Syn-Stereoselective C3-Spirocyclization and C2-Amination of 3-(2-Isocyanoethyl)indole Using C,N-Cyclic Azomethine Imines.

By utilizing an underexplored reaction mode of C,N-cyclic azomethine imines, a catalyst-free [1+2+3] cycloaddition/N-N bond cleavage sequential reaction for accessing spiroindolines with syn-stereoselectivity was developed. On the basis of experimental results and DFT calculations, peroxide and ethereal solvent were identified to trigger the hydrogen abstraction of the unstable [1+2+3] cycloaddition adducts, followed by homolytic cleavage of the N-N bond and hydrogen absorption.

Cobalt-Catalyzed Isocyanide-Based Three-Component Cascade for the Synthesis of Quinazolines.

A Co-catalyzed cyclization reaction of isocyanides, azides, and amines to access quinazoline derivatives was described. This protocol features a high atom economy, mild reaction conditions, excellent yields, and a broad substrate scope. This cascade reaction involved three or four C-N bonds and the formation of one or two rings. The quinazolin-4(H)-imines obtained are proven to be versatile intermediates for further valuable transformations. It was also found that the cobalt catalyst could be isolated from the reaction mixture and reused.

Cascade Reaction of Tryptamine-Derived Isocyanides with Nitrile Oxides: Construction of Oxazine Fused-Spiroindoline Derivatives.

A one-step cascade reaction of tryptamine-derived isocyanides with in situ generated nitrile oxides for the synthesis of fused spiroindolines was described. The desired products could be efficiently synthesized in moderate to good yields (42-87%). The protocol features mild conditions, wide substrate scope, and high efficiency.

Hydrogen-Bonding-Promoted Cascade Rearrangement Involving the Enlargement of Two Rings: Efficient Access to Polycyclic Quinoline Derivatives.

An efficient cascade reaction of tryptamine-derived isocyanides with C,N-cyclic azomethine imines is described. The polycyclic pyrrolo[2,3-c]quinoline derivatives, which benefited from rearrangement process driven by hydrogen bonding, could be directly assembled in moderate to good yields (40-87 %) under metal-free and mild conditions. This transformation involved four new heterocyclic rings formations and uniquely, ring opening of indole as well as ring expansion of C,N-cyclic azomethine imine. Both experimental and DFT studies provided guidance on the in-depth insight into the reaction pathways and hydrogen bonding was identified to lower the free energy barrier in transition states. This work constitutes a rare example of tryptamine-derived isocyanide-based cascade reactions, and potentially could be a powerful synthetic strategy for accessing polycyclic analogues involved in natural products.

Study on Clinical Significance of LncRNA EGOT Expression in Colon Cancer and Its Effect on Autophagy of Colon Cancer Cells.

BACKGROUND: Colon cancer (CC) is a common digestive tract tumor, and the increase of new and dead patients every year still puzzles clinical workers. LncRNA eosinophil granule ontogeny transcript (EGOT), as a newly discovered long-chain noncoding RNA (lncRNA), is differentially expressed in other tumors, but there are fewer studies of it in colon cancer. METHODS: The relative expression and diagnostic value of EGOT in CC were detected and analyzed by starBase online website and qRT-PCR. The patients were followed-up for five years, and Cox regression was used to analyze the independent prognostic factors of CC. The effects of EGOT overexpression (pcDNA-RGOT) on CC cell function were detected by CCK-8, transwell and flow cytometry. WB was applied to detect autophagy. The influence of knocking out EGOT (sh-EGOT) on tumor growth was observed by tumor allogeneic inhibition. The microRNA (miR) and mRNA in the downstream of EGOT were predicted and the ceRNA network map was drawn. RESULTS: The online database and qRT-PCR detection showed that EGOT was highly expression in patients with CC and had good diagnostic value. The five-year survival rate of patients with high expression of EGOT decreased. EGOT and TNM staging were independent prognostic factors of patients with CC. Functional analysis revealed that the growth and invasion abilities of cells increased, and the apoptosis rate decreased after overexpression. Upregulation of EGOT inhibited autophagy of CC cells and promoted cell growth. However, the tumor in nude mice was significantly lessened after knockout of EGOT. Bioinformatic analysis showed that microRNA-33a-5p and microRNA-33b-5p had targeted binding sites with EGOT. CONCLUSION: EGOT is highly expressed in CC and has high diagnostic value. In addition, inhibition of EGOT can promote autophagy of CC cells and inhibit cell growth and metastasis, which is expected to be a potential therapeutic index.

