886061-26-3Relevant academic research and scientific papers
Deep learning-driven scaffold hopping in the discovery of Akt kinase inhibitors
Chen, Hongming,Lu, Xiaoyun,Ran, Ting,Song, Shukai,Wang, Zuqin,Wen, Chang,Xu, Fang,Zhou, Yang
supporting information, p. 10588 - 10591 (2021/10/19)
Scaffold hopping has been widely used in drug discovery and is a topic of high interest. Here a deep conditional transformer neural network, SyntaLinker, was applied for the scaffold hopping of a phase III clinical Akt inhibitor, AZD5363. A number of nove
Site-Specific C(sp3)–H Aminations of Imidates and Amidines Enabled by Covalently Tethered Distonic Radical Anions
Fang, Yuanding,Fu, Kang,Shi, Lei,Zhao, Rong,Zhou, Jia
supporting information, p. 20682 - 20690 (2020/09/07)
The utilization of N-centered radicals to synthesize nitrogen-containing compounds has attracted considerable attention recently, due to their powerful reactivities and the concomitant construction of C?N bonds. However, the generation and control of N-centered radicals remain particularly challenging. We report a tethering strategy using SOMO-HOMO-converted distonic radical anions for the site-specific aminations of imidates and amidines with aid of the non-covalent interaction. This reaction features a remarkably broad substrate scope and also enables the late-stage functionalization of bioactive molecules. Furthermore, the reaction mechanism is thoroughly investigated through kinetic studies, Raman spectroscopy, electron paramagnetic resonance spectroscopy, and density functional theory calculations, revealing that the aminations likely involve direct homolytic cleavage of N?H bonds and subsequently controllable 1,5 or 1,6 hydrogen atom transfer.
Base-induced Sommelet–Hauser rearrangement of N-(α-(2-oxyethyl)branched)benzylic glycine ester-derived ammonium salts via a chelated intermediate
Baba, Souya,Hirano, Kazuki,Tayama, Eiji
, (2020/03/13)
The base-induced Sommelet–Hauser (S–H) rearrangement of N-(α-branched)benzylic glycine ester-derived ammonium salts 1 was investigated. When the α-branched substituent was a simple alkyl, such as a methyl or butyl, desired S–H rearrangement product 2 was obtained in low yield with formation of the [1,2] Stevens rearranged 4 and Hofmann eliminated products 5 and 6. However, when the α-branched substituent had a 2-oxy moiety, such as 2-acetoxyethyl or 2-benzoyloxyethyl, the yields of 2 were improved. These results could be explained by formation of chelated intermediate C that stabilizes the carbanionic ylide, and the subsequent initial dearomative [2,3] sigmatropic rearrangement would be accelerated. The existence of C was supported by mechanistic experiments. This enhancement effect is not very strong or effective; however, it will expand the synthetic usefulness of ammonium ylide rearrangements.
Discovery of 4-amino-N-[(1S)-1-(4-chlorophenyl)-3-hydroxypropyl]-1-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (AZD5363), an orally bioavailable, potent inhibitor of Akt kinases
Addie, Matt,Ballard, Peter,Buttar, David,Crafter, Claire,Currie, Gordon,Davies, Barry R.,Debreczeni, Judit,Dry, Hannah,Dudley, Philippa,Greenwood, Ryan,Johnson, Paul D.,Kettle, Jason G.,Lane, Clare,Lamont, Gillian,Leach, Andrew,Luke, Richard W. A.,Morris, Jeff,Ogilvie, Donald,Page, Ken,Pass, Martin,Pearson, Stuart,Ruston, Linette
supporting information, p. 2059 - 2073 (2013/05/08)
Wide-ranging exploration of analogues of an ATP-competitive pyrrolopyrimidine inhibitor of Akt led to the discovery of clinical candidate AZD5363, which showed increased potency, reduced hERG affinity, and higher selectivity against the closely related AGC kinase ROCK. This compound demonstrated good preclinical drug metabolism and pharmacokinetics (DMPK) properties and, after oral dosing, showed pharmacodynamic knockdown of phosphorylation of Akt and downstream biomarkers in vivo, and inhibition of tumor growth in a breast cancer xenograft model.
PYRROLO [2,3-D] PYRIMIDIN DERIVATIVES AS PROTEIN KINASE B INHIBITORS
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Page/Page column 116, (2009/05/30)
The invention relates to a novel group of compounds of Formula (I) or salts thereof: wherein Y, Z1, Z2, R1, R4, R5 and n are as described in the specification, which may be useful in the treatment or prevention of a disease or medical condition mediated through protein kinase B (PKB) such as cancer. The invention also relates to pharmaceutical compositions comprising said compounds, methods of treatment of diseases mediated by PKB using said compounds and methods for preparing compounds of Formula (I)
Ruthenium-catalyzed asymmetric epoxidation of olefins using H 2O2, part I: Synthesis of new chiral N,N,N,-tridentate pybox and pyboxazine ligands and their ruthenium complexes
Tse, Man Kin,Bhor, Santosh,Klawonn, Markus,Anilkumar, Gopinathan,Jiao, Haijun,Doebler, Christian,Spannenberg, Anke,Magerlein, Wolfgang,Hugl, Herbert,Beller, Matthias
, p. 1855 - 1874 (2008/02/02)
The synthesis of chiral tridentate N,N,N-pyridine-2.6-bisoxazolines 3 (pyhox ligands) and N,N,N-pyridine-2.6-bisoxazines 4 (pyboxazine ligands) is described in detail. These novel ligands constitute a useful tool-box for the application in asymmetric catalysis. Compounds 3 and 4 are conveniently prepared by cyclization of enantiomerically pure α- or β-amino al cohols with dimethyl pyridine-2,6-dicarboximidate. The corresponding ruthenium complexes are efficient asymmetric epoxidation catalysts and have been prepared in good yield and fully char acterized by spectroscopic means. Four of these ruthenium complexes have been characterized by X-ray crystallography. For the first time the molecular structure of a pyboxazine complex (2,6-bis-[(4S)-4-phenyl-5,6- dihydro-4H-[1,3]oxazinyl]pyridine)(pyridine-2,6-dicarboxylate)ruthenium (S)-2aa, is presented.
