Dissertations / Theses on the topic 'Conformational constraint'
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Tucker-Kellogg, Lisa 1969. "Systematic conformational search with constraint satisfaction." Thesis, Massachusetts Institute of Technology, 2002. http://hdl.handle.net/1721.1/8081.
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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Electrical Engineering and Computer Science, 2002.Includes bibliographical references (p. 170-177).
Determining the conformations of biological molecules is a high scientific priority for biochemists and for the pharmaceutical industry. This thesis describes a systematic method for conformational search, an application of the method to determining the structure of the formyl-Met-Leu-Phe-OH (fMLF)peptide by solid-state NMR spectroscopy, and a separate project to determine the structure of a protein-DNA complex by X-ray crystallography. The purpose of the systematic search method is to enumerate all conformations of a molecule (at a given level of torsion angle resolution) that satisfy a set of local geometric constraints. Constraints would typically come from NMR experiments, but applications such as docking or homology modelling could also give rise to similar constraints. The molecule to be searched is partitioned into small subchains so that the set of possible conformations for the whole molecule may be constructed by merging the feasible conformations for the parts. However, instead of using a binary tree for straightforward divide-and-conquer, four innovations are introduced: (1) OMNIMERGE searches a subproblem for every possible subchain of the molecule. Searching every subchain provides the advantage that every possible merge is available; by choosing the most favorable merge for each subchain, the bottleneck subchain(s) and therefore the whole search may be completed more efficiently. (2) A cost function evaluates alternative divide-and-conquer trees, provided that a preliminary OMNIMERGE search of the molecule has been completed. Then dynamic programming determines the optimal partitioning or "merge-tree" for the molecule; this merge-tree can be used to improve the efficiency of future searches.
(cont.) (3) PROPAGATION shares information by enforcing arc consistency between the solution sets of overlapping subchains. By filtering the solution set of each subchain, infeasible conformations are discarded rapidly. (4) An A* function prioritizes each subchain based on estimated future costs. Subchains with sufficiently low priority can be skipped, which improves efficiency. A common theme of these four ideas is to make good choices about how to break the large search problem into lower-dimensional subproblems. These novel algorithms were implemented and the effectiveness of each is demonstrated on a well-constrained peptide with 40 degrees of freedom.
by Lisa Tucker-Kellogg.
Ph.D.
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Lin, Ying. "Design and synthesis of conformationally constrained glucagon analogues to study the conformational features important for glucagon bioactivity." Diss., The University of Arizona, 1993. http://hdl.handle.net/10150/186227.
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We have synthesized ten glucagon analogues that are either conformationally constrained systematically in the middle portion of the molecule, or modified from the known superagonist analogue [Lys¹⁷,¹⁸, Glu²¹]glucagon to study the structure-activity relationships of glucagon. The analogues were prepared using the solid-phase peptide synthesis method. Cyclizations were accomplished by forming the side chain lactam (amide) bridges on the resin. All peptide analogues were cleaved from the solid support, deprotected by the low-high HF procedure, and purified by a combination of gel filtration chromatography and dialysis followed by reverse-phase high performance liquid chromatography. A new characterization method for cyclic glucagon analogues using fast atom bombardment mass spectrometry with endoproteinase Asp-N peptide mapping has been developed that has provided unequivocal confirmation of the presence and site of the rings as well as the amino acid compositions. Receptor binding and adenylate cyclase activity assays and circular dichroism spectroscopy have been used to reveal the role of the structure and conformation of the middle portion of the molecule. The effects of the modification of the 17, 18 and 21 positions on the superagonist activity have also been examined. Several key features of the peptide backbone conformation responsible for binding and transduction have been further studied by theoretical calculations and computer modeling (energy minimization) using the Sybyl program.
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Derrer, Sam. "Medium ring lactams as peptide conformational constraints." Thesis, University of Cambridge, 1998. https://www.repository.cam.ac.uk/handle/1810/251637.
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Wacowich-Sgarbi, Shirley Ann. "Synthesis and conformational studies of constrained oligosaccharides." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape2/PQDD_0013/NQ60036.pdf.
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Harris, Lawrence Daniel. "Conformationally constrained amino acid analogues." Thesis, University of Oxford, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.526527.
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Li, Qing. "Conformationally Constrained Oligonucleotides for RNA Targeting." Doctoral thesis, Uppsala universitet, Kemisk biologi, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-179069.
