Dissertations / Theses on the topic 'Amino acids Design'
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Rubini, Marina. "Protein engineering and design with non canonical amino acids." [S.l. : s.n.], 2004. http://deposit.ddb.de/cgi-bin/dokserv?idn=974166073.
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McArthur, Duncan Robert. "Design and synthesis of novel sila-peptidomimetics." Thesis, University of Glasgow, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.250791.
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Bilgiçer, Zihni Basar. "Protein design using unnatural amino acids with fluorinated side chains /." Thesis, Connect to Dissertations & Theses @ Tufts University, 2005.
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Thesis (Ph.D.)--Tufts University, 2005.Adviser: Krishna Kumar. Submitted to the Dept. of Chemistry. Includes bibliographical references. Access restricted to members of the Tufts University community. Also available via the World Wide Web;
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Petrillo, Betty. "Design and synthesis of artificial receptors for phosphorylated amino acids." Thesis, Cardiff University, 2006. http://orca.cf.ac.uk/54276/.
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The research detailed in this thesis describes the development of a high-throughput molecularly imprinted polymer (MIP) receptor that binds to phosphorylated serine residues. This new receptor would need to be biologically compatible (i.e. binds in aqueous media) and have a high degree of specificity and affinity for the phosphorylated residue compared to the non-phosphorylated amino acid. Importantly, the artificial receptor should not rely on neighbouring amino acid residues for its binding affinity or specificity. Different molecular imprinting approaches were investigated to imprint the template molecule, Boc-phospho-L-serine methyl ester. The most successful approach was found by using an amidine group in stoichiometric monomer-template interactions. To determine the binding affinity and specificity of the MIP, an equilibrium evaluation was used. Batch analyses for the template specie and a range of cross-reactants were performed in aqueous systems and the enantioselectivity was evaluated using the D-enantiomer of the template molecule. Furthermore, the selectivity of the MIP was investigated with a series of peptides containing phosphorylated serine. The results of these studies provide evidence of selective binding sites in the MIP for Boc-phospho-L-serine methyl ester. The thesis concludes by discussing some applications of the MIP in life sciences, e.g. as an alternative to antibody assays.
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Threlfall, Richard Neil. "Design and Synthesis of Foldamers Derived from Nucleoside B-Amino Acids." Thesis, University of Liverpool, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.507631.
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Turtle, Michelle Louise. "Design and synthesis of peptides derived from nucleoside β-amino acids." Thesis, University of Liverpool, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.569173.
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Naturally occurring macromolecules such as proteins and DNA adopt very specific conformations and three dimensional arrangements which allow them to perform their sophisticated functions in nature. Unnatural oligomerscan also adopt well defined conformations and these have been termed 'foldamers'. This project is concerned with the design and synthesis of β-peptide foldamers which are assembled from nucleoside derived β -amino acids. It was hoped that the combination of the inherent helix folding properties of peptides and the associated characteristics of nucleosides would allow us to create novel foldamers with specific recognition properties. The structure of the β -amino acids involves conversion of the 3'-hydroxyl group of the nucleoside sugar into an amino group (with retention of configuration) and oxidation of the 5'-hydroxymethylene group to a carboxylic acid. Beginning with the natural nucleosides thymidine and 2'-deoxyadenosine, syntheses of 4 different nucleoside β -amino acid monomers was accomplished. The syntheses were based around the use of 3'-azido-2'-deoxynucleosides as key synthetic intermediates and also required optimisation of protecting groups to prevent side reactions associated with cleavage of the glycosidic bond. In general, the preferred protecting group strategy involved the 3'-amino group being either protected with a fluorenylmethoxycarbonyl (Fmoc) group or being masked as an azide. The benzhydryl group also proved useful in the protection of the carboxylic acid function for couplings in solution. The synthesis of the β -peptides was investigated by both solid-phase peptide synthesis and standard couplings in solution. A range of peptide dimers, trimers and a tetramer were prepared, but the isolated yields of the final products were low due to difficulties with purification.
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Mavencamp, Terri Lynn. "Design, synthesis and biological evaluation of a family of excitatory amino acid transporter 3 (EAAT3) preferring inhibitors." [Missoula, Mont.] : The University of Montana, 2008. http://etd.lib.umt.edu/theses/available/etd-03212009-152926/unrestricted/Mavencamp_umt_0136D_10009.pdf.
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Eszes, Csilla Monika. "Re-design of proteins to alter enzymic activities." Thesis, University of Bristol, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.324246.
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Mata, David Garcia. "Understanding Protein Structure And Function Using Rational Design And Unnatural Amino Acids." The Ohio State University, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=osu1338392020.
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Qiu, Wei. "Design and synthesis of conformationally and topographically constrained amino acids as peptidomimetics." Diss., The University of Arizona, 2001. http://hdl.handle.net/10150/280486.
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A major goal of peptide research has been to elucidate or understand the relationships between a peptide's three-dimensional structure and its biological activity. De Novo design of peptide mimetics requires assembling all components necessary for molecular recognition and transduction, which needs the proper choice of a template that can place the key side chain residues in 3D space. Two widely used methods are novel β-substituted amino acids and conformationally constrained secondary structure mimetics. In this thesis, we report our efforts to fulfill the aforementioned criteria in synthesizing β-isopropyl aromatic amino acids and constrained reverse turn dipeptide mimetics. Through asymmetric Michael addition reaction, highly topographically constrained β-isopropyl aromatic amino acids have been synthesized. In order to develop a general approach to synthesize these novel amino acids, we re-examined the reaction conditions for Evans' diastereoselective 1,4-addition, and found conditions which gave excellent diastereoselectivities and good chemical yields. A concise and straightforward five-step synthesis of [5.5]-bicyclic reverse turn dipeptide mimetic scaffolds with side chain functionality at the i+1 and i+2 positions has been developed. In the bicyclic structure, two dihedral angles (ψ₂ and φ₃) are greatly restricted. Further development of this synthesis will enable us to prepare various types of reverse turns with different backbone geometry and side chain topography. Enantiomerically pure (S)-trans-cinnamylglycine and (S)-α-trans-cinnamyl-α-alanine have been prepared via reaction of chiral Ni (II)-complexes of glycine and alanine respectively, with cinnamyl halides. Inexpensive and readily available reagents and solvents are used, including a recyclable chiral ligand. The simplicity of the experimental procedures and high stereochemical outcome make this method synthetically attractive for preparing the target amino acids on multi-gram scales. Further studies by incorporating these mimetics into potent peptide analogues will greatly help us to understand the bioactive conformation of the parent peptides.
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Liu, Zhihua. "THE DESIGN AND SYNTHESIS OF NOVEL UNNATURAL AMINO ACIDS AND THE DESIGN AND SYNTHESIS OF PEPTIDES & PEPTIDOMIMETICS CONTAINING UNNATURAL AMINO ACIDS FOR THE STUDY OF G-PROTEIN COUPLED RECEPTORS." Diss., The University of Arizona, 2010. http://hdl.handle.net/10150/204274.
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Nature has gifted peptides as important modulators in the human body, but these types of molecules often have not been favored when we were looking for therapeutic agents. The poor bioavailability, fast degradation and until recent high manufacturing costs of some bioactive peptides lowered their potential usage in the health industry. Under these circumstances, unnatural amino acids were developed as indispensible tools providing enormous support to peptide science. By incorporating proper unnatural amino acids into a peptide or protein, we now can significantly improve peptide's or protein's half-life, cell permeability, bio-distribution, etc. In addition, their potency and receptor/acceptor selectivity could also be enhanced. Site-specific modifications of peptides and proteins under physiological conditions with the use of unnatural amino acids also have been made easier with the advance of biotechnology. Therefore, my research described in this dissertation contributes to the efforts in the development of novel unnatural amino acids. In particular, I have focused on novel methods in the synthesis of anti beta-functionalized gamma,delta-unsaturated amino acids. These amino acids have special interests in peptide chemistry: they can provide conformational constraints to the peptide 3D structures; the beta-functionalization allows the introduction of pharmaceutically interesting side chain groups; and the terminal double bond which is orthogonal to peptide synthesis provides access to further chemical modifications. Two general methodologies for the synthesis of both racemic and optically active anti beta-functionalized gamma,delta--unsaturated amino acids were developed by using the thio-Claisen rearrangement (TCR) reaction. Excellent diastereoselectivies and enantioselectivities were obtained when C2-symmetric chiral auxiliaries were selected to control the stereochemistry outcome. The mechanism and the scope of the TCR reaction were also studied, showing unique advantages in the preparation of these biological interesting amino acids.Another effort of developing angiotensin II type 1 (AT1) receptor biased peptide ligands is also documented in this dissertation. The AT1 receptor is a 7-transmembrane G-protein coupled receptor, which recent researches have shown could be activated through a beta-arrestins only, but G-protein independent, pathway. We synthesized 12 analogs of Sar1,Ile4,Ile8-AngII (SII), and tested them in biological assays, and obtained valuable information for further "perfect" biased ligands design.
