33 research outputs found

    Profiling of Multiple Targets of Artemisinin Activated by Hemin in Cancer Cell Proteome

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    The antimalarial drug artemisinin is found to have diverse biological activities ranging from anti-inflammatory to anticancer properties; however, as of today, the cellular targets and mechanism of action of this important compound have remained elusive. Here, we report the global protein target profiling of artemisinin in the HeLa cancer cell proteome using a chemical proteomics approach. In the presence of hemin, multiple proteins were targeted by artemisinin probe through covalent modification. Further studies revealed that reducing of hemin to heme by protein thiols was essential for endoperoxide activation and subsequent protein alkylation. Artemisinin may exert its synergistic therapeutic anticancer effects <i>via</i> modulation of a variety of cellular pathways through acting on multiple targets

    Reactivity of Alkynylzirconate toward α,β-Unsaturated Carbonyl Compounds

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    The reaction of alkynylzirconates with α,β-unsaturated carbonyl compounds has been achieved. Reactions of alkynylzirconates with cinnamates afford ester-functionalized multisubstituted dienes, in which the C3 attacks cinnamates via Michael addition. Reactions of alkynylzirconates with benzylideneacetone give (1E,3Z)-dienes, in which benzylideneacetone acts as an electrophile to afford a proton

    Copper-Mediated Reaction of Oxazirconacyclopentenes with But-2-ynedioates: A New Pathway for the Formation of α-Methylene-δ-lactone Derivatives

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    Oxazirconacyclopentenes reacted with but-2-ynedioates in the presence of CuCl via tandem Michael addition/nucleophilic substitution to afford α-methylene-δ-lactone derivatives

    Copper-Mediated Reaction of Oxazirconacyclopentenes with But-2-ynedioates: A New Pathway for the Formation of α-Methylene-δ-lactone Derivatives

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    Oxazirconacyclopentenes reacted with but-2-ynedioates in the presence of CuCl via tandem Michael addition/nucleophilic substitution to afford α-methylene-δ-lactone derivatives

    Copper-Catalyzed Electrophilic Amination of Alkenylzirconocenes with <i>O</i>‑Benzoylhydroxylamines: An Efficient Method for Synthesis of Enamines

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    Copper-catalyzed electrophilic amination of alkenylzirconocenes is accomplished under mild reaction conditions. The reaction tolerates a wide range of functional groups and can be used to prepare some hindered enamines

    Copper-Catalyzed Electrophilic Amination of Alkenylzirconocenes with <i>O</i>‑Benzoylhydroxylamines: An Efficient Method for Synthesis of Enamines

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    Copper-catalyzed electrophilic amination of alkenylzirconocenes is accomplished under mild reaction conditions. The reaction tolerates a wide range of functional groups and can be used to prepare some hindered enamines

    Characterization of the Artemisinin Binding Site for Translationally Controlled Tumor Protein (TCTP) by Bioorthogonal Click Chemistry

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    Despite the fact that multiple artemisinin-alkylated proteins in Plasmodium falciparum have been identified in recent studies, the alkylation mechanism and accurate binding site of artemisinin–protein interaction have remained elusive. Here, we report the chemical-probe-based enrichment of the artemisinin-binding peptide and characterization of the artemisinin-binding site of P. falciparum translationally controlled tumor protein (TCTP). A peptide fragment within the N-terminal region of TCTP was enriched and found to be alkylated by an artemisinin-derived probe. MS2 fragments showed that artemisinin could alkylate multiple amino acids from Phe12 to Tyr22 of TCTP, which was supported by labeling experiments upon site-directed mutagenesis and computational modeling studies. Taken together, the “capture-and-release” strategy affords consolidated advantages previously unavailable in artemisinin–protein binding site studies, and our results deepened the understanding of the mechanism of protein alkylation via heme-activated artemisinin

    Copper-Mediated Reaction of Zirconacyclopentadienes with Azides: A One-Pot Three-Component Synthesis of Multiply Substituted Pyrroles from One Azide and Two Alkynes

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    A general method for the synthesis of multiply substituted pyrroles through zirconocene-mediated coupling of two alkynes and an azide in the presence of CuCl has been achieved

    Chemoselective Phosphination of Titanacyclobutene: A Convenient Method for Synthesis of Allylphosphine Derivatives

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    Titanacyclobutenes reacted with chlorophosphine to afford titanoallylphosphines with high chemoselectivity, and the resulting titanoallylphosphine could be converted into functionalized allylphosphine sulfides via reactions with various electrophiles

    Discovery of an Orally Available Janus Kinase 3 Selective Covalent Inhibitor

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    JAK family kinases are important mediators of immune cell signaling and Janus Kinase 3 (JAK3) has long been indicated as a potential target for autoimmune disorders. Intensive efforts to develop highly selective JAK3 inhibitors have been underway for many years. However, because of JAK3’s strong binding preference to adenosine 5′-triphosphate (ATP), a number of inhibitors exhibit large gaps between enzymatic and cellular potency, which hampers efforts to dissect the roles of JAK3 in cellular settings. Using a targeted covalent inhibitor approach, we discovered compound 32, which overcame ATP competition (1 mM) in the enzymatic assay, and demonstrated significantly improved inhibitory activity for JAK3-dependent signaling in mouse CTLL-2 and human peripheral blood mononuclear cells. Compound 32 also exhibited high selectivity within the JAK family and good pharmacokinetic properties. Thus, it may serve as a highly valuable tool molecule to study the overlapping roles of JAK family kinases in complex biological settings. Our study also suggested that for covalent kinase inhibitors, especially those targeting kinases with low Km ATP values, the reversible interactions between molecules and proteins should be carefully optimized to improve the overall potency
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