138165-75-0Relevant academic research and scientific papers
Protein-protein interface mimicry by an oxazoline piperidine-2,4-dione
Li, Xun,Taechalertpaisarn, Jaru,Xin, Dongyue,Burgess, Kevin
supporting information, p. 632 - 635 (2015/03/05)
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.
A multifaceted secondary structure mimic based on piperidine-piperidinones
Xin, Dongyue,Perez, Lisa M.,Ioerger, Thomas R.,Burgess, Kevin
, p. 3594 - 3598 (2014/04/17)
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.
Discovery of the fibrinolysis inhibitor AZD6564, acting via interference of a protein-protein interaction
Cheng, Leifeng,Pettersen, Daniel,Ohlsson, Bengt,Schell, Peter,Karle, Michael,Evertsson, Emma,Pahlén, Sara,Jonforsen, Maria,Plowright, Alleyn T.,Bostr?m, Jonas,Fex, Tomas,Thelin, Anders,Hilgendorf, Constanze,Xue, Yafeng,Wahlund, G?ran,Lindberg, Walter,Larsson, Lars-Olof,Gustafsson, David
supporting information, p. 538 - 543 (2014/06/09)
A class of novel oral fibrinolysis inhibitors has been discovered, which are lysine mimetics containing an isoxazolone as a carboxylic acid isostere. As evidenced by X-ray crystallography the inhibitors bind to the lysine binding site in plasmin thus preventing plasmin from binding to fibrin, hence blocking the protein-protein interaction. Optimization of the series, focusing on potency in human buffer and plasma clotlysis assays, permeability, and GABAa selectivity, led to the discovery of AZD6564 (19) displaying an in vitro human plasma clot lysis IC50 of 0.44 μM, no detectable activity against GABAa, and with DMPK properties leading to a predicted dose of 340 mg twice a day oral dosing in humans.
Synthesis and conformation of fluorinated β-peptidic compounds
Peddie, Victoria,Butcher, Raymond J.,Robinson, Ward T.,Wilce, Matthew C. J.,Traore, Daouda A. K.,Abell, Andrew D.
, p. 6655 - 6662 (2012/07/28)
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
ISOXAZOL-3(2H)-ONE ANALOGS AS THERAPEUTIC AGENTS
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Page/Page column 13, (2010/11/03)
or a pharmaceutically suitable salt thereof, wherein, R1 and R2 independently are hydrogen, deuterium, aryl, hetero aryl, C1-C8 alkyl, optionally being substituted with one or more substituents independently being R3,R3 is an aryl, hetero aryl, fluorine(s), a C1-C6 alkyl containing one or more fluorine, a C1-C6 alkyl containing one or more deuterium, a C1-C6 alkyl containing hydroxy, the aryl and heteroaryl optionally being substituted with one or more halogen, a fluorinated alkoxy, a fluorinated alkyl, a sulfonyl, one or more deuterium, a C1-6 alkyl, a C1-6 alkoxy, a nitrile,or R3 is a C1-6 alkyl optionally substituted with one or more of the following groups: COOR4, OCOR4, CONR5R6, NR5COR6, OR4;wherein, R4 is a C1-10 alkyl optionally substituted with one or more fluorine, deuterium, alkoxy, arylcarboxylate, alkyl carboxylate;R5 and R6 are independently selected from hydrogen, alkyl or they may together form a 4-8 membered carbon ring;or R1 and R2 form a 3-10 membered carbon ring optionally comprising O or N and optionally substituted with a C1-10 alkyl or aryl, hetero aryl optionally substituted with R3.
Succinct synthesis of β-amino acids via chiral isoxazolines
Fuller, Amelia A.,Chen, Bin,Minter, Aaron R.,Mapp, Anna K.
, p. 5376 - 5383 (2007/10/03)
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.
Catalytic enantioselective conjugate addition of carbamates
Palomo, Claudio,Oiarbide, Mikel,Halder, Rajkumar,Kelso, Michael,Gomez-Bengoa, Enrique,Garcia, Jesus M.
, p. 9188 - 9189 (2007/10/03)
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
A concise approach to structurally diverse β-amino acids
Minter, Aaron R.,Fuller, Amelia A.,Mapp, Anna K.
, p. 6846 - 6847 (2007/10/03)
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
β-hairpins generated from hybrid peptide sequences containing both α- and β-amino acids
Gopi, Hosahudya N.,Roy, Rituparna S.,Raghothama, Srinivasa R.,Karle, Isabella L.,Balaram, Padmanabhan
, p. 3313 - 3330 (2007/10/03)
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