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Russell, Keith Casey. "Design and asymmetric synthesis of unusual amino acids for incorporation into peptide hormones." Diss., The University of Arizona, 1992. http://hdl.handle.net/10150/185750.
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One of the central goals of peptide and protein chemistry is the development of peptides with specific biological, chemical, and physical properties. An important method directed towards attaining this goal is the use of conformationally restricted amino acids. The conformationally restricted amino L-isomers of 2'-methyltyrosine, 2',6'-dimethyltyrosine, erythro- and threo-2',β-dimethyltyrosine, and erythro- and threo-2',6',β-trimethyltyrosine were asymmetrically synthesized in good yields and high optical purities. The synthesis of these compounds was based on the chiral boron imidate methodology. Acid precursors were prepared from either 5-methyl-2-nitrophenol, 3-methylanisole, or 3,5-dimethylansole and coupled to optically active 4-phenyl-2-oxazolidinone. Unsaturated coupled products were subjected to 1,4 conjugate additions to set the stereochemistry at the β-carbon with superior stereoselectivity (88-99% de). The Michael adducts and other acyloxazolidinones were asymmetrically brominated to set the chirality at the α-carbon also with excellent stereoselectivity (80-98% de). The bromides were displaced with azide ion to afford the α-azidocyloxazolinones without any detectable racemization. The chiral auxiliary was hydrolyzed and recovered. The azido acids were reduced and methyl ether hydrolyzed to yield the tyrosine derivatives with high optical purity. The absolute stereochemistry of three of the bromide intermediates was determined by X-ray crystallography providing evidence for the selective reactions. The superiority of 4-phenyl-2-oxazolidinone over 4-phenylmethyl-2-oxazolidinone for asymmetric induction was also demonstrated. To examine the sensitivity of the 2' position of tyrosine in oxytocin, (D,L-2'-methylTyr²) oxytocin was synthesized using the standard techniques of solid phase synthesis. Racemic 2'-methyltyrosine was prepared via the classical malonate synthesis. Computer models suggest that the [L-2'-methylTyr²] oxytocin should be a weak agonist.
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Millward, Steven Wesley Roberts Richard W. Dervan Peter B. "The design, synthesis, and evolution of macrocyclic mRNA display libraries containing unnatural amino acids /." Diss., Pasadena, Calif. : California Institute of Technology, 2007. http://resolver.caltech.edu/CaltechETD:etd-05142007-161158.
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Li, Guigen. "Asymmetric synthesis of unusual amino acids for peptide molecular design and molecular recognition studies." Diss., The University of Arizona, 1995. http://hdl.handle.net/10150/187104.
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Asymmetric synthetic organic chemistry of amino acids is of fundamental importance for the study of peptide and protein molecular design and molecular recognition. The designed unusual amino acids can provide unique conformational and topographical properties that are crucial for molecular recognition processes between peptide ligands and specific receptors, receptor subtypes, and the related signal transduction processes. It is necessary to design and synthesize optically pure unusual amino acids to meet different stereochemical requirements for different receptors and the various active sites on receptors. The Evans-type auxiliary has played an important role in the asymmetric synthesis of optically pure amino acids in the past decade. However, a lot of theoretical and practical research aspects in this field which are related to sensitive chiral enolates, new methodologies and new synthetic procedures need to be investigated. This thesis will present some new tactics for peptide molecular design, for asymmetric synthesis of β-branched α-amino acids and for the related mechanistic organic chemistry which include: a one-pot tandem Michael-like addition/electrophilic bromination reaction and its application to the total asymmetric synthesis of four individual four individual isomers of 2', β-di-methyl tyrosine; an efficient mono- and di-demethylation procedure for aryl-methyl ethers of unusual amino acids; 1,2-asymmetric cis electrophilic induction in allylic-strained boron enolates and its potential application for the asymmetric synthesis of unusual amino acids; a new strategy for the total synthesis of the four individual isomers of β-methylphenylalanine by using 4-phenyl-oxazolidinone as a new chiral resolution reagent and simultaneously as a chiral auxiliary which can provide complete stereoselectivities; a concise method to separate racemic Boc-amino acids, including Boc-unusual amino acids, and a new chiral resolution reagent for HPLC and NMR analysis; a mechanistic study of the asymmetric Michael-like addition reaction by using 4-phenyl-oxazolidinone as a chemical probe (and a potential probe to study biological processes in the future when this motif is incorporated into biologically active molecules). In the last part of the thesis, a new method for the synthesis of the peptide Biphalin, which is perhaps the most potent antinociceptive molecule examined thus far, by solution phase procedures which greatly accelerates the synthetic process and the structure-activity relationships study of Biphalin from the new uses of β-constrained unusual amino acids. Finally, some new strategies for peptide molecular design are discussed.
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Kelleman, Audrey. "Design and syntheses of nonnatural amino acids and their incorporation into somatostatin and RGD analogs." Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2007. http://wwwlib.umi.com/cr/ucsd/fullcit?p3249664.
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Thesis (Ph. D.)--University of California, San Diego, 2007.Title from first page of PDF file (viewed April 3, 2007). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references.
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Lung, Feng-Di Tiffany. "Design and synthesis of receptor-selective peptide ligands, and the synthesis of unnatural amino acids." Diss., The University of Arizona, 1995. http://hdl.handle.net/10150/187116.
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The discovery of endogenous opioid peptides has greatly accelerated research in opioid chemistry and biology. Studies of the physiological and pharmalogical roles of these receptors require highly potent and receptor-selective ligands for μ, δ, and κ receptors. The major goal of this project is to design and synthesize highly potent and κ receptor-selective dynorphin A analogues with specific conformational and topographical features. Therefore, a series of linear and cyclic dynorphin A analogues with global and/or local conformational constraints have been designed, synthesized, and evaluated for their biological activities. Several leads from dynorphin A analogues have been developed, and have provided new insights into requirements for high κ receptor-selectivity and potency. The incorporation of side chain conformationally constrained amino acids can provide new insights into topographical requirements for peptide ligand-receptor binding. An efficient synthesis of 2', β-dimethyltyrosine in large quantities and a new strategy of the synthesis of optically pure isomers of β-methylphenylalanine derivatives have been developed. These unnatural amino acids can be incorporated into peptides for the development of novel peptides with high potency and enhanced receptor-selectivity.
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Miranda, Acevedo Ronald Alexander. "Design and synthesis of novel bio-nanohybrid materials: catalytic applications in reactions of interest to the fine-chemical/pharmaceutical industries." Doctoral thesis, Universitat Rovira i Virgili, 2012. http://hdl.handle.net/10803/101524.
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Bio-nanohybrid materials based on the combination of biomolecules and inorganic supports are interesting by their versatile applications in regenerative medicine, drug delivery, bio-engineering and catalysis. In that context, understanding of organic/inorganic interactions offers an important key to design new and more complex bio-systems with modified interactions.
In this thesis, amino acids and synthesised poly-amino acids were immobilised in hydrotalcite-like materials under green, controllable and efficient protocols. Additionally, these nanohybrid materials were used as heterogenized catalysts exhibiting high catalytic activity and selectivity in comparison with their counterpart components.
All result data showed that the location and nature of the immobilization had an important role in the final chemical properties; moreover, this novel bio-nanohybrid material exhibited excellent synergistic behaviour which was unique for each material and could be modified according with the reaction requirements.
All novel bio-nanohybrid materials were easily synthesised, recovered and, in some cases, reused without appreciable deactivation.Materiales bio-nanohíbridos compuestos por la combinación de biomoléculas y soportes inorgánicos son interesantes por sus versátiles aplicaciones en medicina regenerativa, transporte de medicamentos, bio-ingeniería y catálisis. En este contexto, el entendimiento de las interacciones orgánico/inorgánicas ofrece importante información para el diseño de nuevos y más complejos bio-sistemas con interacciones modificadas. En esta tesis, amino ácidos y poli-amino ácidos sintéticos fueron inmovilizados en materiales tipo hidrotalcita a través de eficientes y controlables protocolos amigables con el medioambiente. Adicionalmente, estos materiales fueron usados como catalizadores heterogeneizados mostrando alta actividad y selectividad en comparación con sus componentes de partida. En este sentido, la localización y naturaleza de la interacción tuvo un importante rol en las propiedades catalíticas finales; además, estos novedosos materiales mostraron un excelente comportamiento sinérgico el cual fue único y pudo ser modificado de acuerdo a las necesidades en reacción. Todos los materiales bio-nanohíbirdos fueron sintetizados y recuperados con facilidad del medio de reacción y en algunos casos fueron reutilizados sin desactivación apreciable.
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Greenwood, Jeremy R. "Pyridazinediones and amino acid receptors theoretical studies, design, synthesis and evaluation of novel analogues /." [Sydney : J. Greenwood], 1999. http://www.pharmacol.usyd.edu.au/thesis.
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Thesis (Ph. D.)--Dept. of Pharmacology, University of Sydney, 1999.Title from title screen. Interactive three dimensional molecular data and multiple colour images. Text presented in Hypertext Markup Language (.htm); images in standard formats (.jpg, .gif); molecules presented mostly as Cambridge Protein Data Bank format (.pdb); some molecules presented in alternative X. Mol cartesian co-ordinates format (.xyz); search facility in PERL script. Includes bibliographical references. A printed form was produced with limited features as a Faculty requirement; may also be issued in CD-ROM.
