55970-06-4Relevant articles and documents
Intracellular Trapping of the Selective Phosphoglycerate Dehydrogenase (PHGDH) Inhibitor BI-4924 Disrupts Serine Biosynthesis
Arnhof, Heribert,Bader, Gerd,Bruchhaus, Jens,Burkard, Michelle,Ciftci, Tuncay,Dahmann, Georg,Du, Alicia,Ettmayer, Peter,Fett, Thomas N.,Garavel, Géraldine,Gerstberger, Thomas,Haering, Daniela,Harrer, Christoph,Hofbauer, Karin S.,Kessler, Dirk,Kousek, Roland,Li, Dongyang,Li, Yali,Lv, Xiaobing,Martinelli, Paola,Mayer, Moriz,McConnell, Darryl B.,Mischerikow, Nikolai,Mitzner, Sophie,Pearson, Mark,Peric-Simov, Biljana,Quant, Jens,Rinnenthal, Joerg,Rumpel, Klaus,Savarese, Fabio,Scherbantin, Yvonne,Schnitzer, Renate,Scholz, Guido,Schrenk, Andreas,Sharps, Bernadette,Sommergruber, Wolfgang,Treu, Matthias,Weinstabl, Harald,Wolkerstorfer, Bernhard,Zahn, Stephan K.,Zhang, Xuechun,Zoephel, Andreas
, (2019/09/06)
Phosphoglycerate dehydrogenase (PHGDH) is known to be the rate-limiting enzyme in the serine synthesis pathway in humans. It converts glycolysis-derived 3-phosphoglycerate to 3-phosphopyruvate in a co-factor-dependent oxidation reaction. Herein, we report the discovery of BI-4916, a prodrug of the co-factor nicotinamide adenine dinucleotide (NADH/NAD+)-competitive PHGDH inhibitor BI-4924, which has shown high selectivity against the majority of other dehydrogenase targets. Starting with a fragment-based screening, a subsequent hit optimization using structure-based drug design was conducted to deliver a single-digit nanomolar lead series and to improve potency by 6 orders of magnitude. To this end, an intracellular ester cleavage mechanism of the ester prodrug was utilized to achieve intracellular enrichment of the actual carboxylic acid based drug and thus overcome high cytosolic levels of the competitive cofactors NADH/NAD+
A porous metal-organic cage constructed from dirhodium paddle-wheels: Synthesis, structure and catalysis
Chen, Lianfen,Yang, Tao,Cui, Hao,Cai, Tao,Zhang, Li,Su, Cheng-Yong
, p. 20201 - 20209 (2015/10/19)
Self-assembly of dirhodium(ii) tetraacetate (Rh2(OAc)4) with a dicarboxylic acid 3,3′-(1,3-phenylenebis(ethyne-2,1-diyl))dibenzoic acid (H2pbeddb) gives rise to a metal-organic cage (MOC) containing Rh-Rh bonds with the formula of [Rh4(pbeddb)4(H2O)2(DMAC)2] (MOC-Rh-1). Single-crystal X-ray diffraction analysis reveals that MOC-Rh-1 shows a lantern-type cage structure, in which a pair of Rh2(CO2)4 paddlewheels is linked by four diacid ligands. The dimensions of the inner cavity of MOC-Rh-1 are 9.5 × 14.8 ?2 (atom-to-atom distances across opposite metal and phenyl groups of pbeddb2-). In the solid phase, the cages are aligned by π-π stacking to form one-dimensional channels (9.5 × 11.1 ?2) through cage windows. Therefore, the crystalline samples of MOC-Rh-1 are porous with the inner and outer cavities of the cages accessible under the heterogeneous condition. MOC-Rh-1 has been fully characterized by EA, TGA, PXRD, IR, UV-vis and XPS measurements. The catalytic tests disclose that activated MOC-Rh-1 is effective in the intramolecular C-H amination of vinyl, dienyl and biaryl azides, leading to the formation of indoles, pyrroles and carbazoles, respectively, and the porous catalyst can be recycled easily and used for at least nine runs without significant loss of activity. In the nine runs, the conversions were in the range of 93-99%, whereas in the tenth run, the conversion was reduced to 78%.
Iodine-mediated one-pot synthesis of indoles and 3-dimethylaminoindoles via annulation of enaminones
Jerezano, Alberto V.,Labarrios, Ehecatl M.,Jimenez, Fabiola E.,Del Cruz, Maria Carmen,Pazos, Diana C.,Gutierrez, Rsuini U.,Delgado, Francisco,Tamariz, Joaquin
, p. 18 - 53 (2014/03/21)
The synthesis of 2-carbonylindoles was achieved via a iodine-mediated cyclization of the corresponding enaminone precursors, which were formed by reaction of the ?-arylaminomethylene carbonyl derivatives with N,N'-dimethylformamide dimethyl acetal (DMFDMA). An alternative and more efficient procedure consisted of a similar cyclization of the enaminones, but under solvent-free and grinding reaction conditions. In another iodine-promoted procedure, 2-carbonyl-3-dimethylaminoindoles were synthesized via a one-pot cascade reaction between the α-arylaminomethylene carbonyl derivative and DMFDMA.ARKAT-USA, Inc.
