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The development of enantioselective desymmetrization of para-quinamines with isocyanates catalyzed by chiral phosphoric acid is reported. The strategy provides concise access to functionalized imidazolidin-2-one derivatives in high yields and enantioselectivities under mild reaction conditions. Remarkably, this reaction could be performed on a gram scale using 5 mol % catalyst loading and the chiral imidazolidin-2-one derivatives could be easily transformed into valuable scaffolds without disturbing the enantiopurity, demonstrating the synthetic utility of this protocol.

Proprotein convertase subtilisin kexin 9 (PCSK9) has been identified as a reliable therapeutic target for hypercholesterolemia and coronary artery heart diseases since the monoclonal antibodies of PCSK9 have launched. Disrupting the protein-protein interaction (PPI) between PCSK9 and the low-density lipoprotein receptor (LDLR) has been considered as a promising approach for developing PCSK9 inhibitors. However, PPIs have been traditionally considered difficult to target by small molecules since the PPI surface is usually large, flat, featureless, and without a "pocket" or "groove" for ligand binding. The PCSK9-LDLR PPI interface is such a typical case. In this study, a potential binding pocket was generated on the PCSK9-LDLR PPI surface of PCSK9 through induced-fit docking. On the basis of this induced binding pocket, virtual screening, molecular dynamics (MD) simulation, and biological evaluations have been applied for the identification of novel small molecule inhibitors of PCSK9-LDLR PPI. Among the selected compounds, compound 13 exhibited certain PCSK9-LDLR PPI inhibitory activity (IC50: 7.57 ± 1.40 μM). The direct binding affinity between 13 and PCSK9 was determined with a KD value of 2.50 ± 0.73 μM. The LDLR uptake function could be also restored to a certain extent by 13 in HepG2 cells. This well-characterized hit compound will facilitate the further development of novel small molecule inhibitors of PCSK9-LDLR PPI.

HMGB1 (high-mobility group box 1) protein is a nonhistone chromatin-associated protein that has been widely reported to be a representative damage-associated molecular pattern (DAMP) and to play a pivotal role in proinflammatory process once it is in an extracellular location. Accumulating evidence has shown HMGB1 undergoes extensive PTMs that remarkably regulated its conformation, localization, and intermolecular interaction. However, the PTMrelated study has been dramatically hindered by the difficulty to access to homogenous proteins with site-specific PTMs of interest. Here, we introduce a protein semi-synthesis strategy via salicylaldehyde ester-mediated chemical ligations (Ser/Thr ligation and Cys/Pen ligation, STL/CPL). This methodology has enabled us to generate N-terminal acetylated HMGB1 proteins in high purity. Further studies revealed that the acetylation on N-terminus regulates its interaction with heparin and modulates its stability, representing a regulatory switch to control the HMGB1’s activity.

Nonribosomal peptide synthesis in bacteria has endowed cyclic peptides with fascinating structural complexity via incorporating nonproteinogenic amino acids. These bioactive cyclic peptides provide interesting structural motifs for exploring total synthesis and medicinal chemistry studies. Cyclic glycopeptide mannopeptimycins exhibit antibacterial activity against antibiotic-resistant Gram-positive pathogens and act as the lipid II binder to stop bacterial cell wall biosynthesis. Here, we report a strategy streamlining solution phase-solid phase synthesis and chemical ligation-mediated peptide cyclization for the total synthesis of mannopeptimycin β.