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Lowe, Christopher William George. "An investigation into the design and activity of biocidal agents based upon alkyl-substituted amino acids." Thesis, University of Sunderland, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.290902.
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Marshall, Liam R. "Synthesis of unnatural amino acids for the design of multi-metal binding α-helical coiled coils." Thesis, University of Sheffield, 2017. http://etheses.whiterose.ac.uk/19509/.
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Williams, Lawrence Joseph 1968. "Design and construction of organic crystals: Orthogonal recognition of pioperazinediones derived from unnatural alpha-amino acids." Diss., The University of Arizona, 1996. http://hdl.handle.net/10150/282281.
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A paradigm and theoretical model for the design and construction of acentric crystalline solids is presented. In theory, molecular assembly in a predetermined arrangement will result for molecules that possess and participate in three chemically and geometrically orthogonal intermolecular interactions. A class of piperazinediones was designed to possess such orthogonal recognition elements and may provide an appropriate scaffold for the rational design of molecular building blocks for construction of acentric crystals. The topography and conformational rigidity of this scaffold limit packing options, which facilitate prediction of crystal structures from consideration of readily identified forces associated with three orthogonal recognition elements. Recognition elements can be introduced and modified by changing the functional groups on the scaffold via chemical synthesis. Structural variability facilitates exploration and exploitation of these molecules. A family of organic molecules that satisfy many of the conditions of the theoretical model is described and evaluated on the basis of their design, synthesis, and characterization.
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Mykhailiuk, Pavlo. "New Fluorine-Labelled Amino Acids as 19F-NMR Reporters for Structural Peptide Studies Design, Synthesis, and Applications /." [S.l. : s.n.], 2008. http://digbib.ubka.uni-karlsruhe.de/volltexte/1000009233.
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Greenwood, Jeremy R. (Jeremy Robert) 1971. "Pyridazinediones and amino acid receptors theoretical studies, design, synthesis and evaluation of novel analogues." [Sydney : J. Greenwood], 1999. http://www.pharmacol.usyd.edu.au/thesis.
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Title from title screen. Interactive three dimensional molecular data and multiple colour images. Text presented in Hypertext Markup Language (.htm); images in standard formats (.jpg, .gif); molecules presented mostly as Cambridge Protein Data Bank format (.pdb); some molecules presented in alternative X.Mol cartesian co-ordinates format (.xyz); search facility in PERL script. Includes bibliographical references. Text, numeric and representational data System requirements: for text, any standard web browser on any platform, Netscape 2.x or higher, Internet Explorer 3.x or higher; for molecular structures, viewer such as Rasmol or preferably MDL's Chemscape Chime; for search facility , an appropriately configured web server. Links to all required software for browsing on various platforms are included in the software directory in the thesis. Mode of access: World Wide Web.
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Gruner, Sibylle Annette Wunneda. "Carbohydrate based mimetics in drug design sugar amino acids as structural templates and key residues of bioactive peptidomimetics /." [S.l.] : [s.n.], 2002. http://deposit.ddb.de/cgi-bin/dokserv?idn=964815958.
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Kameda, Minoru. "Molecular design of N-spiro C2-symmetric chiral phase-transfer catalysts for practical asymmetric synthesis of α-amino acids." 京都大学 (Kyoto University), 2004. http://hdl.handle.net/2433/147838.
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Alhedabi, Taleb Flieh Hassen. "Design of a suitable material at the nano to micrometer scale as support for electrolysis. : Study of the electropolymerization of concentrated L-amino acids in aqueous solutions." Thesis, Besançon, 2015. http://www.theses.fr/2015BESA2052.
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L'oxyde d'aluminium anodique poreux (AAO) est formé par anodisationde l'aluminium dans une solution électrolytique acide, sous une tensionconstante et de la température de l'électrolyte. Des techniques spectroscopiquespareilles que la spectroscopie infrarouge FT (ATR-FTIR), diffraction des rayonsX (XRD), spectroscopie Raman, la microscopie à force atomique (AFM) etmicroscopie électronique à balayage (MEB) utilisés pour caractériser la matrice.L'oxydation anodique d'acides L-aminés et des mélanges de monomèrescomprenant 0,1 M aniline et des acides L-aminés dans le milieu aqueux acide deplatine et électrode lisses électrodes Pt modifié (Pt / AAO) est étudié.L'oxydation des acides L-aminés et les électropolymérisation de l'aniline 0,1 Mavec des acides L-aminés tels que la L-alanine, la L-sérine, la L-méthionine,acide L-aspartique, la L-lysine, et phénylalanine en acide le milieu a étéeffectuée par voltammetric cyclique électrochimique couplée à microbalance àcristal de quartz (EQCM). La concentration des acides aminés, le pH del'électrolyte et les effets de balayage de numéros de voltamétrie cyclique ont étéexaminées. L'analyse spectroscopique comme réflectance totale atténuée FTspectroscopie infrarouge (ATR-FTIR), UV-visible, la spectroscopiephotoélectronique à rayons X (XPS), la spectroscopie Raman, et la diffractiondes rayons X (XRD) sont utilisés pour caractériser les couches minces obtenues.Microscopie électronique à balayage (MEB) utilisé pour étudier la morphologiede surface mince de films. La solubilité pour les polymères sont étudiées. Laprésence de liaisons peptidiques est clairement mise en évidence. DFTmodélisation de poly-L-acides aminés volet sur Pt (001) couplée à des mesuresspectroscopiques sont en faveur de L-amino-acides électropolymérisation enacides poly-L-aminés d'une manière irréversible.Les électrosynthèses de poly-L-amino acides, la polyaniline et depolymères ont été utilisées en tant que récepteur de protons à l'état solide pHcapteur solideAnodic aluminum oxide porous (AAO) is formed by the anodization ofaluminum in acidic electrolytic solution under at constant voltage and electrolytetemperature. Spectroscopic techniques such as FT infrared spectroscopy (ATRFTIR),X-ray diffraction (XRD), Raman spectroscopy, atomic force microscopy(AFM) and scanning electron microscopy (SEM) used to characterize thetemplate.The anodic oxidation of L-amino acids and monomer mixtures comprising0.1 M aniline and some L-amino acids in acidic aqueous medium on platinumsmooth electrodes and modified Pt electrode (Pt/AAO) is studied. The oxidationof L-amino acids and in presence of aniline 0.1 M with L-amino acids such as Lalanine,L-serine, L-methionine, L-aspartic acid, L-lysine, and L- phenylalaninein acidic media was carried out by cyclic voltammetry coupled withelectrochemical quartz crystal microbalance (EQCM). The Amino acidconcentration, pH of the electrolyte and the scan number effects on cyclicvoltammetry were examined. Spectroscopic analysis such as attenuated totalreflectance FT infrared spectroscopy (ATR-FTIR), UV-Visible, X-rayphotoelectron spectroscopy (XPS), Raman spectroscopy, and X-ray diffraction(XRD) are used to characterize the resulting thin film coatings. Scanningelectron microscopy (SEM) used to study the morphology of thin films surfaceas well as the solubility are studied. The presence of peptide bonds is clearlyhighlighted. DFT modelization of poly-L-amino acids strand on Pt(001) coupledto spectroscopic measurements are in favor of L-amino acidselectropolymerization into poly-L-amino acids in an irreversible way.The electrosynthesis of poly-L-amino acids, polyaniline and polymerswere used as proton receptor for solid state pH solid sensor
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Ndungu, John M. "The design and synthesis of novel beta-substituted amino acids, bicyclic dipeptide mimetics, and their incorporation into cholecystokinin/opioidchimeric peptides." Diss., The University of Arizona, 2004. http://hdl.handle.net/10150/290126.
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Peptide ligands and protein receptors play critical roles in the regulation of nearly every biological system. However, peptides are characteristically highly flexible and thus identifying the basic conformational elements necessary for recognition between a peptide ligand and it's receptor at the molecular level remains a formidable task. Great emphasis in peptide research has thus focused on the determination of the receptor-bound conformation adopted by bioactive peptides by synthesizing constrained analogues of the peptides. Knowledge of the three dimensional interaction between a peptide ligand and a receptor could be invaluable in understanding bioactivity and in the design of therapeutics. To determine the bioactive conformation of our novel chimeric peptides for the opioid and cholecystokinin receptors, constrained analogues were designed to limit the conformations that the peptides would adopt. In this regard, [5,5]- and [6,5]-bicyclic dipeptide mimetics were designed and synthesized to constrain a dipeptide unit and by extension limit the flexibility of the peptide. The bicyclic dipeptide mimetics were synthesized from precursors obtained by the beta-alkylation of aspartic acid and from the Kazmaier-Claisen rearrangement reaction. A protocol for the alkylkation of aspartic acid with allyl bromide, benzyl bromide, and benzyl disulfide was developed. The bicyclic dipeptide mimetics were then introduced into the peptides whose biological activity was evaluated at both the opioid and cholecystokinin receptors. The peptides showed good binding and functional activities at the CCK receptors, but low activities at the opioid receptors.
