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A domino annulation/oxidation of heterocyclic ketene aminals (HKAs) and 2-aminochalcones has been developed for the selective synthesis of poly-substituted benzo[f]imidazo[2,1-a][2,7]naphthyridines and 3-azaheterocyclic substituted 2-arylquinolines. These reactions proceed well under mild conditions without any additives. Plausible mechanisms for such a polycyclic ring system assembly were also proposed. Moreover, benzo[f]imidazo[2,1-a][2,7]naphthyridine 3g displayed a fluorescence effect, demonstrating the potential applications in organic optical materials.

Proteasome is vital for intracellular protein homeostasis as it eliminates misfolded and damaged protein. Inhibition of proteasome has been validated as a powerful strategy for anti-cancer therapy, and several drugs have been approved for treatment of multiple myeloma. Recent studies indicate that proteasome has potent therapeutic effects on a variety of diseases besides cancer, including parasite infectious diseases, bacterial/fungal infections diseases, neurodegenerative diseases and autoimmune diseases. In this review, recent developments of proteasome inhibitors for various diseases and related structure activity relationships are going to be summarized.

Hypoxia is widespread in solid tumors, such as NSCLC, and has become a very attractive target. On the basis of AZD9291 scaffold, novel hypoxia-targeted EGFR inhibitors without the acrylamide warhead but containing hypoxic reductive activation groups were described. Among them, compound JT21 exhibited impressive inhibitory activity (ICsub50/sub = 23 nM) against EGFRsupL858R/T790M/supand displayed about 21-fold inhibitory activity decrease against EGFRsupwt/sup. Under hypoxia, JT21 exhibited more significant proliferation inhibitory activities against H1975 cells (ICsub50/sub = 7.39 ± 2.20 nM) and HCC827 cells (ICsub50/sub = 5.88 ± 0.85 nM) than that of AZD9291, which was about 5 times more effective than normoxia activities. Meanwhile, the weak inhibition effects on A549 and BEAS-2B cells suggested JT21 might be a selective inhibitor for EGFR mutations with low toxicity. Furthermore, JT21 could induce apoptosis of H1975 cells under hypoxia and showed good bio-reductive property.

Novel divergent domino annulation reactions of sulfur ylides with aryldiazonium tetrafluoroborates have been developed, affording various tetra- and trisubstituted pyrazole derivatives in moderate to good yields. Three molecules of sulfur ylides were applied as C1 synthon to construct the complex products with five new chemical bonds formed in these one-pot reactions.

A domino annulation/oxidation of heterocyclic ketene aminals (HKAs) and 2-aminochalcones has been developed for the selective synthesis of poly-substituted benzo[

Proteasome is vital for intracellular protein homeostasis as it eliminates misfolded and damaged protein. Inhibition of proteasome has been validated as a powerful strategy for anti-cancer therapy, and several drugs have been approved for treatment of multiple myeloma. Recent studies indicate that proteasome has potent therapeutic effects on a variety of diseases besides cancer, including parasite infectious diseases, bacterial/fungal infections diseases, neurodegenerative diseases and autoimmune diseases. In this review, recent developments of proteasome inhibitors for various diseases and related structure activity relationships are going to be summarized.

Background NSCLC is the major type of lung cancer and the survival rates of NSCLC patients remain low. AZD9291 is a third-generation EGFR-TKI and approved to treat NSCLC patients harboring EGFR T790M mutation and common targetable activating EGFR mutations, but it has a limited effect for wtEGFR NSCLC. Purpose The current study investigated whether shikonin could enhance the antitumor effect of AZD9291 in wtEGFR NSCLC cells. Methods SRB and colony formation assay were used to detect the proliferation of NSCLC cells, propidium iodide staining was performed to detect the apoptosis, ROS was analyzed using DCFH-DA staining, and western blot was used to detect the expression of indicated proteins. Results We demonstrated that shikonin, a natural ROS inducer, could enhance the antitumor effect of AZD9291 in wtEGFR NSCLC cells. In addition, shikonin increased AZD9291-induced apoptosis accompanying with the generation of ROS and activation of ER stress. Furthermore, ROS inhibition by NAC or GSH reversed the apoptosis induced by shikonin plus AZD9291, and recovered the ER stress activated by combination treatment, indicating that ROS mediated ER stress played a vital role in this combination therapy. Moreover, shikonin increased the anticancer activity of AZD9291 in primary wtEGFR NSCLC cells through ROS-mediated ER stress. Conclusion Our study suggests that combining shikonin with AZD9291 is a promising therapeutic strategy for treating wtEGFR NSCLC patients.

