91-21-4Relevant articles and documents
Engineering of Thermostable β-Hydroxyacid Dehydrogenase for the Asymmetric Reduction of Imines
Stockinger, Peter,Schelle, Luca,Schober, Benedikt,Buchholz, Patrick C. F.,Pleiss, Jürgen,Nestl, Bettina M.
, p. 3511 - 3514 (2020)
The β-hydroxyacid dehydrogenase from Thermocrinus albus (Ta-βHAD), which catalyzes the NADP+-dependent oxidation of β-hydroxyacids, was engineered to accept imines as substrates. The catalytic activity of the proton-donor variant K189D was further increased by the introduction of two nonpolar flanking residues (N192 L, N193 L). Engineering the putative alternative proton donor (D258S) and the gate-keeping residue (F250 A) led to a switched substrate specificity as compared to the single and triple variants. The two most active Ta-βHAD variants were applied to biocatalytic asymmetric reductions of imines at elevated temperatures and enabled enhanced product formation at a reaction temperature of 50 °C.
Discovery of tetrahydroquinolines and benzomorpholines as novel potent RORγt agonists
Xia, Yuehan,Yu, Mingcheng,Zhao, Yunpeng,Xia, Li,Huang, Yafei,Sun, Nannan,Song, Meiqi,Guo, Huimin,Zhang, Yunyi,Zhu, Di,Xie, Qiong,Wang, Yonghui
, (2020/12/04)
The retinoic acid receptor-related orphan receptor γt (RORγt) is an important nuclear receptor that regulates the differentiation of Th17 cells and production of interleukin 17(IL-17). RORγt agonists increase basal activity of RORγt and could provide a potential approach to cancer immunotherapy. Herein, hit compound 1 was identified as a weak RORγt agonist during in-house library screening. Changes in LHS core of 1 led to the identification of tetrahydroquinoline compound 6 as a partial RORγt agonist (max. act. = 39.3%). Detailed structure-activity relationship on substituent of the LHS core, amide linker and RHS arylsulfonyl moiety was explored and a novel series of tetrahydroquinolines and benzomorpholines was discovered as potent RORγt agonists. Tetrahydroquinoline compound 8g (EC50 = 8.9 ± 0.4 nM, max. act. = 104.5%) and benzomorpholine compound 9g (EC50 = 7.5 ± 0.6 nM, max. act. = 105.8%) were representative compounds with high RORγt agonistic activity in dual FRET assay, and they showed good activity in cell-based Gal4 reporter gene assay and Th17 cell differentiation assay (104.5% activation at 300 nM of 8g; 59.4% activation at 300 nM of 9g). The binding modes of 8g and 9g as well as the two RORγt inverse agonists accidentally discovered were also discussed.
Homogeneous pressure hydrogenation of quinolines effected by a bench-stable tungsten-based pre-catalyst
Heizinger, Christian,Topf, Christoph,Vielhaber, Thomas
, p. 451 - 461 (2021/11/11)
We report on an operationally simple catalytic method for the tungsten-catalyzed hydrogenation of quinolines through the use of the easily handled and self-contained precursor [WCl(η5-Cp)(CO)3]. This half sandwich complex is indefinitely storable on the bench in simple screw-capped bottles or stoppered flasks and can, if required, be prepared on a multi-gram scale while the actual catalytic transformations were performed in the presence of a Lewis acid in order to achieve both decent substrate conversions and product yields. The described method represents a facile and atom-efficient access to a variety of 1,2,3,4-tetrahydroquinolines that circumvents the use of cost-intensive and oxygen-sensitive phosphine ligands as well as auxiliary hydride reagents.