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Aguesseau, Julie. "Design of bio-inspired catalysts based on a gamma-peptide foldamer architecture." Thesis, Montpellier, 2019. http://www.theses.fr/2019MONTS043/document.
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Les travaux décrits dans ce manuscrit concernent la synthèse d’oligomères de γ-amino acides hétérocycliques contraints, appelés ATCs (acides 4-Amino-(méthyl)-1,3-Thiazole-5-Carboxyliques), leur application en catalyse énamine et leur étude structurale. Les monomères d’ATC sont construits autour d’un noyau thiazole inséré entre les carbones Cα-Cβ, permettant de limiter la valeur de l’angle dièdre ζ à 0°. La présence de deux points de substitution, sur le carbone γ asymétrique et en position 2 du noyau aromatique, permet une large diversification structurale des ATCs. Ainsi, plusieurs séries d’oligomères ont été synthétisées par couplages peptidiques sur support solide. Une étude structurale de ces oligomères par RMN, IR-TF, cristallographie RX et dichroïsme circulaire a démontré qu’ils adoptaient une structure en helice C9, résultant d’un réseau de liaisons hydrogène de type COi---NHi+2 s’établissant tout au long de la séquence. L’objectif du projet présenté ici vise à étudier l’impact de la conformation des architectures développées, à la fois sur la sélectivité et sur l’induction asymétrique dans la réaction de nitro-Michael pour trois réactifs différents. Le dernier axe de ce travail a été de développer une méthode de modélisation sous contraintes RMN spécifique à la génération de modèles tridimentionel d’oligomères d’ATCsThe work described in this manuscript is devoted to the synthesis of heterocyclic constrained γ-amino acids, named ATCs (4-Amino-(methyl)-1,3-Thiazole-5-Carboxylic acids), their application in enamine catalysis and their structural study. ATC monomers are built around a thiazole ring providing a conformational limitation around the Cα and Cβ at 0°. The presence of two diversification points both on the γ asymmetric carbon and on the position 2 of the aromatic ring, allows a large structural diversification of the ATCs. Therefore, several oligomers were synthesized using solid phase peptide synthesis. A structural study of these oligomers, employing NMR, FTIR, circular dichroism and crystallography RX, demonstrated that they adopt a C9-right-handed helix stabilized by a hydrogen bond pattern between COi---NHi+2 along the helix. The objective of the project presented in this manuscript was the design and the structural characterization of molecular edifices with predictable folding properties and the systematic study of structure-function relationships in the nitro-Michael addition reaction, for three different substrates. Eventually, the last part of this work focused on the development of a new methodology, specific to ATC-oligomers, to perform 3D-modelling studies using NMR refinement
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Qian, Xinhua. "Topographical design of the message domain pharmacophore of the delta opioid agonists using designer amino acids and design of non-peptide ligand for opioid receptors." Diss., The University of Arizona, 1995. http://hdl.handle.net/10150/187062.
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A series of highly constrained tyrosine derivatives, 2',6'-dimethyl- β-methyltyrosines (TMTs), was designed and asymmetrically synthesized. Incorporation of the TMT isomers into peptide agonists of δ opioid receptors provide analogues that are highly potent and selectively for δ opioid receptors and have revealed the stereochemical requirements for recognizing opioid δ receptors. Moreover, the combination of conformational studies and pharmacological studies of the peptide analogues provided for the first time the stereochemical requirements for specifically recognizing opioid δ receptor subtypes. The biological active conformation of a highly selective and potent δ opioid agonist, ((2S,3R)-TMT¹) DPDPE, was obtained by NMR studies and computer-assisted modeling. This conformation was then further used for designing novel non-peptide opioid ligands. Thus, this study is another achievement of topographical design of peptide hormones and neurotransmitters. Practically, the results of this study can be used to develop more biological stable pharmaceuticals as strong pain reliever without causing side effects such as physical dependence, respiratory depression, etc.
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Tanner, Delia Caroline. "Over-expression, purification and biochemical characterization of DOXP reductoisomerase and the rational design of novel anti-malarial drugs." Thesis, Rhodes University, 2004. http://hdl.handle.net/10962/d1003990.
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Malaria poses the greatest threat of all parasites to human life. Current vaccines and efficacious drugs are available however their use is limited due to toxicity, emergence of drug resistance, and cost. The discovery of an alternative pathway of isoprenoid biosynthesis, the non-mevalonate pathway, within the malarial parasite has resulted in development of novel anti-malarial drugs. 1-Deoxy-D-xylulose-5-phosphate (DOXP) reductoisomerase, the second enzyme in this pathway, is responsible for the synthesis of 2-C-methyl-D-erythritol 4-phosphate (MEP) in an intramolecular rearrangement step followed by a reduction process involving NADPH as a hydrogen donor and divalent cations as co-factors. Fosmidomycin and FR900098 have been identified as inhibitors of DOXP reductoisomerase. However, they lack clinical efficacy. In this investigation recombinant DOXP reductoisomerase from Escherichia coli (EcDXR) and Plasmodium falciparum (pfDXR) were biochemically characterized as potential targets for inhibition. (His)6-EcDXR was successfully purified using nickel-chelate affinity chromatography with a specific activity of 1.77 μmoles/min/mg and Km value 282 μM. Utilizing multiple sequence alignment, previous structural data predictions and homology modeling approaches, critical active site amino acid residues were identified and their role in the catalytic activity investigated utilizing site-directed mutagenesis techniques. We have shown evidence that suggests that Trp212 and Met214 interact to maintain the active site architecture and hydrophobic interactions necessary for substrate binding, cofactor binding and enzyme activity. Replacement of Trp212 with Tyr, Phe, and Leu reduced specific activity relative to EcDXR. EcDXR(W212F) and EcDXR(W212Y) had an increased Km relative to EcDXR indicative of loss in affinity toward DOXP, whereas EcDXR(W212L) had a lower Km of ~8 μM indicative of increased affinity for DOXP. The W212L substitution possibly removed contacts necessary for full catalytic activity, but could be considered a non-disruptive substitution in that it maintained active site architecture sufficient for DOXP reductoisomerase activity. EcDXR(M214I) had 36-fold reduced enzyme activity relative to EcDXR, while its Km (~8 μM) was found to be lower than that of EcDXR. This suggested that the M214I substitution had maintained (perhaps improved) substrate and active site architecture, but may have perturbed interactions with NADPH. Rational drug design strategies and docking methods have been utilized in the development of furan derivatives as DOXP reductoisomerase inhibitors, and the synthesis of phosphorylated derivatives (5) and (6) has been achieved. Future inhibitor studies using these novel potential DOXP reductoisomerase inhibitors may lead to the development of effective anti-malarial drug candidates.
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Xiong, Chiyi. "Asymmetric synthesis of conformationally and topographically constrained amino acids as peptidomimetics: An approach to design and synthesis of opioid receptor selective ligands." Diss., The University of Arizona, 2003. http://hdl.handle.net/10150/280393.
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As part of continuing efforts to obtain backbone and side chain conformationally constrained, novel amino acids,¹⁻⁷ we have successfully developed the asymmetric synthesis of β-phenyl-substituted cysteine, tryptophan, and serene derivatives. In this approach, the key intermediate, enantiomerically pure 3-phenylaziridine-2-carboxylic ester, was prepared from an α, β-unsaturated ester by employing the Sharpless asymmetric dihydroxylation. The aziridine was treated with 4-methoxybenzylthiol, indole, and acetic acid to give β-phenyl-substituted cysteine, tryptophan, and serine, respectively, in a clean S(N)2 type ring opening at the C3 position. This methodology was readily extended to provide a general approach to the synthesis of optically pure anti- and syn-β-substituted cysteines. We also described an effective means to synthesize 8-phenyl-substituted thiaindolizidinone amino acids through a convergent strategy. β-Phenyl-substituted cysteine benzyl esters were prepared according to our new protocol developed above. The doubly protected glutamic acid gamma-aldehyde was prepared according to a known procedure. The key step was the condensation of the aldehyde with β-phenyl-substituted cysteines to afford novel 8-phenylthiaindolizidinone amino acids as epimers at the bridgehead, which can be readily separated. These novel 8-phenylthiaindolizidinone amino acids, which are constrained β-turn dipeptide mimetics, were incorporated into Leu-enkephalin peptides as a replacement of the dipeptide Gly³-Phe⁴ to afford individual isomers of Leu-enkephalin analogues. The conformationally restricted nature of these analogues rendered them amenable to conformational analysis in solution because they are less subject to dynamic averaging than are more the flexible linear compounds.
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Gu, Xuyuan. "The design and synthesis of novel amino acids and their usein synthesis of beta-turn mimetics and their incorporation into biological active peptides." Diss., The University of Arizona, 2003. http://hdl.handle.net/10150/289938.
