Organophosphorus-catalyzed diaza-Wittig reaction: application to the synthesis of pyridazines

The elaboration of the first organophosphorus-catalyzed diaza-Wittig reaction is reported. This catalytic reaction is applied to the synthesis of substituted pyridazine and phthalazine derivatives bearing electron-withdrawing groups with good to excellent yields from substrates containing a diazo functionality as the starting material and a phospholene oxide as the catalyst.status: publishe

Novel strategy for the preparation of 3-perfluoroalkylated-2H-indazole derivatives

Abed HB, Weissing N, Schoene J, Paulus J, Sewald N, Nazare M. Novel strategy for the preparation of 3-perfluoroalkylated-2H-indazole derivatives. Tetrahedron Letters. 2018;59(19):1813-1815.A simple and novel methodology for the synthesis of 3-perfluoroalkylated-2H-indazole derivatives has been elaborated. The perfluoroalkylation of readily available 2-nitrobenzaldimines bearing electron donating groups was performed using the Ruppert-Prakash reagent and its analogues to afford alpha-difluo-romethylated, alpha-trifluoromethylated and alpha-pentafluoroethylated benzylamines. A final reductive cyclization mediated by SnCl2.2H(2)O led to 2H-indazoles containing perfluoroalkyl groups via the generation of a new N-N bond in moderate to good yields. (C) 2018 Elsevier Ltd. All rights reserved

Structural Basis for Highly Selective Class II Alpha Phosphoinositide-3-Kinase Inhibition

Class II phosphoinositide-3-kinases (PI3Ks) play central roles in cell signaling, division, migration, and survival. Despite evidence that all PI3K class II isoforms serve unique cellular functions, the lack of isoform-selective inhibitors severely hampers the systematic investigation of their potential relevance as pharmacological targets. Here, we report the structural evaluation and molecular determinants for selective PI3K-C2α inhibition by a structure–activity relationship study based on a pteridinone scaffold, leading to the discovery of selective PI3K-C2α inhibitors called PITCOINs. Cocrystal structures and docking experiments supported the rationalization of the structural determinants essential for inhibitor activity and high selectivity. Profiling of PITCOINs in a panel of more than 118 diverse kinases showed no off-target kinase inhibition. Notably, by addressing a selectivity pocket, PITCOIN4 showed nanomolar inhibition of PI3K-C2α and >100-fold selectivity in a general kinase panel. Our study paves the way for the development of novel therapies for diseases related to PI3K-C2α function

Structural Basis for Highly Selective Class II Alpha Phosphoinositide-3-Kinase Inhibition

Class II phosphoinositide-3-kinases (PI3Ks) play central roles in cell signaling, division, migration, and survival. Despite evidence that all PI3K class II isoforms serve unique cellular functions, the lack of isoform-selective inhibitors severely hampers the systematic investigation of their potential relevance as pharmacological targets. Here, we report the structural evaluation and molecular determinants for selective PI3K-C2α inhibition by a structure–activity relationship study based on a pteridinone scaffold, leading to the discovery of selective PI3K-C2α inhibitors called PITCOINs. Cocrystal structures and docking experiments supported the rationalization of the structural determinants essential for inhibitor activity and high selectivity. Profiling of PITCOINs in a panel of more than 118 diverse kinases showed no off-target kinase inhibition. Notably, by addressing a selectivity pocket, PITCOIN4 showed nanomolar inhibition of PI3K-C2α and >100-fold selectivity in a general kinase panel. Our study paves the way for the development of novel therapies for diseases related to PI3K-C2α function