A novel access to highly functionalized 2-aminonicotinonitriles via efficient annulations of α-keto vinyl azides and α,α-dicyanoalkenes is described. This annulation was achieved via base-mediated ring-openings and intramolecular rearrangements. A possible mechanism is also proposed.

An efficient annulation of vinyl azides with activated imines has been developed for the synthesis of poly-functionalized imidazole derivatives. This reaction includes thermal decomposition of vinyl azides to 2H-azirines, nucleophilic attack of 2H-azirines with activated imines and subsequent cyclization to desired imidazoles.

This paper reports the successful modification of biaxially oriented polypropylene (BOPP) films to permanently enhance their hydrophilic properties for potential flexible packing applications. This protocol consists of three sequential processes: (1) an on-line dielectric barrier discharge (DBD) plasma pretreatment, (2) a polyvinyl alcohol/silk fibroin/polyethylene glycol (PVA/SF/PEG) coating, and (3) ethanol solution finishing. The optimal modification conditions included: DBD plasma pretreatment for 10 seconds, coating with aqueous PVA/SF/PEG (3%/3%/1%) solution, and finally, 8 minutes of treatment with 60% ethanol solution. The fully modified BOPP films exhibited approximately a 16° static contact angle (SCA), a near zero haze value, and an effectively 100% transmittance value under visible light (400–700 nm). Atomic force microscopy (AFM) images of the surface morphology of the modified BOPP films showed that the surface roughness increased from 3.79 nm (untreated) to 21.10 nm (fully treated). The Fourier transfer infrared spectroscopy (FT-IR) results showed that polar functional CO groups were grafted onto the BOPP film that was pretreated with the DBD plasma. Further modification of the pretreated BOPP film with the PVA/SF/PEG coating significantly enhanced the density of the C–O and N–H groups. The gravure printing images indicated that the adhesive property of the BOPP film for water-based ink improved substantially after the hydrophilic modifications.

A simple and direct synthesis of functionalized imidazoles from α-nitro-epoxides and amidines was developed. This reaction could proceed smoothly in a highly efficient and eco-friendly manner in moderate to excellent yields. A plausible mechanism has also been proposed.

A novel and traceless strategy has been devised that allows a coupling of thioacids and dithiocarbamate-terminal amines. This strategy had been assumed to be dependent on the attachment of a functional equivalent of a cysteine side chain in earlier native chemical ligation approaches. This approach enables the traceless removal of CS2 to directly generate the desired amide bond and is compatible with a range of unprotected side chains of amino acid. The ability to produce amide or peptides by a traceless removal of the auxiliary is a significant virtue of the method. Meanwhile, the application of this new peptide-bond-forming reaction to the synthesis of novel endomorphin (EM) derivatives with various binding potencies was realized.

This letter describes the construction of conformationally constrained quinazoline analogues. Structure-activity relationship studies led to the identification of the lead compound 9n . Compound 9n exhibits effective in vitro activity against A431(WT,overexpression) and H1975([L858R/T790M]) cancer cell lines but is significantly less effective against EGFR negative cancer cell lines (SW620, A549, and K562). Compound 9n was also assessed for potency in enzymatic assays and in vivo antitumor studies. The results indicated that 9n is a potent kinase inhibitor against both wild-type and T790M mutant EGFR kinase. Meanwhile, an oral administration of 9n at a dose of 200 mg/kg produced a considerable antitumor effect in a A431 xenograft model, as compared to gefitinib. A preliminary pharmacokinetic study of 9n also indicates it has good pharmacokinetic properties, and therefore, it is a good starting point for further development.

Palladium-catalyzed C–H functionalization using guanidine as the directing group was achieved under mild reaction conditions. Various guanidine derivatives were produced in moderate to good yields by using simple unactivated arenes or ethyl acrylate as the source of arylation or olefination, respectively.