- Protein-protein interface mimicry by an oxazoline piperidine-2,4-dione
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Representative minimalist mimics 1 were prepared from amino acids. Scaffold 1 was not designed to mimic any particular secondary structure, but simulated accessible conformations of this material were compared with common ideal secondary structures and with >125000 different protein-protein interaction (PPI) interfaces. This data mining exercise indicates that scaffolds 1 can mimic features of sheet-turn-sheets, somewhat fewer helical motifs, and numerous PPI interface regions that do not resemble any particular secondary structure.
- Li, Xun,Taechalertpaisarn, Jaru,Xin, Dongyue,Burgess, Kevin
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- Succinct synthesis of β-amino acids via chiral isoxazolines
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β-Amino acids are important synthetic targets due to their presence in a wide variety of natural products, pharmaceutical agents, and mimics of protein structural motifs. While β-amino acids containing geminal substitution patterns have enormous potential for application in these contexts, synthetic challenges to the stereoselective preparation of this class of compound have thus far limited more complete studies. We present here a straightforward method employing chiral isoxazolines as key intermediates to access five different β-amino acid structural types with excellent selectivity. Of particular note is the use of this approach to prepare highly substituted cis-β-proline analogues. The ready access to these diversely substituted compounds is expected to facilitate future studies of the structure and function of this important class of molecules.
- Fuller, Amelia A.,Chen, Bin,Minter, Aaron R.,Mapp, Anna K.
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- A multifaceted secondary structure mimic based on piperidine-piperidinones
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Minimalist secondary structure mimics are typically made to resemble one interface in a protein-protein interaction (PPI), and thus perturb it. We recently proposed suitable chemotypes can be matched with interface regions directly, without regard for secondary structures. Here we describe a modular synthesis of a new chemotype 1, simulation of its solution-state conformational ensemble, and correlation of that with ideal secondary structures and real interface regions in PPIs. Scaffold 1 presents amino acid side-chains that are quite separated from each other, in orientations that closely resemble ideal sheet or helical structures, similar non-ideal structures at PPI interfaces, and regions of other PPI interfaces where the mimic conformation does not resemble any secondary structure. 68 different PPIs where conformations of 1 matched well were identified. A new method is also presented to determine the relevance of a minimalist mimic crystal structure to its solution conformations. Thus dld-1-faf crystallized in a conformation that is estimated to be 0.91 kcal-mol-1 above the minimum energy solution state. Do we know, when designing a new peptidomimetic scaffold like the one shown, how it can resemble secondary structures? Design and modular synthesis of this elongated mimic is reported, and the structure is related to ideal and real structures at PPI interfaces.
- Xin, Dongyue,Perez, Lisa M.,Ioerger, Thomas R.,Burgess, Kevin
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p. 3594 - 3598
(2014/04/17)
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- Synthesis and conformation of fluorinated β-peptidic compounds
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Experimental and theoretical data indicate that, for α-fluoroamides, the F-C-C(O)-N(H) moiety adopts an antiperiplanar conformation. In addition, a gauche conformation is favoured between the vicinal C-F and C-N(CO) bonds in N-β-fluoroethylamides. This study details the synthesis of a series of fluorinated β-peptides (1-8) designed to use these stereoelectronic effects to control the conformation of β-peptide bonds. X-ray crystal structures of these compounds revealed the expected conformations: with fluorine β to a nitrogen adopting a gauche conformation, and fluorine α to a C=O group adopting an antiperiplanar conformation. Thus, the strategic placement of fluorine can control the conformation of a β-peptide bond, with the possibility of directing the secondary structures of β-peptides. Copyright
- Peddie, Victoria,Butcher, Raymond J.,Robinson, Ward T.,Wilce, Matthew C. J.,Traore, Daouda A. K.,Abell, Andrew D.
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p. 6655 - 6662
(2012/07/28)
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- Catalytic enantioselective conjugate addition of carbamates
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Catalytic, asymmetric conjugate addition of carbamates to enoyl systems has been realized for the first time, providing a two-step access to virtually enantiopure N-protected β-amino acids. Copyright
- Palomo, Claudio,Oiarbide, Mikel,Halder, Rajkumar,Kelso, Michael,Gomez-Bengoa, Enrique,Garcia, Jesus M.
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p. 9188 - 9189
(2007/10/03)
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- A concise approach to structurally diverse β-amino acids
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We have demonstrated that the high yields and selectivities of 1,3-dipolar cycloadditions can be translated into facile stereoselective syntheses of a diverse array of β-amino acids, key components of bioactive natural products, β-lactams, and peptidomimetics. Simply by selecting different combinations of three readily available starting materials (an oxime, a chiral allylic alcohol, and a nucleophile), we used the reaction sequence to prepare four different β-amino acid structural types with a variety of substitution patterns in good overall yield. Of particular note is the use of this approach to prepare highly substituted β-amino acids not readily accessible by previously reported methodologies. This will pave the way for future studies of the structure and function of this important class of molecules. Copyright
- Minter, Aaron R.,Fuller, Amelia A.,Mapp, Anna K.
