126166-68-5Relevant academic research and scientific papers
Phenylalanine-based inactivator of akt kinase: Design, synthesis, and biological evaluation
Nguyen, Thuy,Coover, Robert A.,Verghese, Jenson,Moran, Richard G.,Ellis, Keith C.
, p. 462 - 467 (2014/06/09)
Strategies to inhibit kinases by targeting the substrate binding site offer many advantages, including naturally evolved selectivity filters, but normally suffer from poor potency. In this work we propose a strategy to design and prepare covalent substrate-competitive kinase inhibitors as a method to improve potency. We have chosen AKT as the model kinase for this work. Using the AKT-GSK3β cocrystal structure and a reactive cysteine near the substrate binding site, we have identified phenylalanine (Phe) as an appropriate scaffold for the covalent inactivator portion of these inhibitors. By synthesizing compounds that incorporate cysteine-reactive electrophiles into phenylalanine and testing these compounds as AKT inhibitors, we have identified Boc-Phe-vinyl ketone as a submicromolar inactivator of AKT. We also show that Boc-Phe-vinyl ketone (1) potently inhibits AKT1 and inhibits cell growth in HCT116 and H460 cells nearly as well as AKT inhibitors GSK690693 and MK-2206, (2) is selective for kinases that possess an activation loop cysteine such as AKT, (3) requires the vinyl ketone for inactivation, (4) has inactivation that is time-dependent, and (5) alkylates Cys310 of AKT as shown by mass spectrometry. Identification of Boc-Phe-vinyl ketone as a covalent inactivator of AKT will allow the development of peptide and small-molecule substrate-competitive covalent kinase inhibitors that incorporate additional substrate binding elements to increase selectivity and potency. This proof-of-principle study also provides a basis to apply this strategy to other kinases of the AGC and CAMK families.
Biohybrid-Se-S-coupling reactions of an amino acid derived seleninate
Abdo, Mohannad,Sun, Zhexun,Knapp, Spencer
, p. 1963 - 1972 (2013/04/24)
We describe the synthesis of the N-(2-seleninatoethyl) amide of N-Bocphenylalanine, serving here as a peptide model, and its reductive coupling reactions under mild conditions with unprotected thiouridine and glutathione. Selenosulfide products such as these comprise reversibly conjugated bio-components, and can potentially find uses as probes of biological function, such as enzyme inhibitors, delivery systems, or structural mimics.
Simple Peptides. VII. The Chemical Conversions of C-Terminal α-Amino Acids in Peptides into Unsubstituted or 2-Substituted Taurine via S-Acetylthio- or Halogeno-Intermediates
Higashiura, Kunihiko,Ienaga, Kazuharu
, p. 1901 - 1921 (2007/10/02)
The syntheses of ten dipeptides 5a-c, e, f, h-j, l and m, containing taurine or its 2-substituted derivatives, are described: C-terminal a-amino acids in the dipeptides were chemically converted to the taurines by two main routes.One involves the successive conversion of N-tert-butoxycarbonyl(Boc)-protected dipeptide esters 1 into the 2-(Boc-aminoacyl)aminoethanols 2 and thence into their acetylthio derivatives 4 via β-bromoethylamides 3, followed by the performic acid oxidation of the acetylthio into a sulpho group to give the deprotected taurine dipeptides 5.In the other, 2 was converted into 5 using the substitution reaction of a sulpho group for a halogen or mesyl group via the corresponding β-halogenoethyl or β-(methanesulphonyl)-oxyethyl amides, 3,9 or 7.The preparation of intrinsic γ-L-Glu-Tau (glutaurine) 12a and its D-isomer 12b from the acetylthio derivatives 11a and 11b by performic acid oxidation is also described as examples of the use of S-acetylcysteamine for a taurine precursor.
The Chemical Conversion of C-Terminal Glycines in Peptides into Taurine
Higashiura, Kunihiko,Toyomaki, Yoshio,Ienaga, Kazuharu
, p. 521 - 522 (2007/10/02)
The first chemical conversion of C-glycine in dipeptides into taurine has been achieved using a general substitution of a sulpho group for a halogeno or mesyl group via the corresponding amino acid 2-halogenoethyl- or 2-methanesulphonyloxyethyl-amides, ea