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A short oligonucleotide sequence as in a single-stranded antisense oligo nucleotides (AON) or in double-stranded small interfering RNAs (siRNA) can modulate the gene expression by targeting against the cellular mRNA, which can be potentially exploited for therapeutic purposes in the treatment of different diseases. In order to improve the efficacy of oligonucleotide-based drugs, the problem of target affinity, nuclease stability and delivery needs to be addressed. Chemical modifications of oligonucleotides have been proved to be an effective strategy to counter some of these problems. In this thesis, chemical synthesis of conformationally constrained nucleosides such as 7′-Me-carba-LNA-A, -G, -MeC and -T as well as 6′, 7′-substituted α-L-carba-LNA-T (Papers I-III) was achieved through a key free-radical cyclization. 1D and 2D NMR techniques were employed to prove the formation of bicyclic ring system by free-radical ring closure as well as to identify the specific constrained conformations in sugar moieties. These sugar-locked nucleosides were transformed to the corresponding phosphoramidites and incorporated into antisense oligonucleotides in different sequences, to evaluate their physicochemical and biochemical properties for potential antisense-based therapeutic application. AONs modified with 7′-Me-carba-LNA analogues exhibited higher RNA affinities (plus 1-4°C/modification) (Papers I & III), but AONs containing α-L-carba-LNA analogues showed decreased affinities (minus 2-3°C/ modification) (Paper II) towards complementary RNA compared to the native counterpart. It has been demonstrated in Papers I-III that 7′-methyl substitution in α-L-carba-LNA caused the Tm drop due to a steric clash of the R-configured methyl group in the major groove of the duplex, whereas 7′-methyl group of carba-LNA locating in the minor groove of the duplex exerted no obviously negative effect on Tms, regardless of its orientation. Moreover, AONs containing 7′-Me-carba-LNA and α-L-carba-LNA derivatives were found to be nucleolytically more stable than native AONs, LNA modified AONs as well as α-L-LNA modified ones (Papers I-III). We also found in Paper II & III that the orientations of OH group in C6′ of α-L-carba-LNAs and methyl group in C7′ of 7′-Me-carba-LNAs can significantly influence the nuclease stabilities of modified AONs. It was proved that the methyl substitution in cLNAs which points towards the vicinal 3′-phosphate were more resistant to nuclease degradation than that caused by the methyl group pointing away from 3′-phosphate. Additionally, AONs modified with 7′-Me-carba-LNAs and α-L-carba-LNAs were found to elicit the RNase H mediated RNA degradation with comparable or higher rates (from 2-fold to 8-fold higher dependent upon the modification sites) as compared to the native counterpart. We also found that the cleavage patterns and rates by E. coli RNase H1 were highly dependent upon the modification sites in the AON sequences, regardless of the structural features of modifications (Papers II & III). Furthermore, we have shown that the modulations of Tms of AON/RNA duplexes are directly correlated with the aqueous solvation (Paper III).
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Reilly, Nicholas Anthony. "The synthesis of conformationally constrained peptide mimetics." Thesis, University of Liverpool, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.533934.
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Whitcombe, Nicole Jane. "The synthesis of conformationally constrained amino acids." Thesis, King's College London (University of London), 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.251584.
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Walke, Amol Ashok. "Synthetic approaches towards conformationally constrained amino acids." Thesis, Imperial College London, 2011. http://hdl.handle.net/10044/1/6887.
