53715-52-9Relevant articles and documents
Deconstructing Noncovalent Kelch-like ECH-Associated Protein 1 (Keap1) Inhibitors into Fragments to Reconstruct New Potent Compounds
Pallesen, Jakob S.,Narayanan, Dilip,Tran, Kim T.,Solbak, Sara M. ?.,Marseglia, Giuseppe,S?rensen, Louis M. E.,H?j, Lars J.,Munafò, Federico,Carmona, Rosa M. C.,Garcia, Anthony D.,Desu, Haritha L.,Brambilla, Roberta,Johansen, Tommy N.,Popowicz, Grzegorz M.,Sattler, Michael,Gajhede, Michael,Bach, Anders
, p. 4623 - 4661 (2021/05/07)
Targeting the protein-protein interaction (PPI) between nuclear factor erythroid 2-related factor 2 (Nrf2) and Kelch-like ECH-associated protein 1 (Keap1) is a potential therapeutic strategy to control diseases involving oxidative stress. Here, six classes of known small-molecule Keap1-Nrf2 PPI inhibitors were dissected into 77 fragments in a fragment-based deconstruction reconstruction (FBDR) study and tested in four orthogonal assays. This gave 17 fragment hits of which six were shown by X-ray crystallography to bind in the Keap1 Kelch binding pocket. Two hits were merged into compound 8 with a 220-380-fold stronger affinity (Ki = 16 μM) relative to the parent fragments. Systematic optimization resulted in several novel analogues with Ki values of 0.04-0.5 μM, binding modes determined by X-ray crystallography, and enhanced microsomal stability. This demonstrates how FBDR can be used to find new fragment hits, elucidate important ligand-protein interactions, and identify new potent inhibitors of the Keap1-Nrf2 PPI.
Mild hypervalent iodine mediated oxidative nitration of N-aryl sulfonamides
Kloeckner, Ulrich,Nachtsheim, Boris J.
supporting information, p. 10485 - 10487 (2014/09/29)
An oxidative and acid-free method for the nitration of N-aryl sulfonamides has been developed using a combination of sodium nitrite as cheap and easy to handle NO2-source and the hypervalent iodine reagent PIFA as stoichiometric oxidant. Under
4-Amino-5-(arylaminomethyl)-2-(methylthio)furo[2,3-d]pyrimidines via Mitsunobu reaction of 4-amino-5-(hydroxymethyl)-2-(methylthio)furo[2,3-d] pyrimidine with N-mesyl- and N-nosylarylamines
Masevicius, Viktoras,Petraityte, Grazina,Tumkevicius, Sigitas
experimental part, p. 1329 - 1338 (2012/07/01)
An efficient method for the synthesis of 4-amino-5-(arylaminomethyl)-2- (methylthio)furo[2,3-d]pyrimidines via the Mitsunobu reaction of 4-amino-5-(hydroxymethyl)-2-(methylthio)furo[2,3-d]pyrimidine with N-mesyl- and N-nosylarylamines, and subsequent removal of the mesyl and nosyl groups, has been developed. The influence of substituents in the arylamine moiety on the Mitsunobu reaction was investigated. An unexpected nucleophilic substitution of a nitro group in the reaction of N-({4-amino-2-(methylsulfonyl)furo[2,3-d] pyrimidin-5-yl}methyl)-4-nitro-N-phenylbenzenesulfonamide with sodium methoxide was observed. Georg Thieme Verlag Stuttgart · New York.
