production and quality control processes. The aim of this study is to design a novel IL-15 superagonist to set out the above difficulties, and we constructed F4RLI consisting of the GS-linker spaced IgG4 Fc fragment, soluble IL-15 Rα (sIL-15Rα), and IL-15(N72D). Using a single plasmid transient transfection in HEK293E cells, the matured F4RLI was secreted in the form of homodimer and got purified by an easy step of protein A affinity chromatography. The F4RLI product can significantly stimulate the proliferation of human CD3+CD8+ T cells and NK cells in vitro. Meanwhile, F4RLI greatly extended the half-life and prolonged the exposure of IL-15 in mice nearly by 28- and 200-fold, respectively, in comparison with that of the IL-15 monomer. In vivo, F4RLI vastly expanded mouse splenic CD8+ T lymphocytes, illustrating its potential in tumor immunotherapy. Further studies showed that the combination of F4RLI with the immune checkpoint blocker atezolizumab played a synergistic effect in treating MC38 mouse tumor by increasing the percentage of CD8+ T cells in tumor tissue. Moreover, the combination therapy of F4RLI with the angiogenesis inhibitor bevacizumab resulted in significant tumor growth suppression in a xenograft human HT-29 mouse model. Overall, our results demonstrate a homodimeric IL-15 superagonist F4RLI with advances in manufacturing processes and biopharmaceutical applications for cancer immunotherapy. KEY POINTS: • The homodimeric structure of F4RLI facilitates its easy production processes and quality control. • The fusion with Fc and sIL-15Rα extends the plasma half-life of IL-15 by about 28-fold. • F4RLI can play synergistic antitumor activity with the PD-1/PD-L1 checkpoint inhibitor or angiogenesis inhibitor.

Palladium-Catalyzed gem-Difluoroallylation Reaction between Aryltributyltin and Bromodifluoromethylated Alkenes.

A robust Stille gem-difluoroallylation of arylstannanes with 3-bromo-3,3-difluoropropenes has been established. The catalyst was found to exert critical effect on the reaction chemoselectivity. By using Pd(OH)2/C as the catalyst, a series of 3-(hetero)aryl/vinyl-3,3-difluoropropenes were obtained in high efficiency with α-substitution regioselectivity. The reaction has a broad substrate scope, and various substitution patterns were well tolerated in both substrates. Notably, the reaction can be easily extended to late-stage gem-difluoroallylation of many bioactive molecules with good chemoselectivity.

Preparation of Sulfamates and Sulfamides Using a Selective Sulfamoylation Agent.

Sulfamates and sulfamides are prevalent in biological molecules, but their universal synthetic methods are limited. We herein report a sulfamoylation agent with high solubility and shelf stability. Various sulfamates and sulfamides can be synthesized directly from alcohols or amines by employing this agent with high selectivity and high yields. This protocol was also successfully used for late-stage sulfamoylation of pharmaceuticals containing a hydroxyl or amino group.

Acute and subchronic toxicity of Ag+-laden liposomes on Daphnia magna: the effect of encapsulation.

The toxic effects of various substances on Daphnia magna (D. magna) observed through traditional waterborne uptake may involve alterations to the nutritional quality of the contaminated algae and culture media. It is essential to find an alternative delivery method that will not affect the nutritional quality of D. magna's diet in order to elucidate the mechanisms of dietary metal toxicity. Therefore, this study examined the application of liposome encapsulation on the dietary toxicity of D. magna. Ag+-laden liposomes were prepared and the Ag encapsulation efficiency and inhibition effect on algae growth were examined. Then, acute and 14-day subchronic studies were performed to examine the effect of Ag+-laden liposomes on D. magna. The EC50 for the 24 h immobilization test was 10.59 µg/L for Ag+-laden liposomes and 3.07 µg/L for Ag+. In terms of subchronic effects, the estimated ECx values under the Ag+-laden liposome condition were always higher than the direct exposure condition. Furthermore, the bioaccumulation of Ag+-laden liposomes was about 1.68 times lower than direct exposure. Generally, Ag+-laden liposomes produced less efficient toxicity than direct exposure, e.g., lower D. magna mortality, production of more neonates, higher intrinsic rate of natural increase (rm), earlier time to first brood, and higher enzyme activities.

Effect of Kefir on Soybean Isoflavone Aglycone Content in Soymilk Kefir.

Kefir is a traditional fermented milk originating in the Caucasus area and parts of Eastern Europe. In this study, the kefir culture, which is modified upon the addition of lactic acid bacteria (LAB) cells, specifically for soymilk kefir fermentation with the highest capacity of isoflavone biotransformation, was successfully produced, and the metagenomics composition of soymilk or milk fermented using these kefir cultures was investigated. The metagenome analysis showed that the microbiota of kefir in M-K (milk inoculated with kefir), SM-K (equal volumes of soymilk and milk inoculated with kefir), and S-K (pure milk inoculated with kefir) were related to the addition of soymilk or not. Furthermore, the HPLC chromatogram revealed that Guixia 2 (Guangzhou, China) may be a good source of soymilk kefir fermentation due to its high isoflavone aglycone content (90.23 ± 1.26 µg/g in daidzein, 68.20 ± 0.74 µg/g in genistein). Importantly, the starter culture created by adding 1.5 g probiotics (Biostime®, Guangzhou, China) to Chinese kefir showed a significant increase in the levels of isoflavone aglycones (72.07 ± 0.53 µg/g in isoflavone aglycones). These results provided insight into understanding the suitable soybean cultivar and starter cultures, which exhibit promising results of isoflavone biotransformation and flavor promotion during soymilk kefir fermentation.