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Peptide ligands represent the most important hormones and neurotransmitters in physiological processes. Although native biologically active peptides have a great potential for medical applications, they often need to be modified to overcome certain inherent problems. A new research area called peptidomimetics has been developed in the last twenty years. The first generation of β-turn mimetics was focused on mimicking the β-turn backbone. In the last decade, many types of bicyclic β-turn dipeptides (BTD) have been design and synthesized. However, these methods do not have straightforward ways to introduce side chain groups on both rings. The introduction of functionalities on BTD, as the second generation of β-turn mimetics, is the major goal of my dissertation. By retrosynthetic analysis, convergent synthetic methodologies were initiated for [5,5]- and [6,5]-BTDs. Two kinds of nonproteinous amino acids are required in the strategies. One is the β-substituted cysteine derivatives and the other is β-substituted ω-unsaturated amino acids. The racemic β-vinylphenylalanine was synthesized by using Kazmaier-Claisen rearrangement, and the ω-unsaturated amino acids and β-substituted δ,ε-unsaturated amino acids were synthesized by using Ni(II)-complexes as chiral auxiliaries. Using these starting materials, [5,5]-BTD analogues were synthesized by a five-step strategy. The synthesis of [6,5]-BTDs has to proceed without formation of the 5-membered hemiaminal, which blocks further reaction. A Nᵅ-TFA protection group was used in this strategy and finally an efficient methodology was developed to generate the side chain groups into [6,5]-BTD analogues in nine steps. During the development of these methods, we solved the challenge to synthesize all 16 or 32 of the possible diastereomeric dipeptide mimetics. A novel idea to solve these problems was to synthesize the targeted peptide mimetics by solid phase methods in a combinatorial fashion, as the third generation of β-turn mimetics. We have succeeded in the synthesis of [3,3,0]-BTD²,³-Leu-enkephalins by unconventional solid phase synthesis, and four analogues have been synthesized and purified. This method is ready to expand to other sizes of BTD and to other target peptides with different functionalities.
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Zhang, Wenyu. "Targeting HIV-1 RNAs with Medium Sized Branched Peptides Featuring Boron and Acridine-Branched Peptide Library Design, Synthesis, High-Throughput Screening and Validation." Diss., Virginia Tech, 2014. http://hdl.handle.net/10919/56731.
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RNAs have gained significant attention in recent years because they can fold into well-defined secondary or tertiary structures. These three dimensional architectures provide interfaces for specific RNA-RNA or RNA-protein interactions that are essential for biological processes in a living system. These discoveries greatly increased interest in RNA as a potential drug target for the treatment of diseases. Two of the most studied RNA based regulatory systems are HIV-1 trans-activating response element (TAR)/Tat replication pathway and Rev response element (RRE)/Rev export pathway. To efficiently target TAR and RRE RNA, we designed and synthesized three generations of branched peptide libraries that resulted in medium sized molecules.
The first generation of BPs were discovered from screening a one-bead one-compound library (4,096 compounds) against HIV-1 TAR RNA. One peptide FL4 displayed a binding affinity of 600 nM to TAR RNA, which is tighter than its native protein counterpart, Tat. Biophysical characterization of these BP demonstrated that "branches" in BPs impart multivalency, and they are cell permeable and non-toxic.
The second generation peptides were discovered from an on-bead high-throughput screening of a 3.3.4 branched peptide boronic acids (BPBAs) library that bind selectively to the tertiary structure of RRE IIB. The library comprised of 46,656 unique sequences. We demonstrate that our highest affinity BPBA (BPBA1) selectively binds RRE IIB in the presence of competitor tRNAs as well as against six RRE IIB structural variants. Further, we show that the boronic acid moieties afford a novel binding mode towards RNA that is tunable; their Lewis acidity has critical effects on binding affinity. In addition, biophysical characterizations provide evidence that "branching" in these peptides is a key structural motif for multivalent interactions with the target RNA. Finally, RNA footprinting studies revealed that the BPBA1 binding site encompasses a large surface area that spans both the upper stem as well as the internal loop regions of RRE IIB. BPBA1 is cell permeable and non-toxic.
In the next generation of branched peptides, a 3.3.4 branched peptide library composed of 4,096 unique sequences that featured boronic acid and acridine moieties was designed. We chose acridine as the amino acid side chain due to its potential for π-stacking interaction that provides high binding affinity to RNA target. The library was screened against HIV-1 RRE IIB RNA. Fifteen peptides were sequenced and four contained acridine alone and/or in conjunction with boronic acid moieties displayed dissociation constants lower than 100 nM. The ribonuclease protection assays of A7, a sequence that contains both boronic acid and acridine residues, showed a similar protection pattern compared to previous peptide BPBA1, suggesting that the 3.3.4 branched peptides shared similar structural elements and contacted comparable regions of the RRE IIB RNA.
The results from this research indicated that "branching" in peptides imparts multivalent interactions to the RNA, and that functional groups such as boronic acid and acridine are key structural features for efficient binding and selectivity for the folded RNA target. We demonstrated that the branched peptides are cell permeable and non-toxic.Ph. D.
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Cao, Haibo. "Protein Structure Recognition From Eigenvector Analysis to Structural Threading Method." Washington, D.C. : Oak Ridge, Tenn. : United States. Dept. of Energy. Office of Science ; distributed by the Office of Scientific and Technical Information, U.S. Dept. of Energy, 2003. http://www.osti.gov/servlets/purl/822060-2L2Xvm/native/.
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Thesis (Ph.D.); Submitted to Iowa State Univ., Ames, IA (US); 12 Dec 2003.Published through the Information Bridge: DOE Scientific and Technical Information. "IS-T 2028" Haibo Cao. 12/12/2003. Report is also available in paper and microfiche from NTIS.
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Keyari, Charles Mambo. "Glycosylating Enkephalins: Design, Glycosylation Using Sugar Acetates in the Preparation of Glycosyl Amino Acids for Glycopeptide Syntheses, Binding at the Opioid Receptors and Analgesic Effects." Diss., The University of Arizona, 2007. http://hdl.handle.net/10150/193652.
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Improved procedures for the glycosylation of serine and threonine utilizing Schiff base activation are reported. The procedures are less expensive and more efficient alternatives to previously published methods. The Schiff bases exhibited ring-chain tautomerism in CDCl₃ as shown by ¹H NMR. Acting as glycosyl acceptors, the Schiff bases reacted at RT with simple sugar peracetate donors with BF₃•OEt₂ promotion to provide the corresponding protected amino acid glycosides in good yields. With microwave irradiation, the reactions were complete in 2-5 minutes. Glycosylation with the dipeptide Schiff base shows the potential of this method in the preparation of peptide building blocks. To investigate this reaction further, direct glycosylation of sugar acetates with FMOC-Ser-OH/OBZl under BF₃•OEt₂ promotion in a microwave provided glycosides in high yield. In addition to the expected glycoside products acetylated side products resulting from acetate migration were isolated, suggesting that activation of the anomeric sugar acetates with a Lewis acid such BF₃•OEt₂ led to an oxocarbenium ion, which rearranged to a 1,2-dioxocarbenium ion because of the acetate participating group at C-2. Solvent participation was also illustrated with acetate migration being more pronounced when CH₃CN was used as a solvent and resulted in less product yield and higher amounts of the acetylated product. The acyl transfer products in these reactions where sugar acetates serve as glycosyl donors is reported for the first time, which also implies that ortho-ester like intermediates are important in the reaction mechanism. Keeping the message segment constant in the sequence H-Tyr-DThr-Gly-Phe-Leu- Ser-CO-NH₂ and modification of the address segment with different carbohydrate moieties had little effect on selectivity for binding at the μ, δ, or κ-opiod receptors. However, substitution of D-threonine with D-serine or the less polar D-alanine in the message segment resulted in a loss of κ-receptor affinity. Further replacement of D-threonine with the more hydrophobic D-valine resulted in complete loss of κ-binding affinity generating pure μ-δ agonists. These data suggests that changes in the message segment of the pharmacophore results in the glycopeptide adopting a conformation that is less favorable for -binding receptor activity. Finally, the peripheral administration and i.c.v. tests of the drugs suggest that modifications in the message segment of the pharmacophore influences the potency of these compounds.
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Liao, Subo 1963. "Design and synthesis of topographically constrained amino acids, and bioactive peptides for studies of ligand-receptor interaction, and for de novo design of delta-opioid selective non-peptide mimetics as potential therapeutics." Diss., The University of Arizona, 1997. http://hdl.handle.net/10150/282418.