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p. 6846 - 6847
(2007/10/03)
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- β-hairpins generated from hybrid peptide sequences containing both α- and β-amino acids
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The incorporation of the β-amino acid residues into specific positions in the strands and β-turn segments of peptide hairpins is being systematically explored, The presence of an additional torsion variable about the C(α)-C(β) bond (θ) enhances the confor
- Gopi, Hosahudya N.,Roy, Rituparna S.,Raghothama, Srinivasa R.,Karle, Isabella L.,Balaram, Padmanabhan
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p. 3313 - 3330
(2007/10/03)
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- Synthesis of optically active β-amino acid N-carboxyanhydrides
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(Equation presented) Methodology has been developed for the general synthesis of optically active β-amino acid N-carboxyanhydrides (β-NCAs) through cyclization of Nβ-Boc or Nβ-Cbz β-amino acids using phosphorus tribromide. The format
- Cheng, Jianjun,Ziller, Joseph W.,Deming, Timothy J.
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p. 1943 - 1946
(2007/10/03)
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- α-Oxymethyl ketone enolates for the asymmetric Mannich reaction. From acetylene and N-alkoxycarbonylimines to β-amino acids
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The insufficient diastereoselectivity and generality, which are the main problems of the 'acetate' aza - aldol reaction, can now be addressed through the reaction of the lithium enolate of endo-O-trimethylsilyl acetyl isoborneol with various N[(p-tolylsul
- Palomo, Claudio,Oiarbide, Mikel,Gonzalez-Rego, M. Concepcion,Sharma, Arun K.,Garcia, Jesus M.,Gonzalez, Alberto,Landa, Cristina,Linden, Anthony
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p. 1063 - 1066
(2007/10/03)
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- 2,2'-dithiobisbenzamides derived from α-, β- and γ-amino acids possessing anti-HIV activities: Synthesis and structure-activity relationship
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Nucleocapsid protein (NCp7), which contains highly conserved retroviral zinc fingers, is essential in the early as well as the late phase of human immunodeficiency virus (HIV) life cycle and constitutes a novel target for AIDS therapy. HIV-1 NCp7 is a basic 55 amino acid protein containing two C(X)2C(X)4H(X)4C motif zinc fingers flanked by basic amino acids on each side. 2,2'-dithiobisbenzamides have previously been reported to release zinc from these NCp7 zinc fingers and also to inhibit HIV replication. Specifically, 2,2'-dithiobisbenzamides derived from simple amino acids showed good antiviral activities. The benzisothiazolone 3, the cyclic derivative of 2, was selected for clinical trials as an agent for AIDS therapy. Herein we report the syntheses and antiviral activities, including therapeutic indices, of 2,2'-dithiobisbenzamides derived from α-, β- and γ-amino acids. Electrospray ionization mass spectrometry was used to study the zinc-ejection activity of these compounds. Among the α-amino acid derived 2,2'-dithiobisbenzamides, analogues containing alkyl side chains were found to be antivirally active with good therapeutic indices. 2,2'-Dithiobisbenzamides, derived from β- and γ-amino acids, were found to possess better antiviral and therapeutic efficacies than the α-amino acid analogues. Thus compound 59 was found to possess an EC50 of 1.9μM with a therapeutic index of >50. Interestingly, 2,2'-dithiobisbenzamides derived from α-amino acids containing a protected acid function and polar side chains also exhibited very good antiviral activity. Copyright (C) 1998 Elsevier Science Ltd.
- Vara Prasad,Loo, Joseph A.,Boyer, Frederick E.,Stier, Michael A.,Gogliotti, Rocco D.,Turner, William J.,Harvey, Patricia J.,Kramer, Melissa R.,Mack, David P.,Scholten, Jefferey D.,Gracheck, Stephen J.,Domagala, John M.
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p. 1707 - 1730
(2007/10/03)
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- Syntheses and biological activities of bombesin analogs modified in the C-terminal dipeptide part
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Bombesin receptor antagonists are possible therapeutic agents due to their ability to act as inhibitors of cellular proliferation. On the basis of our hypothesis on the mechanism of action of gastrin associating an activating enzyme system to the receptor and on the results reported in the litterature, we have synthesized bombesin analogues which have been modified in the C-terminal Leu13-Leu14 amide part. We have shown that modification in the C-terminal part of the bombesin strongly affected the biological activity in rat pancreatic acini. The most potent compound which is described here, H-D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-Ψ/(CH2)Leu-NH2, was able to recognize the bombesin receptor on rat pancreatic acini (Ki 4.3 nM) and antagonized the bombesin stimulated amylase secretion (Ki 7.7 nM).
- Llinares,Devin,Azay,Berge,Fehrentz,Martinez
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p. 767 - 780
(2007/10/03)
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- Synthesis of enantiomerically pure β- and γ-amino acids from aspartic and glutamic acid derivatives
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An efficient synthesis of enantiomerically pure β- and γ-amino acids starting from commercially available aspartic and glutamic acid derivatives is described. The acid function, α to the amino group, is first transformed to a good leaving group and the pr
- El Marini,Roumestant,Viallefont,Razafindramboa,Bonato,Follet
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p. 1104 - 1108
(2007/10/02)
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- 'CARBA' peptide bond surrogates: Synthesis of Boc-L-Leu-Ψ(CH2-CH2)-L-Phe-OH and Boc-L-Leu-Ψ(CH2-CH2)-D-Phe-OH through a Horner-Emmons reaction
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A synthesis of Boc-L-Leu-Ψ(CH2-CH2)-L-Phe-OH and Boc-L-Leu-Ψ(CH2-CH2)-D-Phe-OH from Boc-βhomo-L-leucinal, through a Horner-Emmons reaction with ethyl 2-(diethylphosphono)-3-phenylpropionate is described. Interme
- Rodriguez,Heitz,Martinez
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p. 7319 - 7322
(2007/10/02)
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