- Unconventional Secondary Structure Mimics: Ladder-Rungs
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Secondary structures tend to be recognizable because they have repeating structural motifs, but mimicry of these does not have to follow such well-defined patterns. Bioinformatics studies to match side-chain orientations of a novel hydantoin triazole chemotype (1) to protein-protein interfaces revealed it tends to align well across parallel and antiparallel sheets, like rungs on a ladder. One set of these overlays was observed for the protein-protein interaction uPA?uPAR. Consequently, chemotype 1 was made with appropriate side-chains to mimic uPA at this interface. Biophysical assays indicate these compounds did in fact bind uPAR, and elicit cellular responses that affected invasion, migration, and wound healing.
- Arancillo, Maritess,Burgess, Kevin,Lin, Chen-Ming,Whisenant, Jonathan
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- Synthesis and evaluation of spumigin analogues library with thrombin inhibitory activity
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Spumigins are marine natural products derived from cyanobacteria Nodularia spumigena, which mimics the structure of the D-Phe-Pro-Arg sequence and is crucial for binding to the active site of serine proteases thrombin and factor Xa. Biological evaluation of spumigins showed that spumigins with a (2S,4S)-4-methylproline central core represent potential lead compounds for the development of a new structural type of direct thrombin inhibitors. Herein, we represent synthesis and thrombin inhibitory activity of a focused library of spumigins analogues with indoline ring or L-proline as a central core. Novel compounds show additional insight into the structure and biological effects of spumigins. The most active analogue was found to be a derivative containing L-proline central core with low micromolar thrombin inhibitory activity.
- ?ula, Ale?,B?dziak, Izabela,Kikelj, Danijel,Ila?, Janez
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- Diversity-oriented synthesis of macrocyclic peptidomimetics
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Structurally diverse libraries of novel small molecules represent important sources of biologically active agents. In this paper we report the development of a diversity-oriented synthesis strategy for the generation of diverse small molecules based around a common macrocyclic peptidomimetic framework, containing structural motifs present in many naturally occurring bioactive compounds. Macrocyclic peptidomimetics are largely underrepresented in current small-molecule screening collections owing primarily to synthetic intractability; thus novel molecules based around these structures represent targets of significant interest, both from a biological and a synthetic perspective. In a proof-of-concept study, the synthesis of a library of 14 such compounds was achieved. Analysis of chemical space coverage confirmed that the compound structures indeed occupy underrepresented areas of chemistry in screening collections. Crucial to the success of this approach was the development of novel methodologies for the macrocyclic ring closure of chiral α-azido acids and for the synthesis of diketopiperazines using solid-supported N methylmorpholine. Owing to their robust and flexible natures, it is envisaged that both new methodologies will prove to be valuable in a wider synthetic context.
- Isidro-Llobet, Albert,Murillo, Tiffanie,Bello, Paula,Cilibrizzi, Agostino,Hodgkinson, James T.,Galloway, Warren R. J. D.,Bender, Andreas,Welch, Martin,Spring, David R.
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scheme or table
p. 6793 - 6798
(2012/03/26)
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- Triazolopeptides: chirospecific synthesis and cis/trans prolyl ratios of structural isomers
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As cis/trans prolyl isomerization plays a crucial role in various biological processes, peptide mimics capable of modifying the cis/trans Xaa-Pro ratio are of particular interest. A practical approach toward proline derived triazolopeptides employing [3+2] azide-alkyne cycloadditions as the key reaction step and the analysis of their cis/trans prolyl ratios are reported. Structural investigations indicated the adjustability of both the cis-percentage and the conformational stability toward intramolecular H-bonding effects.
- Paul, Andreas,Bittermann, Holger,Gmeiner, Peter
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p. 8919 - 8927
(2007/10/03)
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- A novel application of a [3+2] cycloaddition reaction for the synthesis of the piperazinone rings of pseudotheonamides A1 and A2
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A novel approach to synthesize the piperazinone ring system of pseudotheonamide A1 and A2 is described. The key step is the intramolecular [3+2] cycloaddition reaction of a suitably orientated azide and an α,β-unsaturated ester.
- Gurjar, Mukund K,Karmakar, Sukhen,Mohapatra, Debendra K,Phalgune, Usha D
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p. 1897 - 1900
(2007/10/03)
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- Efficient method to prepare hydroxyethylamine-based aspartyl protease inhibitors with diverse P1 side chains
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An efficient procedure for the solid-phase synthesis of hydroxyethylamine-based aspartyl protease inhibitors is described. The 1,2-bromo alcohol 4 is the key intermediate and is prepared in four-steps in good overall yield from commercial available amino acids.