Synthesis of Polysubstituted Maleimides via Metal-Free Cascade Reaction of Isocyanides and α-Diazoketones.

In this paper, synthesis of polysubstituted maleimides was described via cascade reaction of isocyanides and α-diazoketones. This strategy features readily available substrates, high atom-economy and metal-free conditions. A variety of valuable polysubstituted maleimides are assembled in good yields.

Dearomatization of Indoles via Azido Radical Addition and Dioxygen Trapping To Access 2-Azidoindolin-3-ols.

Efficient copper-catalyzed aerobic oxidative dearomatization of indoles with trimethylsilyl azide (TMSN3) for the synthesis of 2-azidoindolin-3-ols has been developed. Molecular oxygen served as the oxygen-atom source in this transformation. The multicomponent reaction is appreciated by its high site- and diastereoselectivity, broad substrate scope, and mild conditions at room temperature.

Efficient synthesis of 2-arylquinazolin-4-amines via a copper-catalyzed diazidation and ring expansion cascade of 2-arylindoles.

Copper-catalyzed synthesis of 2-arylquinazolin-4-amines from readily available 2-arylindoles and TMSN3 has been developed. The mechanism study shows that the domino reaction may involve a free radical diazidation, denitrogenation, intramolecular cyclization and ring expansion sequence.

[4 + 1] Cycloaddition Reaction of α,ß-Alkynic Hydrazones and KSCN under Transition-Metal-Free Conditions: Synthesis of N-Iminoisothiazolium Ylides.

A novel heteroannulation reaction between α,ß-alkynic hydrazones and potassium thiocyanate has been developed for the synthesis of N-iminoisothiazolium ylides. The transformation features wide substrate scope, functional tolerance, and easy operation. This investigation involves a [4 + 1]-type cycloaddition reaction and C-S/S-N bond formation under transition-metal-free conditions. The application of this transformation to the gram-scale preparation of the N-imide ylide is also accomplished.

Ag(I)-Promoted Dehydroxylation and Site-Selective 1,7-Disulfonylation of Diaryl(1 H-indol-2-yl)methanols.

A novel dehydroxylation and site-selective 1,7-disulfonylation reaction of diaryl(1 H-indol-2-yl)methanols with sodium sulfinates was described. The protocol provided an efficient strategy for the synthesis of disulfonylated 2-(diarylmethyl)indoles by exploring a range of substrates. The mechanistic studies revealed that silver nitrate served as both a Lewis acid and an oxidant for the sequential 1,7-disulfonylation process leading to the formation of final products.

BCR-ABL enhances the prolyl isomerase activity of Pin 1 by interacting with DAPK1 in ph+ ALL.

Philadelphia chromosome (Ph)/BCR-ABL-positive (ph+ ) ALL is the most common genetic abnormality associated with ALL and has been shown to confer the worst prognosis to both children and adults. Increasing evidence has revealed that the dysregulation of prolyl isomerase Pin 1 contributes to multicancer development and progression, including ALL, although the underlying molecular mechanisms remain unclear. Here, we report that the expression of Pin 1 was enhanced in ph+ ALL patient samples and was associated positively with the expression of BCR-ABL. Genetically or pharmacologically inhibiting Pin 1 expression or activity produces potent therapeutic efficacy against ph+ ALL. We further demonstrated that BCR-ABL enhances the prolyl isomerase activity of Pin 1 by decreasing the phosphorylated level of Pin 1 at Ser 71 and interacting with DAPK1. The inhibition of BCR-ABL activity by imatinib in human ph+ ALL cells reduces the prolyl isomerase activity of Pin 1, further suggesting a key role of the newly identified BCR-ABL-Pin 1 axis in ph+ ALL progression. Thus, the combined suppression of Pin 1 and BCR-ABL proteins may be exploited as an additional target therapy for ph+ ALL.

