The azide group has a diverse and extensive role in organic chemistry, reflected in the power of azide anion as a strong nucleophile, the role of organic azides as excellent substrates for cycloaddition reactions, the uses of azides as precursors of amines and nitrenes, and azide rearrangements known as the Curtius and Schmidt reactions. In recent years the scope of the Schmidt reaction has begun to be explored in depth, so that it now represents an important reaction in synthetic chemistry. This tutorial review analyses and summarises key recent developments in the field of Schmidt reactions.
Isocyanides possess a rich history in the world of synthetic chemistry. Recently the scope of this already versatile class of reagent has been expanded into its use in palladium-catalysed cascade sequences. The scope of this type of reaction is explored in depth and this tutorial review focuses on its various applications in chemical synthesis, and the wide range of systems that can be efficiently prepared using this strategy are documented.
Efficient and convenient three-component couplings of an aryl halide, isocyanide, and an amino alcohol under palladium catalysis provide a range of oxazolines and benzoxazoles in excellent yield.
IKKβ
plays a central role in the canonical NF-kB pathway, which has been
extensively characterized. The role of IKKα in the noncanonical
NF-kB pathway, and indeed in the canonical pathway as a complex with
IKKβ, is less well understood. One major reason for this is
the absence of chemical tools designed as selective inhibitors for
IKKα over IKKβ. Herein, we report for the first time a
series of novel, potent, and selective inhibitors of IKKα. We
demonstrate effective target engagement and selectivity with IKKα
in U2OS cells through inhibition of IKKα-driven p100 phosphorylation
in the noncanonical NF-kB pathway without affecting IKKβ-dependent
IKappa-Bα loss in the canonical pathway. These compounds represent
the first chemical tools that can be used to further characterize
the role of IKKα in cellular signaling, to dissect this from
IKKβ and to validate it in its own right as a target in inflammatory
diseases.
Increasing evidence has linked dysregulated interleukin (IL)-10 production by IL-10+ve B cells to autoimmunity, highlighting the importance of improving the understanding of the regulation of IL-10 production in these cells. In both B cells and myeloid cells, IL-10 can be produced in response to Toll-like receptor (TLR) agonists. In macrophages, previous studies have established that mitogen- and stress-activated protein kinases (MSKs) regulate IL-10 production via the phosphorylation of cAMP response element–binding (CREB) protein on the IL-10 promoter. We found here that although MSKs are activated in peritoneal B cells in response to TLR4 agonists, neither MSKs nor CREB are required for IL-10 production in these cells. Using a combination of chemical inhibitors and knockout mice, we found that IL-10 induction in B cells was regulated by an ERK1/2- and p90 ribosomal S6 kinase-dependent mechanism, unlike in macrophages in which p90 ribosomal S6 kinase was not required. This observation highlights fundamental differences in the signaling controlling IL-10 production in B cells and macrophages, even though these two cell types respond to a common TLR stimulus.
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