- The Regioselective Synthesis of o -Nitrobenzyl DOPA Derivatives
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Photocaged DOPA derivatives may serve for non-invasive unmasking of the catechol fragment in biological systems. This would enable efficient control of the redox and metal-coordinating properties associated with the free catechol moiety, in particular, in biosynthetically produced adhesive proteins and synthetic peptides. Synthetic routes towards photocaged DOPA derivatives are reported herein. A new method for preparing para -alkylated DOPA starting from 3,4-dihydroxybenzaldehyde is described for the first time.
- Schneider, Tobias,Martin, Joshua,Durkin, Patrick M.,Kubyshkin, Vladimir,Budisa, Nediljko
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p. 2691 - 2699
(2017/06/13)
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- Iminoboronate-Based Peptide Cyclization That Responds to pH, Oxidation, and Small Molecule Modulators
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As a rich source of therapeutic agents, peptide natural products usually adopt a cyclic or multicyclic scaffold that minimizes structural flexibility to favor target binding. Inspired by nature, chemists have been interested in developing synthetic cyclic and multicyclic peptides that serve as biological probes and potential therapeutics. Herein we describe a novel strategy for peptide cyclization in which intramolecular iminoboronate formation allows spontaneous cyclization under physiologic conditions to yield monocyclic and bicyclic peptides. Importantly the iminoboronate-based cyclization can be rapidly reversed in response to multiple stimuli, including pH, oxidation, and small molecules. This highly versatile strategy for peptide cyclization should find applications in many areas of chemical biology.
- Bandyopadhyay, Anupam,Gao, Jianmin
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supporting information
p. 2098 - 2101
(2016/03/05)
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- Dual-fluorescence l -amino acid reports insertion and orientation of melittin peptide in cell membranes
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Monitoring insertion and orientation of peptides in situ on cell membranes remains a challenge. To this end, we synthesized an l-amino acid (AFaa) containing a dual-fluorescence dye of the 3-hydroxyflavone family, as a side chain. In contrast to other labeling approaches using a flexible linker, the AFaa fluorophore, introduced by solid phase synthesis into desired position of a peptide, is attached closely to its backbone with well-defined orientation, and, therefore, could reflect its localization in the membrane. This concept was validated by replacing the leucine-9 (L9) and tryptophan-19 (W19) residues by AFaa in melittin, a well-studied membrane-active peptide. Due to high sensitivity of AFaa dual emission to the environment polarity, we detected a much deeper insertion of L9 peptide position into the bilayer, compared to the W19 position. Moreover, using fluorescence microscopy with a polarized light excitation, we found different orientation of AFaa at L9 and W19 positions of melittin in the bilayers of giant vesicles and cellular membranes. These results suggested that in the natural membranes, similarly to the model lipid bilayers, melittin is preferentially oriented parallel to the membrane surface. The developed amino acid and the proposed methodology will be of interest to study other membrane peptides.
- Postupalenko, Viktoriia Y.,Zamotaiev, Oleksandr M.,Shvadchak, Volodymyr V.,Strizhak, Aleksandr V.,Pivovarenko, Vasyl G.,Klymchenko, Andrey S.,Mely, Yves
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p. 1998 - 2007
(2014/01/06)
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- Two-color fluorescent L-amino acid mimic of tryptophan for probing peptide-nucleic acid complexes
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Non-natural amino acids are important tools for site-selective probing of peptide properties and interactions. Here, for the first time a fluorescent l-amino acid, exhibiting excited-state intramolecular proton transfer (ESIPT) and hydration-sensitive dual emission, was synthesized. It is an analogue of l-tryptophan bearing a slightly larger 2-(2-furyl)-3-hydroxychromone aromatic moiety instead of indole. This new amino acid was incorporated through solid-phase synthesis into NC(11-55), the zinc finger domain of the HIV-1 nucleocapsid protein, that exhibits potent nucleic acid chaperone properties. It was substituted for the Trp37 and Ala30 residues, located in the distal finger motif and the linker between the fingers of NC(11-55), respectively. Though the highly conserved Trp37 residue plays a key role in NC(11-55) structure and activity, its substitution for the new fluorescent analogue preserved the folding, the nucleic acid binding and chaperone activity of the peptide, indicating that the new amino acid can conservatively substitute Trp residues. In the presence of oligonucleotides, the Trp37-substituted peptide, but not the Ala30 variant, showed strong changes of the dual emission corresponding to local dehydration. The results are in line with NMR data, suggesting that the fluorescent amino acid interacts similarly to Trp37 with the nucleobases and is thus screened from water. Due to the exceptional sensitivity of its ESIPT fluorophore to hydration in highly polar environment, the new amino acid appears as a promising tool for substituting Trp residues and site-selectively investigating peptide-nucleic acid complexes.
