NOD2 (nucleotide-binding oligomerization domain-containing protein 2) is an internal pattern recognition receptor that recognizes bacterial peptidoglycan and stimulates host immune responses. Dysfunction of NOD2 pathway has been associated with a number of autoinflammatory disorders. To date, direct inhibitors of NOD2 have not been described due to technical challenges of targeting the oligomeric protein complex. Receptor interacting protein kinase 2 (RIPK2) is an intracellular serine/threonine/tyrosine kinase, a key signaling partner, and an obligate kinase for NOD2. As such, RIPK2 represents an attractive target to probe the pathological roles of NOD2 pathway. To search for selective RIPK2 inhibitors, we employed virtual library screening (VLS) and structure based design that eventually led to a potent and selective RIPK2 inhibitor with excellent oral bioavailability, which was used to evaluate the effects of inhibition of RIPK2 in various assays and and pharmacodynamic models.
Direct iridium-catalyzed multi-borylation provides a valuable tool for the symmetric functionalization of various polycyclic aromatic hydrocarbons, inter alia, regular fivefold derivatization of corannulene. In this paper, highly efficient microwave-assisted synthesis of 1,3,5,7,9-(Bpin) 5 -corannulene is reported, resulting in a significant decrease in reaction time compared to the routine bench-top preparation. In addition, conversion to more reactive boron species, such as the corresponding pentatrifluoroborate and pentaboronic acid, was realized under mild conditions in excellent yields. 1,3,5,7,9-corannulene pentaboronic acid gave further access to a series of boronic esters of corannulene via simple alcohol exchange. This convenient methodology to 1,3,5,7,9-corannulene pentaboronic acid portends its ability to serve as a key building block for formation of icosahedral supramolecules, alone or together with suitable bridging ligands. † Electronic supplementary information (ESI) available. CCDC 1042202-1042203.For ESI and crystallographic data in CIF or other electronic format see
Potassium acyltrifluoroborates (KATs)
undergo chemoselective amide-forming
ligations with hydroxylamines. Under aqueous, acidic conditions these
ligations can proceed rapidly, with rate constants of ∼20 M–1 s–1. The requirement for lower
pH to obtain the fastest rates, however, limits their use with certain
biomolecules and precludes in vivo applications. By mechanistic investigations
into the KAT ligation, including kinetic studies, X-ray crystallography,
and DFT calculations, we have identified a key role for a proton in
accelerating the ligation. We applied this knowledge to the design
and synthesis of 8-quinolyl acyltrifluoroborates, a new class of KATs
that ligates with hydroxylamines at pH 7.4 with rate constants >4
M–1 s–1. We trace the enhanced
rate at physiological pH to unexpectedly high basicity of the 8-quinoline-KATs,
which leads to their protonation even under neutral conditions. This
proton assists the formation of the key tetrahedral intermediate and
activates the leaving groups on the hydroxylamine toward a concerted
1,2-BF3 shift that leads to the amide product. We demonstrate
that the fast ligations at pH 7.4 can be carried out with a protein
substrate at micromolar concentrations.
A new prosthetic group is reported for quantitative 18F-labelling of peptides and proteins based on the chemoselective ligation of potassium acyltrifluoroborates (KATs) and hydroxylamines without any detectable 18F/19F isotope exchange at the KAT moiety.
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