1352657-25-0Relevant articles and documents
Discovery of GSK251: A Highly Potent, Highly Selective, Orally Bioavailable Inhibitor of PI3Kδ with a Novel Binding Mode
Down, Kenneth,Amour, Augustin,Anderson, Niall A.,Barton, Nick,Campos, Sebastien,Cannons, Edward P.,Clissold, Cole,Convery, Maire A.,Coward, John J.,Doyle, Kevin,Duempelfeld, Birgit,Edwards, Christopher D.,Goldsmith, Michael D.,Krause, Jana,Mallett, David N.,McGonagle, Grant A.,Patel, Vipulkumar K.,Rowedder, James,Rowland, Paul,Sharpe, Andrew,Sriskantharajah, Srividya,Thomas, Daniel A.,Thomson, Douglas W.,Uddin, Sorif,Hamblin, J. Nicole,Hessel, Edith M.
, p. 13780 - 13792 (2021/09/28)
Optimization of a previously reported lead series of PI3Kδ inhibitors with a novel binding mode led to the identification of a clinical candidate compound 31 (GSK251). Removal of an embedded Ames-positive heteroaromatic amine by reversing a sulfonamide followed by locating an interaction with Trp760 led to a highly selective compound 9 . Further optimization to avoid glutathione trapping, to enhance potency and selectivity, and to optimize an oral pharmacokinetic profile led to the discovery of compound 31 (GSK215) that had a low predicted daily dose (45 mg, b.i.d) and a rat toxicity profile suitable for further development.
Generation of Phosphoranyl Radicals via Photoredox Catalysis Enables Voltage-Independent Activation of Strong C-O Bonds
Stache, Erin E.,Ertel, Alyssa B.,Rovis, Tomislav,Doyle, Abigail G.
, p. 11134 - 11139 (2018/11/21)
Despite the prevalence of alcohols and carboxylic acids as functional groups in organic molecules and the potential to serve as radical precursors, C-O bonds remain difficult to activate. We report a synthetic strategy for direct access to both alkyl and acyl radicals from these ubiquitous functional groups via photoredox catalysis. This method exploits the unique reactivity of phosphoranyl radicals, generated from a polar/SET crossover between a phosphine radical cation and an oxygen-centered nucleophile. We show the desired reactivity in the reduction of benzylic alcohols to the corresponding benzyl radicals with terminal H atom trapping to afford the deoxygenated products. Using the same method, we demonstrate access to synthetically versatile acyl radicals, which enables the reduction of aromatic and aliphatic carboxylic acids to the corresponding aldehydes with exceptional chemoselectivity. This protocol also transforms carboxylic acids to heterocycles and cyclic ketones via intramolecular acyl radical cyclizations to forge C-O, C-N, and C-C bonds in a single step.
Synthesis of boron-containing primary amines
Chung, Sheng-Hsuan,Lin, Ting-Ju,Hu, Qian-Yu,Tsai, Chia-Hua,Pan, Po-Shen
, p. 12346 - 12367 (2013/11/06)
In this study, boron-containing primary amines were synthesized for use as building blocks in the study of peptoids. In the first step, Gabriel synthesis conditions were modified to enable the construction of seven different aminomethylphenyl boronate esters in good to excellent yields. These compounds were further utilized to build peptoid analogs via an Ugi four-component reaction (Ugi-4CR) under microwave irradiation. The prepared Ugi-4CR boronate esters were then successfully converted to the corresponding boronic acids. Finally, the peptoid structures were successfully modified by cross-coupling to aryl/heteroaryl chlorides via a palladium-mediated Suzuki coupling reaction to yield the corresponding derivatives in moderate to good yields.
