87976-65-6Relevant 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.
supporting information, 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.
Process for lowering the viscosity of highly concentrated protein solutions
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Paragraph 0357, (2014/03/21)
A process of lowering the viscosity of a solution includes preparing a solution comprising a compound of formula I, at a concentration in the final formulation of between 10 and 250 mM, and a protein having at least one antibody fragment whose concentration is between 50 and 350 mg/mL and whose pH is between 5 and 8. The compound lowers the viscosity of the solution, which is difficult to inject, by a value of at least 15% relative to the viscosity of a solution of at least one protein having at least one antibody fragment of the same concentration and of the same pH not containing the compound.
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.
A synthetic dolastatin 10 analogue suppresses microtubule dynamics, inhibits cell proliferation, and induces apoptotic cell death
Gajula, Praveen Kumar,Asthana, Jayant,Panda, Dulal,Chakraborty, Tushar Kanti
supporting information, p. 2235 - 2245 (2013/05/22)
We have synthesized eight analogues (D1-D8) of dolastatin 10 containing several unique amino acid subunits. Of these agents, D5 was found to be most effective in inhibiting both HeLa cell proliferation and microtubule assembly in vitro. At low nanomolar concentrations, D5 inhibited the proliferation of several types of cancer cells in culture. D5 bound to tubulin with a dissociation constant of 29.4 ± 6 μM. D5 depolymerized microtubules in cultured cells and produced mulitpolar spindles. At its half-maximal inhibitory concentration (15 nM), D5 strongly suppressed the dynamics of individual microtubules in live MCF-7 cells. D5 increased the accumulation of checkpoint proteins BubR1 and Mad2 at the kinetochoric region and caused G2/M block in these cells. The blocked cells underwent apoptosis with the activation of Jun N-terminal kinase. The results suggested that D5 exerts its antiproliferative action by dampening microtubule dynamics.
Synthesis of the orthogonally protected amino alcohol Phaol and analogs
Nelissen, Jo,Nuyts, Koen,Dehaen, Wim,De Borggraeve, Wim M.
experimental part, p. 527 - 532 (2012/05/04)
The development of a multigram synthesis of the orthogonally protected amino acid-derived Phaol [2-{[(2S)-2-amino-3-phenylpropyl]amino}ethanol] is described. The goal of this work is to synthesize an orthogonally protected Phaol in a multigram scale up to
Employing the structural diversity of nature: Development of modular dipeptide-analogue ligands for ruthenium-catalyzed enantioselective transfer hydrogenation of ketones
Pastor, Isidro M.,Vaestilae, Patrik,Adolfsson, Hans
, p. 4031 - 4045 (2007/10/03)
A library of novel dipeptideanalogue ligands based on the combination of tert-butoxycarbonyl(N-Boc)-protected a-amino acids and chiral vicinal amino alcohols were prepared. These highly modular ligands were combined with [{RuCl2(p-cymene)}2 and the resulting metal complexes were screened as catalysts for the enantioselective reduction of acetophenone under transfer hydrogenation conditions using 2-propanol as the hydrogen donor. Excellent enantioselectivity of 1-phenylethanol (up to 98% ee) was achieved with several of the novel catalysts. Although most of the ligands contained two stereocenters, it was demonstrated that the absolute configuration of the product alcohol was determined by the configuration of the amino acid part of the ligand. Employing ligands based on L-amino acids generated S-configured products, and catalysts based on Damino acids favored the formation of the R-configured alcohol. The combination N-Boc-L-alanine and (R)-phenylglycinol (Boc-L-Ab) or its enantiomer (N-Boc-D-alanine and (S)-phenylglycinol, Boc-D-Aa) proved to be the best ligands for the reduction process. Transfer hydrogenation of a number of aryl alkyl ketones were evaluated and excellent enantioselectivity, up to 96 % ee, was obtained.
Conformational analysis and mu-opioid receptor affinity of short peptides, endomorphin models in a low polarity solvent.
Cardillo, Giuliana,Gentilucci, Luca,Tolomelli, Alessandra,Qasem, Ahmed R,Spampinato, Santi,Calienni, Maria
, p. 3010 - 3014 (2007/10/03)
Peptide carbamates containing the sequence H-Pro-Trp-PheNH2 showed in CDCl3 restricted conformations stabilized by the presence of a gamma-turn. To test the reliability of the peptides as endomorphin conformational models, we measured the affinities for mu-receptors labelled with [3H]-DAMGO. In particular, Cbz-Pro-Trp-PheNH2 displayed a nanomolar affinity.
New Dimeric Tetrapeptide Enkephalin Analogues with Five- or Six-Carbon Hydrophilic Spacers
Zajaczkowski, I.,Stepinski, J.,Temeriusz, A.,Tam, S. W.
, p. 1329 - 1334 (2007/10/03)
To investigate the role of distance between two opioid peptide pharmacophores on binding activities to delta, mu and kappa receptor in vitro, a number of new dimeric enkephalin analogues were synthesized in which two identical tetrapeptides: Tyr-D-Ala-Gly
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
