- Solid-phase synthesis of biaryl bicyclic peptides containing a 3-aryltyrosine or a 4-arylphenylalanine moiety
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A methodology for the solid-phase synthesis of biaryl bicyclic peptides containing a Phe-Phe, a Phe-Tyr or a Tyr-Tyr motif has been devised. This approach comprises two key steps. The first one involves the cyclization of a linear peptidyl resin containing the corresponding halo- and boronoamino acids via a microwave-assisted Suzuki–Miyaura cross coupling. This step is followed by the macrolactamization of the resulting biaryl monocyclic peptidyl resin leading to the formation of the expected biaryl bicyclic peptide. This study provides the first solid-phase synthesis of this type of bicyclic compounds being amenable to prepare a diversity of synthetic or natural biaryl bicyclic peptides.
- Ng-Choi, Iteng,Oliveras, àngel,Feliu, Lidia,Planas, Marta
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supporting information
p. 761 - 768
(2019/04/17)
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- Discovery of small-molecule interleukin-2 inhibitors from a DNA-encoded chemical library
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Libraries of chemical compounds individually coupled to encoding DNA tags (DNA-encoded chemical libraries) hold promise to facilitate exceptionally efficient ligand discovery. We constructed a high-quality DNAencoded chemical library comprising 30 000 drug-like compounds; this was screened in 170 different affinity capture experiments. High-throughput sequencing allowed the evaluation of 120 million DNA codes for a systematic analysis of selection strategies and statistically robust identification of binding molecules. Selections performed against the tumor-associated antigen carbonic anhydrase IX (CA IX) and the pro-inflammatory cytokine interleukin-2 (IL-2) yielded potent inhibitors with exquisite target specificity. The binding mode of the revealed pharmacophore against IL-2 was confirmed by molecular docking. Our findings suggest that DNA-encoded chemical libraries allow the facile identification of drug-like ligands principally to any protein of choice, including molecules capable of disrupting high-affinity protein-protein interactions.
- Leimbacher, Markus,Zhang, Yixin,Mannocci, Luca,Stravs, Michael,Geppert, Tim,Scheuermann, Jcrg,Schneider, Gisbert,Neri, Dario
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supporting information; experimental part
p. 7729 - 7737
(2012/09/07)
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- Synthesis and binding studies of two new macrocyclic receptors for the stereoselective recognition of dipeptides
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We present here the design, synthesis, and analysis of a series of receptors for peptide ligands inspired by the hydrogen-bonding pattern of protein β-sheets. The receptors themselves can be regarded as strands 1 and 3 of a three-stranded β-sheet, with crosslinking between the chains through the 4-position of adjacent phenylalanine residues. We also report on the conformational equilibria of these receptors in solution as well as on their tendency to dimerize. 1H NMR titration experiments are used to quantify the dimerization constants, as well as the association constant values of the 1:1 complexes formed between the receptors and a series of diamides and dipeptides. The receptors show moderate levels of selectivity in the molecular recognition of the hydrogen-bonding pattern present in the diamide series, selecting the α-amino acid-related hydrogen-bonding functionality. Only one of the two cyclic receptors shows modest signs of enantioselectivity and moderate diastereoselectivity in the recognition of the enantiomers and diastereoisomers of the Ala-Ala dipeptide (DDG0 1 (DD-DL) = -1.08 kcal/mol and DDG0 1(DD-LD) = -0.89 kcal/mol). Surprisingly, the linear synthetic precursors show higher levels of stereoselectivity than their cyclic counterparts.
- Castilla, Ana Maria,Ballester, Pablo,Conn, M. Morgan
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supporting information; experimental part
(2010/07/18)
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- Expanding the scope of PNA-encoded libraries: divergent synthesis of libraries targeting cysteine, serine and metallo-proteases as well as tyrosine phosphatases
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Seven PNA-encoded combinatorial libraries targeting proteases and phosphatases with covalent reversible and irreversible mechanism-based inhibitors were prepared. The libraries were synthesized using modified PNA monomers, which dramatically increase the water solubility of the libraries in biologically relevant buffers. The libraries were shown to selectively inhibit targeted enzymes.
- Debaene, Fran?ois,Da Silva, Julien A.,Pianowski, Zbigniew,Duran, Fernando J.,Winssinger, Nicolas
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p. 6577 - 6586
(2008/02/05)
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- A concise synthesis of photoactivatable 4-aroyl-L-phenylalanines
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An efficient preparation of the title compounds from 4-iodo-L-phenylalanines using a carbonylative Stille cross-coupling reaction as the key-step is described. (C) 2000 Elsevier Science Ltd. All rights reserved.
- Morera, Enrico,Ortar, Giorgio
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p. 1815 - 1818
(2007/10/03)
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- A NOVEL DOUBLE DEPROTECTION-PEPTIDE CYCLISATION PROCEDURE AND ITS APPLICATION TO THE SYNTHESIS OF ANALOGUES OF THE CYCLIC TETRAPEPETIDE HC-TOXIN.
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A hydroxy-mediated Fmoc/methyl ester double deprotection procedure followed by an improved bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-Cl) cyclisation reaction are reported.This novel methodology was applied to the synthesis of three new HC-toxin analogues.
- Shute, Richard E.,Rich, Daniel H.
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p. 3419 - 3422
(2007/10/02)
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- Tritiated peptides. 12. Synthesis and biological activity of [4-3H-Phe8]substance P
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Substance P has been prepared 3H-labeled at Phe8 by catalytic deiodination of a protected precursor. Synthesis of the precursor was by solid-phase methodology on polydimethylacrylamide resin and by condensation in solution of fragments covering sequences 1-4, 5-7, and 8-11. Free peptide made by each route analyzed satisfactorily and had the same chromatographic characteristics as unlabeled substance P. It was distinguishable from the latter by radioimmunoassay when N and C terminally directed antisera were used and in the ability to cause contractions of isolated guinea pig ileum. Specific radioactivity was 23 Ci/mmol.
- Allen,Brundish,Wade,Sandberg,Hanley,Iversen
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p. 1209 - 1213
(2007/10/02)
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