- A reappraisal of the Ni-[(Benzylprolyl)amino]benzophenone complex in the synthesis of α,α-disubstituted amino acid derivatives
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α,α-Disubstituted alkenyl amino acid derivatives (e.g. Fmoc-S5-OH) are valuable monomers in the construction of stapled peptide derivatives. Synthetic access to these is possible using the Ni-[(Benzylprolyl)amino]benzophenone (BPB) complex as a chiral auxiliary. We discuss a reappraisal of the use of this, and demonstrate that epimerisation of the proline α-centre occurs during formation of the complex, leading to erosion in the enantiomeric excess of the final product. Modified conditions have been developed, providing the target compounds in high enantiomeric excess.
- Watson, Morag E.,Jamieson, Craig,Kennedy, Alan R.,Mason, Andrew M.
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- Improved synthesis of unnatural amino acids for peptide stapling
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The procedures for the synthesis of various α-alkenyl and alkyne amino acids were systematically optimized in light of enhancing atom economy, reducing hazardous reagent usage, and simplifying workup. By starting with Boc-Pro-OH and coupling with EDCI/DMAP followed by alkylation, chiral auxiliary was synthesized with high yield and enantioselectivity. For alkylation of the chiral complex, tBuONa was found and proved by quantitative calculation to be superior to tBuOK in generating more nucleophilic enolate salt, thereby can significantly enhance yield under room temperature. Final Fmoc protection was also dramatically facilitated in one-pot sequential manner by adding EDTA-2Na as the nickel chelator. Synthesis of α-bisalkenyl amino acid was also accomplished by achiral complex approach with high yield and efficacy. Accordingly, five most commonly used N-Fmoc protected α-alkenyl and alkynyl amino acids were synthesized and characterized.
- Li, Bo,Zhang, Jie,Xu, Yongjuan,Yang, Xiaoxiao,Li, Li
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supporting information
p. 2374 - 2377
(2017/05/29)
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- Stabilized alpha helical peptides and uses thereof
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Novel polypeptides and methods of making and using the same are described herein. The polypeptides include cross-linking (“hydrocarbon stapling”) moieties to provide a tether between two amino acid moieties, which constrains the secondary structure of the polypeptide. The polypeptides described herein can be used to treat diseases characterized by excessive or inadequate cellular death.
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- STITCHED POLYPEPTIDES
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The present invention provides inventive stitched polypeptides, pharmaceutical compositions thereof, and methods of making and using inventive stitched polypeptides.
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- DISUBSTITUTED AMINO ACIDS AND METHODS OF PREPARATION AND USE THEREOF
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Provided are crystalline α, α-disubstituted amino acids and their crystalline salts containing a terminal alkene on one of their side chains, as well as optionally crystalline halogenated and deuterated analogs of the α, α-disubstituted amino acids and their salts; methods of making these, and methods of using these.
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Paragraph 0100; 0192; 0193
(2014/05/20)
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- Robust asymmetric synthesis of unnatural alkenyl amino acids for conformationally constrained α-helix peptides
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The efficient asymmetric synthesis of unnatural alkenyl amino acids required for peptide 'stapling' has been achieved using alkylation of a fluorine-modified NiII Schiff base complex as the key step.
- Aillard, Boris,Robertson, Naomi S.,Baldwin, Adam R.,Robins, Siobhan,Jamieson, Andrew G.
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supporting information
p. 8775 - 8782
(2014/12/11)
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- Influence of α-methylation in constructing stapled peptides with olefin metathesis
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Ring-closing metathesis is commonly utilized in peptide macro-cyclization. The influence of α-methylation of the amino acids bearing the olefin moieties has never been systematically studied. In this report, controlled reactions unambiguously indicate that α-methylation at the N-terminus of the metathesis sites is crucial for this reaction to occur. Also, we first elucidated that the E-isomers of stapled peptides are significantly more helical than the Z-isomers.
- Zhang, Qingzhou,Shi, Xiaodong,Jiang, Yanhong,Li, Zigang
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p. 7621 - 7626
(2014/12/11)
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- Design of cell-permeable stapled peptides as HIV-1 integrase inhibitors
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HIV-1 integrase (IN) catalyzes the integration of viral DNA into the host genome, involving several interactions with the viral and cellular proteins. We have previously identified peptide IN inhibitors derived from the α-helical regions along the dimeric interface of HIV-1 IN. Herein, we show that appropriate hydrocarbon stapling of these peptides to stabilize their helical structure remarkably improves the cell permeability, thus allowing inhibition of the HIV-1 replication in cell culture. Furthermore, the stabilized peptides inhibit the interaction of IN with the cellular cofactor LEDGF/p75. Cellular uptake of the stapled peptide was confirmed in four different cell lines using a fluorescein-labeled analogue. Given their enhanced potency and cell permeability, these stapled peptides can serve as not only lead IN inhibitors but also prototypical biochemical probes or nanoneedles for the elucidation of HIV-1 IN dimerization and host cofactor interactions within their native cellular environment.
- Long, Ya-Qiu,Huang, Shao-Xu,Zawahir, Zahrah,Xu, Zhong-Liang,Li, Huiyuan,Sanchez, Tino W.,Zhi, Ying,De Houwer, Stephanie,Christ, Frauke,Debyser, Zeger,Neamati, Nouri
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p. 5601 - 5612
(2013/07/26)
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- Monosubstituted alkenyl amino acids for peptide "stapling"
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Alkenylglycine amino acids were assessed as potential candidates for hydrocarbon stapling and shown to be effective in stapling of the BID BH3 peptide.
- Yeo, David J.,Warriner, Stuart L.,Wilson, Andrew J.
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p. 9131 - 9133
(2013/09/24)
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