Flavonoids are an important group of polyphenolic compounds which are widely distributed throughout the plant kingdom especially in colored fruits and flowers. They play important roles in many plant biological functions and have therapeutic effect on many chronic diseases in humans. The flavonoid biosynthesis and productivity in plants could be stimulated by many biotic and abiotic factors. Bitter pit in apple is an important physiological disorder in apple production, which consequently affects the quality of apple fruits and causes significant economic losses. This study was aimed to investigate the influence of bitter pit on the flavonoid contents in apple fruits and its molecular biological mechanism, so as to explore the alternative bioresource of flavonoids for medical application in human chronic diseases. The total flavonoid content was determined using the aluminum chloride colorimetric method. The result showed that the total flavonoid content in bitter-pit apple fruits (BG) were 4.28-fold as that in healthy apple fruits (JKG). By RNA sequencing, 257.002 and 225.713 M raw reads containing 38.55 and 33.857 Gb raw bases were obtained from JKG and BG respectively, after trimming the adapter sequences, primers, Ns, and reads with quality scores below 30, 226.702 and 202.951 M clean reads containing 32.807 G and 29.626 nucleotides were obtained respectively, their base ratios with quality values higher than 20 and 30 in reads (Q20 and Q30) were more than 98.3% and 95.0%, respectively. By miRNA sequencing, 4331 clean reads associated with 3753 target genes (2571 upregulated and 1181 downregulated) were obtained. After annotation, a total of 41894 RNAs were obtained, of which, 15852 were known transcripts and 26042 were novel transcripts. Among the obtained transcripts, there were 33582 mRNAs (12645 known and 20937 novel), 1860 lncRNAs (0 known and 1860 novel), 98 circRNAs (52 known and 46 novel), 5894 miRNAs (3017 known and 2877 novel), 322 other type of RNAs(0 known and 322 novel) and 138 unknown type of RNAs (138 known and 0 novel). Based on Gene Ontology (GO) gene functional annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, 2632 differentially expressed genes (DEGs) were obtained from JKG vs. BG comparison, in which, 2080 DEGs were upregulated and 552 were downregulated. Among the obtained DEGs, 26 DEGs (2 downregulated and 24 upregulated) were involved in flavonoid biosynthesis [ko00941], all of them are mRNAs, there were no lncRNAs, circRNAs and miRNAs related to flavonoid biosynthesis. Then, 8 of the 26 DEGs [ CYP98A3 (1), CYP98A3 (2), BADH , DAT , MdHCT (1), MdHCT (2), CHI (1) and CHI (2)] with fold change>1.0 (1.43–29.42) were selected for qRT-PCR validation, the result exhibited the consistent expression patterns with that of RNA-seq analysis ( R 2=0.8551), that is, the expression of the 8 DEGs were upregulated with the BG/JKG ratio of 1.05–7.17 in JKG vs BG comparison, and the ratios of qRT-PCR relative expression level were less than the fold change of RNA-seq FPKM value except DAT . The results of this study showed that the flavonoid biosynthesis and accumulation in apple fruits was significantly stimulated by bitter pit disease, which provided new insights into the influence of bitter pit on the flavonoid biosynthesis and accumulation in apples and indicated that the bitter-pit apples could be use as the potential bioresource of flavonoids for therapeutic utilization in human chronic diseases.

Light and low temperatures induce anthocyanin accumulation, but intense sunlight causes photooxidative sunburn. Nonetheless, there have been few studies of anthocyanin synthesis under different sunlight intensities and low nighttime temperatures. Here, low nighttime temperatures followed by low light intensity were associated with greater anthocyanin accumulation and the expression of anthocyanin biosynthesis genes in “Fuji” apple peel. UDP-glucose flavonoid-3-O-glucosyltransferase (UFGT) activity was positively associated with anthocyanin enrichment. Ascorbic acid can be used as an electron donor of APX to scavenge H2O2 in plants, which makes it play an important role in oxidative defense. Exogenous ascorbate altered the anthocyanin accumulation and reduced the occurrence of high light–induced photooxidative sunburn by removing hydrogen peroxide from the peel. Overall, low light intensity was beneficial for the accumulation of anthocyanin and did not cause photooxidative sunburn, whereas natural light had the opposite effect on the apple peel at low nighttime temperatures. This study provides an insight into the mechanisms by which low temperatures induce apple coloration and high light intensity causes photooxidative sunburn.