- Strizhak, Aleksandr V.,Postupalenko, Viktoriia Y.,Shvadchak, Volodymyr V.,Morellet, Nelly,Guittet, Eric,Pivovarenko, Vasyl G.,Klymchenko, Andrey S.,Mely, Yves
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p. 2434 - 2443
(2013/02/23)
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- Discovery of a novel nonphosphorylated pentapeptide motif displaying high affinity for Grb2-SH2 domain by the utilization of 3′-substituted tyrosine derivatives
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The growth factor receptor-bound protein 2 (Grb2) is an SH2 domain-containing docking module that represents an attractive target for anticancer therapeutic intervention. An impressive number of synthetic Grb2-SH2 domain inhibitors have been identified; however, clinical agents operating by this mechanism are lacking, due in part to the unique requirement of anionic phosphate-mimicking functionality for high SH2 domain-binding affinity or the extended peptide nature of most inhibitors. In the current study, a new binding motif was successfully developed by the incorporation of 3′-substituted tyrosine derivatives into a simplified nonphosphorylated cyclic pentapeptide scaffold (4), which resulted in high affinity Grb2-SH2 inhibitors without any phosphotyrosine or phosphotyrosine mimetics. The new L-amino acid analogues bearing an additional nitro, amino, hydroxy, methoxy or carboxy group at the 3′-position of the phenol ring of tyrosine were prepared in an orthogonally protected form suitable for solid-phase peptide synthesis using Fmoc protocols. The incorporation of these residues into cyclic peptides composed of a five-amino acid sequence motif, Xx′-Leu-(3′- substituted-Tyr)-Ac6c-Asn, provided a brand new class of nonphosphorylated Grb2 SH2 domain inhibitors with reduced size, charge and peptidic character. The highest binding affinity was exhibited by the 3′-aminotyrosine (3′-NH2-Tyr)-containing (R)-sulfoxide-cyclized pentapeptide (10b) with an IC50 = 58 nM, the first example with low-nanomolar affinity for a five-amino acid long sequence binding to Grb2-SH2 domain free of any phosphotyrosine or phosphotyrosine mimics. However, the incorporation of 3′-NO2-Tyr, 3′-OH-Tyr or 3′-OCH3-Tyr surrogates in the pentapeptide scaffold is detrimental to Grb2-SH2 binding. These observations were rationalized using molecular modeling. More significantly, the best Grb2-SH2 inhibitor 10b showed excellent activity in inhibiting the growth of erbB2-dependent MDA-MB-453 tumor cell lines with an IC50 value of 19 nM. This study is the first attempt to identify novel nonphosphorylated high affinity Grb2 SH2 inhibitors by the utilization of 3′-substituted tyrosine derivatives, providing a promising new strategy and template for the development of non-pTyr-containing Grb2-SH2 domain antagonists with potent cellular activity, which potentially may find value in chemical therapeutics for erbB2-related cancers.
- Song, Yan-Li,Peach, Megan L.,Roller, Peter P.,Qiu, Su,Wang, Shaomeng,Long, Ya-Qiu
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p. 1585 - 1596
(2007/10/03)
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- USE OF ROSMARINIC ACID AND DERIVATIVES THEREOF AS AN IMMUNOSUPPRESSANT OR AN INHIBITOR OF SH2-MEDIATED PROCESS
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The present invention relates to use of rosmarinic acid and/or derivatives thereof as immunosuppressive agents and/or as inhibitor of SH2 domain function. Disclosed in the present invention is that rosmarinic acid and derivatives thereof specifically inhibit the binding of ligand peptides to Lck SH2 domain, disturb the Lck-mediated signal transduction in T cells, also inhibit cytoline gene expression, and suppress immune responses in the transplanted tissue. These activities of rosmarinic acid and derivatives thereof support their applicability to treatment, prevention and/or diagnosis of graft rejection, GVHD, autoimmune diseases, inflammatory diseases, etc.
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Page/Page column 8
(2008/06/13)
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- Effective syntheses of quinoline-7,8-diol, 5-amino-L-DOPA, and 3-(7,8-dihydroxyquinolin-5-yl)-L-alanine
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A modification of the Baeyer-Villiger reaction allows the conversion of aromatic 2-hydroxy-3-nitroketones and aldehydes into 3-nitrocatechols, which can be reduced to 3-aminocatechols. Reaction of the latter with acrolein yields quinoline-7,8-diols under exceptionally mild conditions. This new reaction sequence was successfully applied to the synthesis of the title compounds.
- Heinrich, Markus R.,Steglich, Wolfgang
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p. 9231 - 9237
(2007/10/03)
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- Synthesis of enantiomeric (+)- and (-)-rosmarinic acid methylesters
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Starting from L-tyrosine (L-1), the phenyl lactic acid ester (-)-4 was prepared by reported procedures. (-)-4 could then be converted to the benzyl ether (-)-5. From (-)-5, the corresponding optical antipode (+)-5 is available via (+)-6 by Mitsunobu reaction. The enantiomeric excess of 5 was determined by NMR spectroscopy from camphanic acid esters (+)- and (-)-8, respectively. The phenyl lactic acid esters (+)- and (-)-5 were acylated by caffeoyl chloride (9) to yield the O-protected enantiomeric rosmarinic acid esters (+)- and (-)-10. Deprotection of 10 by BCl3 afforded the title compounds (+)- and (-)-11 in fair yields.
- Reimann, Eberhard,Pflug, Thomas
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p. 187 - 193
(2007/10/03)
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- The crafting of peptide segments with Cu(II) uptake potential
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Ethylenediamine-acetyl acetone mono-Schiff base (AEH) and hydroxylamine hydrochloride readily condense with peptides, prepared by normal procedures, having 3-acetyl tyrosine side chains, to templates having two types of structural profile with AEH having independent Cu(II) uptake potential and with hydroxylamine hydrochloride requiring two peptide units.
- Ranganathan,Tamilarasu
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p. 447 - 450
(2007/10/02)
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