A novel assessment of the traction forces upon settlement of two typical marine fouling invertebrates using PDMS micropost arrays.

Marine biofouling poses a severe threat to maritime and aquaculture industries. To prevent the attachment of marine biofouling organisms on man-made structures, countless cost and effort was spent annually. In particular, most attention has been paid on the development of efficient and environmentally friendly fouling-resistant coatings, as well as larval settlement mechanism of several major biofouling invertebrates. In this study, polydimethylsiloxane (PDMS) micropost arrays were utilized as the settlement substrata and opposite tractions were identified during early settlement of the barnacle Amphibalanus amphitrite and the bryozoan Bugula neritina The settling A. amphitrite pushed the periphery microposts with an average traction force of 376.2 nN, while settling B. neritina pulled the periphery microposts with an average traction force of 205.9 nN. These micropost displacements are consistent with the body expansion of A. amphitrite during early post-settlement metamorphosis stage and elevation of wall epithelium of B. neritina during early pre-ancestrula stage, respectively. As such, the usage of micropost array may supplement the traditional histological approach to indicate the early settlement stages or even the initiation of larval settlement of marine fouling organisms, and could finally aid in the development of automatic monitoring platform for the real-time analysis on this complex biological process.

Copper-catalyzed construction of eight-membered rings via oxidative ring expansion and intermolecular cyclization sequencing of indoles with amidines: efficient synthesis of benzo[1,3,5]triazocin-6(5H)-ones.

Novel and efficient synthesis of eight-membered nitrogen heterocycles in one pot by copper-catalyzed oxidative ring expansion and intermolecular cyclization sequencing of indoles with amidines has been described. This protocol features easily available substrates and high step-economy. More importantly, dioxygen as the most ideal oxidant was employed under mild reaction conditions. A variety of valuable benzo[1,3,5]triazocin-6(5H)-one derivatives bearing functional groups were assembled in middle to good yields.

TRIB3 Promotes APL Progression through Stabilization of the Oncoprotein PML-RARα and Inhibition of p53-Mediated Senescence.

Acute promyelocytic leukemia (APL) is driven by the oncoprotein PML-RARα, which antagonizes myeloid differentiation and promotes APL-initiating cell self-renewal. Combined all-trans retinoic acid (ATRA) with arsenic trioxide (As2O3) or chemotherapy dramatically improves the prognosis of APL patients. Here we report that expression of pseudokinase Tribble 3 (TRIB3) associates positively with APL progression and therapeutic resistance. The elevated TRIB3 expression promotes APL by interacting with PML-RARα and suppressing its sumoylation, ubiquitylation, and degradation. This represses PML nuclear body assembly, p53-mediated senescence, and cell differentiation, and supports cellular self-renewal. Genetically inhibiting TRIB3 expression or combination of a peptide disturbing TRIB3/PML-RARα interaction with ATRA/As2O3 eradicates APL by accelerating PML-RARα degradation. Our study provides insight into APL pathogenesis and a potential therapeutic option against APL.

Synthesis of fused indoline heterocycles via dearomatization of indoles with α-bromohydrazones: a systematic study on the substrates.

An efficient metal-free dearomatization of indoles with α-bromohydrazones is reported. Various fused indoline heterocycles, which are potentially biologically active, were achieved in good yields (up to 94%) under mild conditions. A systematic study on electronic- and steric effects of substrate and reagents revealed that they have great influence upon the reaction. Based on this, the scope of indoles and α-bromohydrazones was widely exploited.

Iron Catalysis for Modular Pyrimidine Synthesis through ß-Ammoniation/Cyclization of Saturated Carbonyl Compounds with Amidines.

An efficient method for the modular synthesis of various pyrimidine derivatives by means of the reactions of ketones, aldehydes, or esters with amidines in the presence of an in situ prepared recyclable iron(II)-complex was developed. This operationally simple reaction proceeded with broad functional group tolerance in a regioselective manner via a remarkable unactivated ß-C-H bond functionalization. Control experiments were performed to gain deep understanding of the mechanism, and the reactions are likely to proceed through a designed TEMPO complexation/enamine addition/transient α-occupation/ß-TEMPO elimination/cyclization sequence.

