33 research outputs found
Profiling of Multiple Targets of Artemisinin Activated by Hemin in Cancer Cell Proteome
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
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
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
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
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
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
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
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
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
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