A practical and scalable process for the manufacture of cladribine (1) is described. Vorbrüggen glycosylation of doubly silylated 2-chloroadenine 2 with protected 1-O-acetyl-2-deoxy-α,β-d-ribofuranose 3 under reversible conditions in the presence of 20 mol % triflic acid in a solvent that selectively precipitated the desired β-anomer β-4a whilst leaving the unwanted α-anomer α-4a in solution to isomerise allowed good overall stereoselectivity with exclusive regioselectivity. An aging step allowed anomerisation of α-4a to β-4a, thereby improving the isolable yield of the β-anomer. Direct filtration of the product mixture without a catalyst quench or aqueous workup furnished the crude β-anomer β-4a in good yield (up to 68%) and purity (>95% by HPLC) with no regioisomers detected and only ∼1–3% (by HPLC) of the undesired α-anomer. Deprotection of the crude, unpurified intermediate β-4a followed by recrystallisation provided drug-grade cladribine (1). The process includes three isolation steps and was demonstrated on kilogram scales using cGMP providing 99.8–99.9% pure cladribine in up to an overall 43% yield based on 2-chloroadenine (5). In contrast to previous methods, column chromatography and/or bulky directing groups were not required in the glycosylation step, a high pressure vessel was not needed in the deprotection step, and only one dedicated recrystallisation step was necessary.
Mushrooms with edible and medicinal potential have received widespread attention because of their diverse biological functions, nutritional value, and delicious taste, which are closely related to their rich active components. To date, many bioactive substances have been identified and purified from mushrooms, including proteins, carbohydrates, phenols, and vitamins. More importantly, molecules derived from mushrooms show great potential to alleviate the pathological manifestations of Alzheimer’s disease (AD), which seriously affects the health of elderly people. Compared with current therapeutic strategies aimed at symptomatic improvement, it is particularly important to identify natural products from resource-rich mushrooms that can modify the progression of AD. This review summarizes recent investigations of multiple constituents (carbohydrates, peptides, phenols, etc.) isolated from mushrooms to combat AD. In addition, the underlying molecular mechanisms of mushroom metabolites against AD are discussed. The various mechanisms involved in the antiAD activities of mushroom metabolites include antioxidant and anti-neuroinflammatory effects, apoptosis inhibition, and stimulation of neurite outgrowth, etc. This information will facilitate the application of mushroom-derived products in the treatment of AD. However, isolation of new metabolites from multiple types of mushrooms and further in vivo exploration of the molecular mechanisms underlying their antiAD effect are still required.
Ultrasonic-assisted extraction (UAE) of flavonoids (JMBF) from Juglans mandshurica Maxim., an important industrial crop in China, was investigated in the present study. To improve the extraction efficiency of JMBF, suitable UAE was proposed after optimization using a hybrid response surface methodology–artificial neural network–genetic algorithm approach (RSM–ANN–GA). The maximum extraction yield (6.28 mg·g−1) of JMBF was achieved using the following optimum UAE conditions: ethanol concentration, 62%; solid–liquid ratio, 1:20 g·mL−1; ultrasonic power, 228 W; extraction temperature, 60 °C; extraction time, 40 min; total number of extractions, 1. Through the investigation of extraction kinetics, UAE offered a higher saturated concentration (Cs) for JMBF in comparison to traditional solvent extraction (TSE). Scanning electron microscopy (SEM) images showed that deeper holes were generated in J. mandshurica powder under the action of ultrasound, indicating that ultrasound significantly changed the structure of the plant materials to facilitate the dissolution of active substances. Extracts obtained using UAE and TSE were compared by Fourier-transform infrared spectroscopy analysis, the results of which revealed that the functional group of bioactive compounds in the extract was unaffected by the ultrasonication process. Moreover, JMBF was further shown to exhibit significant antioxidant properties in vitro. This study provides a basis for the application of JMBF as a natural antioxidant.
The self-assembly of flexible bended dicarboxylate ligand, 2,2 0 -(2,4,6-trimethyl-1,3-phenylene)bis(methylene)-bis(sulfanediyl)dibenzoic acid (H 2 L), with Mn(OAc) 2 $4H 2 O resulted in the formation of a novel metal-organic coordination cage with binuclear manganese SBU as the vertex, which represents the first metalorganic coordination cage constructed from a flexible dicarboxylate ligand and a binuclear SBU.
In our previous study, human fibroblast growth factor 1 was successfully fused with oleosomes, energy-storing organelles of seeds, which are considered to be excellent “expression carriers” for substances with a convenient purification process. The present work aimed to explore the beneficial effects of oleosomes fused with human fibroblast growth factor 1 (OLAF) on wound healing. The data showed marked improvements in terms of the angiogenesis, vascular integrity, collagen and inflammation on the wound sites of rats with a full-thickness skin defect. Moreover, the positive role of OLAF in promoting angiogenesis and its possible pathways were clarified in vivo and in vitro. The results showed that the number, length and branches of the blood vessels of the chick embryo chorioallantoic membrane were markedly increased after OLAF treatment. Meanwhile, the in vitro results also revealed that 100 ng/mL OLAF exhibited a promoting effect on the proliferation, migration and tube formation of human umbilical vein endothelial cells. In addition, the potential of OLAF to improve wound angiogenesis was demonstrated to be associated with an up-regulated PI3K/Akt pathway by transcriptome sequencing analysis and the introduction of a PI3K/Akt pathway inhibitor (LY294002). These findings suggest that OLAF has many prospects in the development of drugs for wound healing.
The use of Paecilomyces tenuipes (P. tenuipes), a Chinese medicinal fungus in scientific research, is limited due to its low adenosine content. To improve adenosine production, the present study investigated the gene network of adenosine biosynthesis in P. tenuipes via transcriptome analysis. Mycelia of P. tenuipes cultured for 24 h (PT24), 102 h (PT102) and 196 h (PT192) were subjected to RNA sequencing. In total, 13,353 unigenes were obtained. Based on sequence similarity, 8,099 unigenes were annotated with known proteins. Of these 8,099 unigenes, 5,123 had functions assigned based on Gene Ontology terms while 4,158 were annotated based on the Eukaryotic Orthologous Groups database. Moreover, 1,272 unigenes were mapped to 281 Kyoto Encyclopedia of Genes and Genomes pathways. In addition, the differential gene expression of the three libraries was also performed. A total of 601, 1,658 and 628 differentially expressed genes (DEGs) were detected in PT24 vs. PT102, PT24 vs. PT192 and PT102 vs. PT192 groups, respectively. Reverse transcription-quantitative PCR was performed to analyze the expression levels of 14 DEGs putatively associated with adenosine biosynthesis in P. tenuipes. The results showed that two DEGs were closely associated with adenosine accumulation of P. tenuipes. The present study not only provides an improved understanding of the genetic information of P. tenuipes but also the findings can be used to aid research into P. tenuipes.
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