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Topographical constraint is the most powerful approach for the design of bioactive peptides to explore the bioactive conformation of crucial side-chain pharmacophores of amino acid residues in peptide-receptor recognition and signal transduction. Novel topographically constrained amino acids β-isopropylphenylalanine and 2',6'-dimethyl-2,3-methanophenylalanine have been designed and synthesized. Incorporation of the four optically pure β-isopropylphenylalanine stereoisomers into deltorphin I produced four peptide analogues of [β-iPrPhe]Deltorphin I with differentiated bioactivities. The most potent and selective analogue, [(2S,3R)-β-iPrPhe]Deltorphin I showed an IC₅₀ nM binding affinity, and a 29000 fold selectivity for the δ-opioid receptor over the μ opioid receptor. Combined molecular modeling and NMR studies indicated that the (2S,3R)-β-iPrPhe³ residue in the analogue favors the trans rotamer, and can induce the linear peptide to form a low-energy folded conformation which was proposed as the bioactive conformation for the δ-opioid receptor. Coupling four optically pure, conformationally constrained β-methyl-2',6'-dimethyltyrosine (TMT) with L-Tic formed four dipeptide analogues of TMT-L-Tic. The most potent and selective analogue, (2S,3R)-TMT-L-Tic showed 9 nM binding affinity and 4000 fold selectivity to the δ vs μ opioid receptor. The lowest-energy conformation of (2S,3R)-TMT-L-Tic was suggested to be the bioactive one in which TMT side chain is trans and Tic side chain is in a gauche (+) conformation. Bicyclic oxytocin antagonist [dPen¹, cyclo(Glu⁴ Lys⁸)]OT (BC-OT) (pA₂ = 8.10) is an excellent template to examine further topographical ideas. Substitution of Tyr² with the topographically constrained para-methoxy-β-methyl-2',6'-dimethyltyrosine (p-MeOTMT) amino acids produced two very potent antagonists [(2S,3S)-p-MeOTMT²]BC-OT (pA₂ = 8.26) and [(2R,3R)-p-MeOTMT²]BC-OT(pA₂ = 7.80), and two inactive analogues [(2S,3R)-p-MeOTMT²]BC-OT and [(2R,3S)-p-MeOTMT²]BC-OT. These interesting results can be attributed to the biased side-chain conformation, gauche(+) and gauche(-) in (2S,3S)-p-MeOTMT and (2R,3R)-p-MeOTMT respectively, and trans in both (2S,3R)-p-MeOTMT and (2R,3S)-p-MeOTMT residues. Rational design of non-peptide mimetics from peptide leads is still elusive. Based on the δ-opioid selective lead [(2S,3R)-TMT¹]DPDPE and SAR of δ-opioid selective ligands, the first generation of non-peptide mimetics have been designed and synthesized. The new lead SL-3111 showed binding affinity IC₅₀ = 8 nM, and over 2000 fold selectivity for the δ-opioid receptor over the μ receptor.
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Wan, Yang. "Synthesis of β,γ-diamino acids and their use to design new analogues of the antimicrobial peptide Gramicidin Septide antimicrobien, la Gramicidine S." Thesis, Université Paris-Saclay (ComUE), 2017. http://www.theses.fr/2017SACLS407/document.
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Dans notre groupe, nous nous intéressons au développement de peptides contenant des acides γ-aminés. Comme d’autres peptides contenant des acides aminés non naturels, ils ont montré leur capacité à posséder des conformations stables et/ou des propriétés biologiques intéressantes. De plus, ces peptides sont généralement résistant à la protéolyse. Dans l’objectif de synthétiser des acides -diaminés sous la forme d’un seul stéréoisomère, nous avons développé une voie de synthèse reposant sur une réaction de Blaise suivie d’une réduction diastéréosélective. En appliquant cette méthode, nous avons synthétisé des acides β,γ-diaminés dérivés de la D-phénylalanine et de l’acide L-glutamique. Le premier a été utilisé pour concevoir des analogues d’un peptide antimicrobien, la gramicidine S. Comparé à la molécule parent, les analogues ont montré une cytotoxicité beaucoup moins importante pour les cellules hôtes tout en conservant une activité antibactérienne intéressante. Cette étude nous a donné de meilleures connaissances pour développer d’autres analogues de la gramicidine S ainsi que d’autres peptides antimicrobiens. Nous avons également effectué de nombreuses optimisations pour synthétiser de façon efficace des acides β,γ-diaminés cycliques à partir de l’acide L-glutamique. Les oligomères incorporant ces acides β,γ-diaminés et des acides α-aminés ont montré un fort potentiel pour l’adoption de conformations stables. Ces études vont être poursuiviesIn our group, we are interested in developing peptides containing β,γ-diamino acids . Along with many other peptides containing unnatural amino acids, they have shown the ability to possess stable conformations and/or interesting biological activities. Moreover, those peptides are usually more resistant to proteolysis. In order to synthesize stereopure γ-amino acids, we have developed a synthetic route using Blaise reaction and subsequent diastereoselective reduction as key reactions. Through applying this method, we have synthesized β,γ-diamino acids derived from D-phenylalanine and L-glutamic acid. The former β,γ-diamino acid was used for designing antimicrobial peptide gramicidin S analogues. Compared with mother molecule, the analogues exerted much less host cell cytotoxicity while remaining interesting antibacterial activity. Meanwhile, it gave us more knowledge for further developing analogues of gramicidin S as well as other antimicrobial peptides. We also paid lots of effort to efficiently synthesize cyclic β,γ-diamino acids starting from L-glutamic acid. Interestingly, when oligomers incorporating this β,γ-diamino acids and α-amino acids, they have shown the potential to adopt stable conformations. The following studies will be continuously investigated
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Mozaffari, Saghar. "Amphiphilic Cell-Penetrating Hybrid Cyclic-Linear Peptides as a Drug Delivery System." Chapman University Digital Commons, 2019. https://digitalcommons.chapman.edu/pharmaceutical_sciences_dissertations/2.
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A number of cyclic peptides containing a positively charged ring composed of arginine residues attached to hydrophobic tail made of tryptophan residues through a lysine linker namely [R5K]W5, [R6K]W5, [R5K]W6, [R7K]W5, [R5K]W7, [R6K]W6, and [R7K]W7 were synthesized and evaluated as molecular transporters. The peptides were evaluated for their ability to deliver, fluorescence-labeled cell-impermeable negatively charged phosphopeptide (F′-GpYEEI), and fluorescent labeled anti-HIV drugs (F′-FTC and F′-d4T). The results indicated that the presence of positively charged arginine residues on the ring and hydrophobic tryptophan residues in a sequential linear outside the ring was an optimal approach to improve the intracellular uptake of cargo molecules through non-covalent interactions. Some of these peptides were also evaluated for their efficiency for intracellular delivery of siRNA to triple-negative breast cancer cell lines in the presence and absence of 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE). [R6K]W6 and [R5K]W5 were found to be very efficient in the delivery of siRNA. Furthermore, co-formulation of peptides with lipid DOPE significantly enhanced the efficiency of siRNA delivery compared to peptide alone. Silencing of kinesin spindle protein (KSP) and Janus kinase 2 (JAK2) was evaluated in MDA-MB-231 cells in the presence of the peptides. The addition of DOPE significantly enhanced the silencing efficiency for all selected peptides.
A chemotherapeutic drug, doxorubicin (Dox) was covalently conjugated to the cyclic peptide [R5K]W7A and linear peptide R5KW7A, and the biological activity was evaluated in cell-based assays. Comparative antiproliferative assays between covalently conjugated peptide-Dox and the corresponding noncovalent physical mixtures of the peptides and Dox were performed. The conjugation of Dox with cyclic [R5K]W7A-Dox exhibited similar antiproliferative activity compared to Dox alone after 72 h incubation time in all cancer cell lines, such as leukemia, ovarian and gastric cancer cells. However, [R5K]W7A-Dox significantly reduced the cell cytotoxicity in normal cell lines such as normal heart muscle and normal kidney cells after 72 h when compared with Dox alone. These results revealed that this cyclic peptide prodrug can be used as a potential candidate for the treatment of cancer cells with reduced side effects against normal cells in the body.
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Lesma, Jacopo. "β-Hairpin peptidomimetics as inhibitors of hIAPP amyloid protein aggregation : design, synthesis and evaluation Introducing sequential aza-amino acids units induces repeated ß-turns and helical conformations in peptides β-Hairpin peptide mimics decrease human Islet Amyloid Polypeptide (hIAPP) Aggregation." Thesis, université Paris-Saclay, 2020. http://www.theses.fr/2020UPASQ018.
