Bromodomains are epigenetic reader modules that regulate gene transcription through their recognition of acetyl-lysine modified histone tails. Inhibitors of this protein-protein interaction have the potential to modulate multiple diseases as demonstrated by the profound anti-inflammatory and antiproliferative effects of a recently disclosed class of BET compounds. While these compounds were discovered using phenotypic assays, here we present a highly efficient alternative approach to find new chemical templates, exploiting the abundant structural knowledge that exists for this target class. A phenyl dimethyl isoxazole chemotype resulting from a focused fragment screen has been rapidly optimized through structure-based design, leading to a sulfonamide series showing anti-inflammatory activity in cellular assays. This proof-of-principle experiment demonstrates the tractability of the BET family and bromodomain target class to fragment-based hit discovery and structure-based lead optimization.
An efficient method for the copper-catalyzed N-arylation of hydroxylamines with aryl iodides is described. A variety of N- and O-functionalized hydroxylamines were transformed in good to excellent yield with a broad range of aryl coupling partners. Methods for the selective deprotection of either the N- or O-substituents for further functionalization are also described.
The bis-pyrazole phosphine ligand BippyPhos is effective for the palladium-catalyzed cross-coupling of hydroxylamines with aryl bromides, chlorides, and iodides. Reactions proceed smoothly at 80 degrees C in toluene in the presence of Cs(2)CO(3) to give synthetically versatile N-arylhydroxylamine products in good to excellent yield.
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