- Chino, Masao,Wakao, Masahiro,Ellman, Jonathan A
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p. 6305 - 6310
(2007/10/03)
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- Staudinger ligation of α-azido acids retains stereochemistry
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The Staudinger ligation of peptides with a C-terminal phosphinothioester and N-terminal azide is an emerging method in protein chemistry. Here, the first Staudinger ligations of nonglycyl azides are reported and shown to proceed both in nearly quantitative yield and with no detectable effect on the stereochemistry at the α-carbon of the azide. These results demonstrate further the potential of the Staudinger ligation as a general method for the total synthesis of proteins from peptide fragments.
- Soellner, Matthew B.,Nilsson, Bradley L.,Raines, Ronald T.
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p. 4993 - 4996
(2007/10/03)
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- Improved solid-phase peptide synthesis method utilizing alpha-azide-protected amino acids.
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[structure: see text]. Pure alpha-azido acids were prepared using an efficient diazo transfer method followed by buffered workup. These building blocks were used to prepare small peptides on Wang resin by two approaches. Peptides prone to diketopiperazine formation were prepared in good yields by coupling acids to resin bound iminophosphoranes during Fmoc-Wang synthesis. The iminophosphoranes can also be hydrolyzed under neutral conditions to provide unprotected amines ready for further coupling.
- Lundquist 4th.,Pelletier
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p. 781 - 783
(2007/10/03)
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- Design, synthesis, resolution, and application of a highly efficient chiral auxiliary: cis-2-amino-3,3-dimethyl-1-indanol
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The chiral amino alcohol, cis-2-amino-3,3-dimethyl-1-indanol was synthesized and resolved. Its oxazolidinone derivative was found to be a highly efficient chiral auxiliary in diastereoselective alkylation, acylation, bromination, and hydroxylation reactions.
- Sudo, Atsushi,Saigo, Kazuhiko
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p. 2939 - 2956
(2007/10/03)
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- Preparation of (R)-2-azidoesters from 2-((p-nitrobenzene)sulfonyl)oxy esters and their use as protected amino acid equivalents for the synthesis of di- and tripeptides containing D-amino acid constituents
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(R)-2-Azidoesters and their derived (R)-2-azido acids are readily prepared from common amino acids by an inversion methodology that employs (S)-2-nosyloxyesters as key intermediates. The (R)-2-azidoesters can be used as protected amino acid equivalents in peptide synthesis. Basic hydrolysis frees the carboxyl group. Triphenylphosphine/water is used to free the amine group. By these reactions a variety of L-D and D-L dipeptides, L-D-L tripeptides, and depsipeptides can be prepared easily in good yields, and without detectable epimerization.
- Hoffman,Kim
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p. 3007 - 3020
(2007/10/02)
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- The asymmetric synthesis of α-amino acids. Electrophilic azidation of chiral imide enolates, a practical approach to the synthesis of (R)- and (S)-α-azido carboxylic acids
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Two complementary approaches to the asymmetric synthesis of α-amino acids have been achieved. In the initially investigated reaction sequence, the diastereoselective bromination of the illustrated boron enolate with N-bromosuccinimide was followed by stereospecific azide displacement by tetramethylguanidinium azide. The resulting α-azido carboximides may be readily purified to high diastereomeric purity by chromatography on silica. equation presented In the second reaction sequence, the illustrated potassium enolate was treated with 2,4,6-triisopropylbenzenesulfonyl azide, and the intermediate sulfonyl triazene was decomposed through an acetic acid quench to give the α-azido carboximide. The diastereoselection of the reaction as a function of R is as follows: R = Me, CH2Ph, 97:3; R = CHMe2, 98:2; R = CMe3, >99:1; R = Ph, 91:9. The important parameters of this azidation process were evaluated, and experiments were conducted to help elucidate the mechanism of the reaction. equation presented The α-azido carboximide products have been shown to be versatile α-amino acid synthons that may be readily converted to α-amino acids as well as to N-protected α-amino acid derivatives. The racemization-free removal of the chiral auxiliary was achieved in high yield both by saponification and transesterification, either before or after reduction and acylation of the azide functionality.
- Evans, David A.,Britton, Thomas C.,Ellman, Jonathan A.,Dorow, Roberta L.
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p. 4011 - 4030
(2007/10/02)
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- ASYMMETRIC HALOGENATION OF CHIRAL IMIDE ENOLATES. A GENERAL APPROACH TO THE SYNTHESIS OF ENANTIOMERICALLY PURE α-AMINO ACIDS.
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The chiral N-acyl oxazolidones 2, as the derived dibutyl boron enolates, have been demonstrated to undergo diastereoselective bromination and subsequent azide displacement to give the α-azido carboximides 4a (5 cases).These adducts may be hydrolyzed under mild conditions to the enantiomerically pure α-azido carboxylic acids 5a.
- Evans, David A.,Ellman, Jon A.,Dorow, Roberta L.
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p. 1123 - 1126
(2007/10/02)
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