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Le diabète de type 2 (DT2), qui compte plus de 400 millions de cas dans le monde, représente 90 % du nombre total de cas de diabète. T2D est une maladie dégénérative associée à la résistance à l’insuline et à la mort des β-cellules pancréatiques liées aux dépôts de la protéine amyloïde hIAPP (également appelée amyline), qui sont observés dans le pancréas de plus de 95 % des patients atteints de DT2. Les traitements actuellement disponibles sont symptomatiques et caractérisés soit par des effets secondaires significatifs, soit par un faible impact sur l’incidence des pathologies associées et la réduction de la mortalité. Ainsi, pour trouver un traitement étiologique contre DT2, le ciblage de hIAPP est devenu une stratégie prometteuse à explorer. À ce jour, peu de classes de composés ont été proposées pour inhiber le processus d’agrégation de hIAPP. Cependant, à notre connaissance, seuls de très rares exemples de β-hairpin acycliques ont été décrits. Puisque l’agrégation hIAPP est un processus très complexe et dynamique, nous avons émis l’hypothèse que desβ-hairpins flexibles pourraient mieux s’adapter aux différentes conformations de hIAPP formées au cours du processus d’agrégation. Notre conception a été basée sur différents β-turn flexibles constitué d’un motif pipéridino-pyrrolidine lié à deux bras différents inspirés de la séquence primaire du peptide hIAPP, avec un élément d’auto-reconnaissance peptidique (SRE) dérivé de la séquence amyloïdogène de hIAPP, et faisant face à une séquence de blocage peptidique ou peptidomimétique. Afin de confirmer la conformation en β-hairpin de nos inhibiteurs, la conformation de nos composés a été étudiée par RMN et dans quelques cas par une dynamique moléculaire. Ensuite, leur capacité à interférer avec le processus d’agrégation de hIAPP a été principalement évaluée par la spectroscopie de fluorescence à la thioflavine-T. Les composés les plus prometteurs de la série ont ensuite été étudiés par d’autres essais biophysiques comme la microscopie électronique à transmission (TEM), l’électrophorèse capillaire (CE) et l’IMS-MS. Les meilleurs composés de la série ont ensuite été étudiés pour déterminer leur capacité à réduire la toxicité du hIAPP sur les cellules pancréatiques INS-1 du rat.Ayant prouvé la possibilité de moduler le processus d’agrégation de hIAPP par des petits mimes de β-hairpins acycliques portant à la fois des bras peptidiques et peptidomimétiques, nous avons ensuite concentré notre attention sur le développement de β-hairpins fluorés qui, jusqu’à présent, n’ont jamais été explorés ni comme inhibiteurs d’agrégation hIAPP, ni, à notre connaissance, plus largement en chimie médicinale. La préparation de ces analogues fluorés avait le double objectif d’étudier comment le fluor, avec ses caractéristiques uniques, pouvait influencer à la fois l’activité et la conformation de nos inhibiteurs. En conclusion, les travaux présentés dans cette thèse fournissent des informations précieuses pour le développement de nouveaux mimes de β-hairpins acycliques comme modulateurs de hIAPP et potentiellement comme nouveaux outils fluorés pour approfondir son processus d’agrégationType 2 Diabetes (T2D) with over 400 million cases worldwide represents 90% of total diabetes cases. T2D is a degenerative disease associated with insulin resistance and pancreatic β-cells death linked to deposits of the amyloid protein hIAPP (also called amylin), that are observed in the pancreas of over 95% of the T2D patients. The treatments currently available are symptomatic and characterized either by significant side effects or low impact on the incidence of related pathologies and mortality reduction. Thus, to find an etiological treatment for T2D, targeting hIAPP has become a promising strategy to explore. To date, few classes of compounds have been proposed to inhibit hIAPP aggregation process. However, to the best of our knowledge, only very scarce examples of acyclic β-hairpin have been described. Since hIAPP aggregation is a highly complex and dynamic process, we hypothesized that flexible β-hairpins could better adapt to different hIAPP conformations formed during the aggregation process. Our design was based on flexible piperidine pyrrolidine β-turn inducers linked to two different arms inspired by the primary sequence of hIAPP peptide, with a peptidic self-recognition element (SRE) derived from the hIAPP amyloidogenic sequence facing to a peptidic or peptidomimetic blocking sequence. In order to confirm β-hairpin conformation of our inhibitors, our compounds were conformationally studied by NMR and in few cases by molecular dynamics. Then, their ability to interfere with hIAPP aggregation process was primarily evaluated by thioflavin-T fluorescence spectroscopy. The most promising compounds of the series were then investigated by other biophysical assays such as transmission electron microscopy (TEM), capillary electrophoresis (CE) and IMS-MS. The best compounds of the series were then studied to determine their ability to reduce hIAPP toxicity on rat INS-1 pancreatic cells.Having proved the possibility to modulate hIAPP aggregation process employing small acyclic β-hairpin mimics bearing both peptidic and peptidomimetic arms, we then focused our attention on the development of fluorinated hairpin peptidomimetics that, until now, have never been explored either as hIAPP aggregation inhibitors, nor, to our knowledge, more broadly in medicinal chemistry. The preparation of these fluorinated analogues had the double scope to investigate how fluorine, with its unique characteristics, could influence both the activity and the conformations of our inhibitors. In conclusion, the work presented in this thesis provides valuable insight for the development of new acyclic β-hairpin mimics as modulators of hIAPP and potentially new fluorinated tools to further investigate its aggregation process
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Tang, Xue-jun. "Asymmetric synthesis of stereochemically-defined and conformationally-constrained novel amino acids via direct alkylation of chiral nickel(II)-coordinated Schiff bases of glycine and alanine, and design and synthesis of selective peptide and non-peptide ligands for the delta-opioid receptor." Diss., The University of Arizona, 2002. http://hdl.handle.net/10150/279911.
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A systematic practical method to prepare highly chi (χ)-constrained amino acids has been developed. It was found that increasing the size of R¹ (see figure) from H to Me to Et to n-Pr led to decreased reactivity of the starting complexes. In the case of R¹ as i-Pr, no alkylation was observed. With an increase of the size of R² from H to Me to Et to i-Bu, the reactivities of the alkyl bromides decreased. The starting Schiff bases had more effective stereocontrol at the α-carbon center than at the β-carbon center. The starting Schiff bases showed differential reactivity toward the racemic electrophile (kinetic resolution). Satisfactory differentiations were obtained at room temperature which makes this method synthetically useful. In the case of R¹ as H (NiGlyBPB), the thermodynamically-controlled stereoselectivity of alkylation was as high as 30:1. [DIAGRAM OMITTED]* A series of dipeptide analogues (TMT-Tic and DMT-Tic) were designed and synthesized to mimic the potent and highly selective delta-opioid receptor pentapeptide ligand-[(2S,3R)TMT¹]-DPDPE and thus to explore the topographical requirements for recognition of ligands at the opioid receptor through bioassays and NMR studies to facilitate the design of non-peptide compounds to be used as therapeutic agents for pain. (2S,3R)-TMT-L-Tic was found to have best binding affinities at the δ-opioid receptor in TMT-Tic series. In preliminary NMR studies, it was found that these designed peptide ligands have their own distinct conformations in the aqueous media. Meanwhile some modified non-peptide analogues of SL-3111 were prepared to continue our efforts to find effective non-peptide ligands for the δ-opioid receptor. More systematic studies are still ongoing using NMR and computational methods. *Please refer to dissertation for diagram.
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Duggan, Heather Mary Ellen. "Design and synthesis of bicyclic beta-turn mimetics." Thesis, University of Sussex, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.249079.
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Kyne, Graham M. "Rational design and synthesis of receptors for carboxylates." Thesis, University of Southampton, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.326397.
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Mutthamsetty, Vinay. "Design and Synthesis of Amino Acid-based Inhibitors Against Key Enzymes." University of Toledo / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1513014525316672.
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Tan, Christopher Y. K. "Rational design and synthesis of ß-amino acid analogues as antiepileptogenic agents." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape3/PQDD_0012/NQ59537.pdf.
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Zhang, Hui. "Design and synthesis of novel prodrugs to modulate GABA receptors in cancer." Thesis, Edinburgh Napier University, 2017. http://researchrepository.napier.ac.uk/Output/978678.
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GABA (gamma-amino butanoic acid) is the main inhibitory neurotransmitter in the mammalian central nervous system. GABA has been found to play an inhibitory role in some cancers, including colon carcinoma, cholangiocarcinoma, and lung adenocarcinoma. Growing evidence shows that GABAB receptors are involved in tumour development. The expression level of GABAB receptors was found to be upregulated in some human tumours, including the pancreas, and cancer cell lines, suggesting that GABAB receptors may be potential targets for cancer therapy and diagnosis. In this research programme, several diverse series of potential anticancer prodrugs of GABA and GABA receptor-targeting agents have been rationally designed and synthesised for selective activation in the tumour microenvironment. In one approach, a series of oligopeptide conjugate prodrugs have been synthesised as protease-activatable substrates for either the extracellular matrix metalloproteinase MMP-9 or the lysosomal endoprotease legumain; each of which are overexpressed in the tumour environment and are effectors of tumour growth and metastasis. Specifically, a novel fluorogenic, oligopeptide FRET substrate prodrug of legumain HZ101 (Rho-Pro-Ala-Asn~GABA-spacer-AQ) has been characterised and shown to have theranostic potential. Proof of principle has been demonstrated using recombinant human legumain for which HZ101 is an efficient substrate and is latently quenched until cleaved. HPLC methods have been developed to monitor prodrug activation. In another approach, cyclic prodrugs of the GABA-B receptor agonist baclofen have been designed to be activated in the acidic environment of solid tumours to exert antitumour effects through modulation of the receptor response. During the oligopeptide synthetic work, novel, coloured, anthraquinone-based reagents have been designed and evaluated as new chemical tools for amine detection and monitoring in solid phase peptide synthesis (SPPS); characterisation by spectroscopic and HPLC methods have demonstrated their advantages over existing methods and their potential applications for use on solid supported resins.
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Stennett, Bethany Ann. "Novel Therapy for Nicotine Addiction in Alcohol Dependent Rats." UNF Digital Commons, 2013. http://digitalcommons.unf.edu/etd/465.