The preharvest application of Ca-containing foliar fertilizers can reduce the incidence of bitter pit (BP) in apples and improve fruit quality by increasing the Ca content and decreasing both the N content and the N/Ca ratio in fruits. In this study, we aimed to investigate the control efficacy of Ca-containing fertilizers on the incidence of BP and their effects on the Ca and N contents in bagged 'Fuji' apples by spraying foliar fertilizer containing calcium chloride (CaCl2 ), calcium nitrate [Ca(NO3 )2 ] or calcium formate [Ca(HCOO)2 ] at an early stage, five days after full bloom (DAFB) and 40 DAFB, and at a late stage, 80 DAFB and 125 DAFB.; Results: The incidences of BP were reduced significantly by 43.2-73.0%, and the efficacy of spraying at an early stage was significantly higher than that of spraying at a late stage. The Ca content of bagged apple fruits increased whereas the N content and N/Ca ratio decreased after spraying Ca-containing foliar fertilizers; however, the Ca content, N content and N/Ca ratio of apple leaves were differentially influenced.; Conclusion: Foliar fertilizer containing CaCl2, Ca(NO3 )2 or Ca(HCOO)2 can be used at an early stage to control BP in apple and improve the quality of bagged apple fruits. © 2018 Society of Chemical Industry.; © 2018 Society of Chemical Industry.

Non-ribosomal cyclic peptides are abundant in natural sources, exhibiting attractive bioactivities and favorable pharmacological properties. Furthermore, their structural complexity renders them as attractive synthetic targets. A general task for cyclic peptide synthesis is the peptide cyclization. Compared to the traditional dehydration-based peptide macrolactamization, chemoselective peptide ligation provides an alternative, sometimes advantageous, strategy to cyclize peptides. Herein, we provide a series of structurally complex cyclic peptide examples whose total syntheses were achieved via peptide ligation-mediated peptide cyclization. The special features of these strategies for achieving the total synthesis are highlighted.

Chronic hepatitis B virus (HBV) infection has been a serious public health burden worldwide. Current anti-HBV therapies could not eliminate HBV ultimately. Considering the characteristics of HBV, it is impossible to be entirely cured based on current therapies. Therefore, it is urgently needed to develop novel therapeutic agents with new mechanism of action. The dihydroquinolizinone (DHQ) derivatives exhibited potent anti-HBV activity by decreasing HBV DNA and HBsAg level in an obscure mechanism of action. In this study, we have optimized the DHQ scaffold, developed the photoaffinity probe, with which to identify potential binding proteins.

Anthocyanin synthesis and degradation processes were analyzed at transcript, enzyme, and metabolite levels to clarify the effects of high temperature on the concentration of anthocyanin in plum fruit (Prunus salicina Lindl.). The transcript levels of PsPAL, PsCHS, and PsDFR decreased while those of PsANS and PsUFGT were similar at 35 °C compared with 20 °C. The activities of the enzymes encoded by these genes were all increased in fruits at 35 °C. The concentrations of anthocyanins were higher at 35 °C on day 5 but then decreased to lower values on day 9 compared with that at 20 °C. Furthermore, high temperature (35 °C) increased the concentration of hydrogen peroxide and the activity of class III peroxidase in the fruit. The concentration of procatechuic acid, a product of the reaction between anthocyanin and hydrogen peroxide, hardly changed at 20 °C but was significantly increased at 35 °C on day 9, indicating that anthocyanin was degraded by hydrogen peroxide, which was catalyzed by class III peroxidase. Based on mathematical modeling, it was estimated that more than 60–70% was enzymatically degraded on day 9 when the temperature increased from 20 °C to 35 °C. We conclude that at the high temperature, the anthocyanin content in plum fruit depend on the counterbalance between its synthesis and degradation.

Herpesvirus-associated Ubiquitin-Specific Protease (HAUSP, also called USP7) interacts with and stabilizes Mdm2, and represents one of the first examples that deubiquitinases oncogenic proteins. USP7 has been regarded as a potential drug target for cancer therapy. Inhibitors of USP7 have been recently shown to suppress tumor cell growth in vitro and in vivo. Based on leading USP7 inhibitors P5091 and P22077, we designed and synthesized a series of thiazole derivatives. The results of in vitro assays showed that the thiazole compounds exhibited low micromolar inhibition activity against both USP7 enzyme and cancer cell lines. The compounds induced cell death in a p53-dependent and p53-independent manner. Taken together, this study may provide thiazole compounds as a new class of USP7 inhibitors.