Palladium-catalyzed alcohol oxidation allows the chemo- and regioselective modification of unprotected 1,4 linked glucans. This is demonstrated in the two-step bisfunctionalization of 1,4 linked glucans up to the 7-mer. Introduction of an anomeric azide is followed by a highly regioselective mono-oxidation of the terminal C3-OH functionality. The resulting orthogonal bis-functionalized oligosaccharides are a viable alternative to PEG-spacers as demonstrated in the conjugation of a cysteine mutant of 4-oxalocrotonate tautomerase with biotin.
In
chemical biology, azides are used to chemically manipulate target
structures in a bioorthogonal manner for a plethora of applications
ranging from target identification to the synthesis of homogeneously
modified protein conjugates. While a variety of methods have been
established to introduce the azido group into recombinant proteins,
a method that directly converts specific amino groups in endogenous
proteins is lacking. Here, we report the first biotin-tethered diazotransfer
reagent DtBio and demonstrate that it selectively modifies the model
proteins streptavidin and avidin and the membrane protein BioY on
cell surface. The reagent converts amines in the proximity of the
binding pocket to azides and leaves the remaining amino groups in
streptavidin untouched. Reagents of this novel class will find use
in target identification as well as the selective functionalization
and bioorthogonal protection of proteins.
The receptor tyrosine kinase EPHA2 has gained attention as a therapeutic drug target for cancer and infectious diseases. However, EPHA2 research and EPHA2-based therapies have been hampered by the lack of selective small-molecule inhibitors. Herein we report the synthesis and evaluation of dedicated EPHA2 inhibitors based on the clinical BCR-ABL/SRC inhibitor dasatinib as a lead structure. We designed hybrid structures of dasatinib and the previously known EPHA2 binders CHEMBL249097, PD-173955, and a known EPHB4 inhibitor in order to exploit both the ATP pocket entrance as well as the ribose pocket as binding epitopes in the kinase EPHA2. Medicinal chemistry and inhibitor design were guided by a chemical proteomics approach, allowing early selectivity profiling of the newly synthesized inhibitor candidates. Concomitant protein crystallography of 17 inhibitor co-crystals delivered detailed insight into the atomic interactions that underlie the structure-affinity relationship. Finally, the anti-proliferative effect of the inhibitor candidates was confirmed in the glioblastoma cell line SF-268. In this work, we thus discovered a novel EPHA2 inhibitor candidate that features an improved selectivity profile while maintaining potency against EPHA2 and anticancer activity in SF-268 cells.
Chemical probes that covalently modify proteins of interest are powerful tools for the research of biological processes. Important in the design of a probe is the choice of reactive group that forms the covalent bond, as it decides the success of a probe. However, choosing the right reactive group is not a simple feat and methodologies for expedient screening of different groups are needed. We herein report a modular approach that allows easy coupling of a reactive group to a ligand. α‐Nucleophile ligands are combined with 2‐formylphenylboronic acid derived reactive groups to form iminoboronate probes that selectively label their target proteins. A transimination reaction on the labeled proteins with an α‐amino hydrazide provides further modification, for example to introduce a fluorophore.
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