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The co-dependence of nicotine and alcohol addiction occurs at high rates, complicates treatment, and is often associated with significant morbidity and mortality. Treatment options of alcohol and tobacco co-dependence are limited. Currently, there are drugs available for nicotine dependence or alcohol dependence. However, there are no therapeutic drugs available on the market for the co-dependence of nicotine and alcohol. Therefore, and important opportunity of new therapeutic options and drug development has presented itself. NT69L, a non-selective neurotensin (NT) agonist, provides a potential novel therapy for nicotine addiction in alcoholics by interacting with the common neurotransmitter circuits supporting the rewarding process for both nicotine and alcohol. Considering the behavioral effects of NT69L in attenuating nicotine self-administration in rats and alcohol consumption in mice, the present study was designed to assess the effects of NT69L as a new drug. NT69L was used in the treatment of nicotine addiction in an animal model of alcoholics and in attempts to attenuate withdrawal signs associated with nicotine and alcohol dependence. Wistar rats pre-exposed to alcohol vapor or air were allowed to self-infuse nicotine (0.03mg/kg/infusion) or saline. When the rats reached a stable level of responding, the effect of pretreatment with NT69L (1mg/kg i.p.) on the reinforcing effect of nicotine was determined. Animals self-infused nicotine at a significantly (p < .05) higher rate compared to saline in both air and alcohol vapor exposed groups. Acute pretreatment with a single injection of NT69L significantly (p < .05) reduced nicotine self-infusion in both the alcohol vapor and the air exposed groups for 5 days post-injection. Additionally, NT69L attenuated the alcohol- and nicotine-induced withdrawal signs associated with the discontinuation of alcohol and nicotine administration. Neurotensin agonist, NT69L, may represent a potential novel therapy to treat the co-addiction of alcohol and nicotine.
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Litten, J. Christopher. "The design, synthesis and protease inhibitor properties of latent reactive amino acid analogues." Thesis, University of Canterbury. Chemistry, 1992. http://hdl.handle.net/10092/7300.
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This thesis examines the synthesis and proteolytic properties of a new class of latent reactive amino acid analogue, eg: 1-(N-Phthaloyl-Lphenylalanyl)-2-hydroxymethylpyrrole 2.52, designed to inhibit serine proteases and the HN protease.
Chapter One discusses the possible mode of protease inhibition by these derivatives. The substrate specificity of chymotrypsin, and HN -1 protease suggests that the pyrrole occupies the P₁’ subsite, and the N-acyl group the P₁ subsite. Acceptance into the active site, and subsequent cleavage of the amide bond releases the highly reactive 1-azafulvene 1.3 that can alkylate an active site nucleophilic residue.
Chapter Two presents procedures for the N-acylation of pyrrole derivatives. Pyrrole-2-carboxaldehyde was successfully N-acylated with non-amino acid acylating agents using either, NaH, MeLi, or BuLi. A new mild procedure was developed for the N-acylation of pyrroles using a DMAP/organic base combination. The DMAP/organic base (TEA or Hünigs base) methodology was extended to the N-acylation of pyrrole-2-carboxaldehyde with N-Pth protected amino acid acid chlorides. The subsequent reduction of the N-acylated formyl pyrrole, 1-(N-Phthaloyl-L-phenylalanyl)-2-formylpyrrole 2.37, with Zn(BH₄)₂ produced high yields of the N-acylated hydroxymethyl pyrrole 2.52. A ¹H NMR analysis of the camphanate prepared from 2.37 demonstrated that racemisation had not occurred. A detailed ¹H and ¹³C NMR spectral analysis of the formyl and hydroxymethyl pyrroles is discussed in this chapter.
Chapter Three extends the synthesis to incorporate potential hydrogen bonding sites in the Px’ sub site direction. The imine N-(2-Pyrrolylmethylene)-L-alanine Ethyl Ester 3.12 was prepared from pyrrole-2-carboxaldehyde, by reaction with H₂N-Ala-OEt and pyrrole-2-carboxaldehyde with removal of water. The analogous imine formation using the N-acylated formyl pyrrole 1-(3-Phenylpropionyl)-2-formylpyrrole 2.31 produced high yields of the non-acylated imine 3.12. The N-acylation of 3.12 under the DMAP/Hünigs base conditions using hydroclnnamoyl chloride did not proceed.
Esterification of the hydroxymethyl pyrrole 2.52 under Mitsunobu conditions with the dipeptide N-Cbz-Val-Val-OH produced the tetrapeptide, N-benzyloxycarbonyl-L-valinyl-L-valine-l-(Nphthaloyl-L-phenylalanyl)pyrrol-2-ylmethyl Ester 3.39.
Chapter Four presents a hydrolysis and mechanistic study on the deacylation of 1-(3-Phenylpropionyl)-2-hydroxymethylpyrrole 2.32 with HO-. The deacylation of 2.32 in CD₃CN, containing one equivalent of KOH, produced 2-(3-Phenylpropionyl)-2-methylpyrrole Ester 4.5. This species was shown to form via an intramolecular mechanism. Chiral, deuterium labelling of the methylene position showed that racemisation at this position had not occurred in the formation of 4.5. An azafulvene intermediate is therefore precluded. A kinetic analysis of the subsequent conversion of 4.5 to 2-Butylaminomethylpyrrole 4.6, in the presence of n-butylamine, showed the reaction to be first order with respect to HO-.
The hydrolysis of deuterium labelled [6-d₁]-(6S)-1-(N-Phthaloyl-L-leucyl)-2-hydroxymethylpyrrole 4.14 with HO- in CD₃CN, gave the corresponding O-acetylated pyrrole 4.9 without racemisation. The addition of (S)-(+)-sec-butylamine to the reaction, trapped the azafulvene as [6-d₁]-(8S)-(+)-2-(1-methylpropionylamino)methylpyrrole 4.36.N-acylation was also shown to suppress azafulvene chemistry and therefore increase the stability of the hydroxymethyl pyrrole system. The camphanate from [6-d₁]-(6S)-1-(3-Phenylpropionyl)-2-hydroxy methylpyrrole 4.10 formed under the Mitsunobu conditions proceeded with 62% inversion of configuration of the methylene position.
Chapter Five deals with the α-chymotrypsin and HN-1 protease inhibitor properties of the pyrrole derivatives 2.32, 2.52, 1-(NPhthaloyl-D-phenylalanyl)-2-hydroxymethylpyrrole 2.55, 3.39, 1-(Undecyl)-2-hydroxymethylpyrrole 3.53 and 1-((5-Methoxycarbonyl)hexanyl)-2-hydroxymethylpyrrole 3.55. These compounds were found to be modest inhibitors of α-chymotrypsin, but poor inhibitors of HIV-1 protease. The stability of the hydroxymethyl pyrrole 2.52 was shown to be low under the HN protease assay conditions. A discussion on molecular modelling and docking the proposed inhibitors into the active site of HIV-1 protease is presented.
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Richmond, Meaghan L. "The design, synthesis, and application of new amino acid-based modular N-ethylenediamine ligands /." View online version; access limited to Brown University users, 2005. http://wwwlib.umi.com/dissertations/fullcit/3174664.
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Greenwood, Jeremy Robert. "Pyridazinediones and amino acid receptors: theoretical studies, design, synthesis, and evaluation of novel analogues." University of Sydney, Department of Pharmacology, 1999. http://hdl.handle.net/2123/394.
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http://www.pharmacol.usyd.edu.au/thesis This thesis is primarily concerned with a class of chemical compounds known as pyridazinediones, being 6-membered aromatic rings containing two adjacent nitrogen atoms (pyridazine), doubly substituted with oxygen. In particular, the work focuses on pyridazine-3,6-diones, derivatives of maleic hydrazide (1). Understanding of the chemistry of these compounds is extended, using theoretical and synthetic techniques. This thesis is also concerned with two very important classes of receptors which bind amino acids in the brain: firstly, the inhibitory GABA receptor, which binds g-aminobutyric acid (GABA) (2) in vivo, and for which muscimol (3) is an agonist of the GABAA subclass; secondly, Excitatory Amino Acid (EAA) receptors, which bind glutamate (4) in vivo, and in particular the AMPA subclass, for which (S)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) (5) is an agonist. The connection between pyridazinediones and amino acid receptors is the design, synthesis, and evaluation of structures based on pyridazinediones as potential GABA and EAA receptor ligands. Techniques of theoretical chemistry, molecular modelling, synthetic chemistry, and in vitro pharmacology are used to explore pyridazine-3,6-dione derivatives as ligands.
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Zhang, Deqiang Roberts Richard W. Goddard William A. "Structure-based design of mutant proteins : I. Molecular docking studies of amino acid binding to wild-type aminoacyl-tRNA synthetases. II. Structure-based design of mutant aminoacyl-tRNA synthetases for non-natural amino acid incorporation /." Diss., Pasadena, Calif. : California Institute of Technology, 2003. http://resolver.caltech.edu/CaltechETD:etd-12182002-190040.
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