Targeting acute myeloid leukemia with a proapoptotic peptide conjugated to a Toll-like receptor 2-mediated cell-penetrating peptide.

Cell-penetrating peptides provide a unique platform to create a new generation of cancer therapeutics with enhanced efficacy and diminished toxicity. In our study, enhanced expression of toll-like receptor 2 (TLR2) was observed in acute myeloid leukemia (AML) cells. Screening of a phage display peptide library using Biopanning and Rapid Analysis of Selective Interactive Ligands (BRASIL) identified a TLR2-binding peptide motif, Pep2. We show that the TLR2-binding peptide motif targeted and penetrated into leukemia cells in a TLR2-dependent manner. Moreover, a synthetic, chimeric peptide composed of the TLR2-binding motif linked to a programmed cell death-inducing sequence, D(KLAKLAK)2, induced apoptosis in AML cells with high TLR2 expression (TLR2(high)) but not in chronic myeloid leukemia (CML) cells with low TLR2 expression (TLR2(low)). The antileukemia activity of this chimeric peptide was confirmed in leukemia patient samples and an animal model of myeloid leukemia, as the development of leukemia was significantly delayed in mice with TLR2(high) AML compared to TLR2(low) CML NOD/SCID mice. TUNEL assays on bone marrow tissue slices revealed that the chimerical peptide induced leukemia cell apoptosis in a TLR2-dependent manner. Together, our findings indicate that TLR2 is a potential therapeutic target for the prevention and treatment of AML, and the prototype, Pep2-D(KLAKLAK)2, is a promising drug candidate in this setting.

[Clinical features and antimicrobial resistance of Gram positive bacterial blood stream infection in patients with hematologic diseases].

OBJECTIVE: To study the clinical characteristics and antimicrobial resistance of bloodstream infections caused by Gram positive bacteria, so as to provide reference for the rational use of antimicrobial agent. METHODS: One hundred and eight patients with bloodstream infections of Gram positive bacteria in our hospital from January 2009 to December 2009 were retrospectively reviewed. The clinical manifestations, pathogen types and antimicrobial susceptibility results of pathogens isolated from bloodstream were analyzed. RESULTS: All patients had fever and 31.89% with rigor, 22.41% of the patients had no local infection lesions, 77.59% had clear infection lesions, including oral infections, respiratory tract infections and soft tissue infections. The pathogen testing showed that 12.82% were staphylococci aureus, 50.42% coagulase-negative staphylococci, 24.8% streptococci, 9.4% enterococci and 2.56% Listeria monocytogenes. Antibiotics resistance of staphylococcus and enterococci in our hospital was severe. The percentage of methicillin-resistant staphylococcus aureus in this investigation was 68.92%. The resistant rates of methicillin-resistant coagulase-negative staphylococci (MRCNS) to the most antimicrobial agents were higher than that methicillin-sensitive coagulase-negative staphylococci. One strain of MRCNS was found resistant to teicoplanin and linezolid, and 1 strain of enterococci resistant to teicoplanin and linezolid. CONCLUSION: Gram positive bacteria shows serious drug resistance, but still keeps highly sensitive to vancomycin, linezolid, teicoplanin and quinupristin/dalfopristin.

Preparation of (Fe, N)-doped TiO2 powders and their antibacterial activities under visible light irradiation.

Yellowish (Fe, N)-doped nanocrystalline TiO2 powders have been prepared using TiOSO4, CO(NH2)2, Fe(NO3)3.9H2O and CN3H5.HCl as precursors by hydrothermal method. The as-synthesized powders were anatase in phase and the grain size was about 10 nm according to the TEM photos. The ratio of Fe/Ti is 2.2 at% and N/O is 0.8 at% respectively. TiO2 powders were mixed with organic silicon and acrylic syrup to test their antibacterial performance by the colony counting method. The results show that the sterilization ratio of E. coli by the heat-treated (Fe, N)-doped nanocrystalline TiO2 powders is reached up to 94.5% while that of the powders without any heat treatment is 91.1% by 8 hours-400 lux-Visible-light irradiation with humidity of 55% RH.