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This thesis describes research undertaken on the synthesis of conformationally constrained analogues of phenylalanine. The work is introduced by an overview of the significance of conformationally constrained amino acids in chemical biology. An example of how a potent and selective conformationally constrained tryptophan was designed and synthesized is provided. This section also reviews constrained phenylalanine analogues, detailing the influence of their constraints on their stereochemistry. The introductory Chapter ends with the description of an investigation into the use of a conformationally constrained phenylalanine analogue, Tic, in the development of potent bioactive peptides, and a discussion of the potential applications of higher homologues of Tic. The second Chapter commences with a short discussion about asymmetric synthesis and chiral resolution, followed by an example which illustrates these concepts. This is followed by a discussion on the work done in the modification and optimization of the Gibson synthesis of the amino acid Sic, which gave multigram quantities of this amino acid. Attempts to resolve racemic Sic were unsuccessful. The next Chapter begins with an introduction to aromatic C-H bond activation and a discussion of conventional Heck and oxidative Heck methodologies used in C-C bond formation. The syntheses of three novel cyclization substrates with varying degrees of electron densities in their aromatic rings are documented. Attempts to achieve intramolecular cyclization of these molecules via the Fujiwara addition method, the Gaunt oxidative Heck method and the Glorius oxidative Heck method, are described. The fourth Chapter introduces the concept of aromatic C-H bond activation via chelation assistance. A concise survey of different functional groups that are commonly used as ortho-directing groups via chelation with organometallic catalysts is presented along with an example that illustrates how this methodology has been used to synthesize potentially bioactive compounds. This is followed by a description of the synthesis of a new potential cyclization substrate with a ketone as a directing group. Attempts to achieve an intramolecular cyclization of this substrate using different [Ru] and [Rh] catalysts were unsuccessful. Chapter five begins with a brief summary of the use of gold catalysts for C-C bond formation via aromatic C-H activation. Four new substrates with potential for cyclization with varying degrees of electron densities in their aromatic rings were synthesized. Intramolecular cyclization of these substrates using Au(III) and Au(I) catalysts proved to be unsuccessful. Finally, Chapter six contains the experimental details that support the results described and discussed in Chapters 2-5.
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Zhao, Jielu. "Design, Syntheses and Biological Activities of Paclitaxel Analogs." Diss., Virginia Tech, 2011. http://hdl.handle.net/10919/77272.
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The conformation of paclitaxel in the bound state on the protein has been proposed to be the T-taxol conformation, and paclitaxel analogs constrained to the T-taxol conformation proved to be significantly more active than paclitaxel in both cytotoxicity and tubulin polymerization assays, thus validating the T-taxol conformation as the tubulin-binding conformation. In this work, eight compounds containing an aza-tricyclic moiety as a mimic of the baccatin core of paclitaxel have been designed and synthesized as water-soluble simplified paclitaxel analogs, among which 3.50-3.52 and 3.55 were conformationally constrained analogs designed to bind to the paclitaxel binding site of tubulin, based on their similarity to the T-taxol conformation. The open-chain analogs 3.41-3.43 and 3.57 and the bridged analogs 3.50-3.52 and 3.55 were evaluated for their antiproliferative activities against the A2780 cell lines. Analogs 3.50-3.52 and 3.55 which were designed to adopt the T-taxol conformation showed similar antiproliferative activities compared to their open-chain counterparts. They were all much less active than paclitaxel. In the second project, a series of paclitaxel analogs with various thio-containing linkers at C-2′ and C-7 positions were designed and synthesized in our lab. These analogs were attached to the surfaces of gold nanoparticles by CytImmune Sciences for the development of mutifunctional tumor-targeting agents. The native analogs and the gold bound analogs were evaluated for their antiproliferative activities against the A2780 cell line. All the compounds tested showed comparable or better activities than paclitaxel. Stability studies were performed for selected analogs in hydrolysis buffer, which showed that the analogs released paclitaxel in buffer over time. In the third project, the synthesis of a conformationally constrained paclitaxel analog which was designed to mimic the REDOR-taxol conformation was attempted. Two synthetic routes were tried and significant progress was made toward the synthesis of the conformationally constrained analog. However, both of the current synthetic routes failed to produce the key intermediate that would serve as the precursor for a ring-closing metathesis reaction to furnish the macrocyclic ring.Ph. D.
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HILL, PATRICIA ANNE SCHROEDER. "CONFORMATIONALLY CONSTRAINED ANALOGUES OF THE NEUROHYPOPHYSEAL HORMONE OXYTOCIN." Diss., The University of Arizona, 1986. http://hdl.handle.net/10150/183863.
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The synthesis of seventeen novel conformationally constrained analogues of the neurohypophyseal peptide hormone oxytocin is described. Synthesis of the peptides was accomplished using solid-phase synthesis techniques on either Merrifield or p-methyl-benzhydrylamine resin. Cleavage of peptides from the solid support and deprotection were carried out by either ammonolysis followed by treatment with sodium in liquid ammonia or anhydrous HF. Disulfide formation was accomplished by treatment of the deprotected peptide with aqueous potassium ferricyanide. Purification of the peptide analogues involved a combination of either partition and/or size exclusion chromatography followed by reverse-phase high-performance liquid chromatography. Several conformationally constrained unnatural amino acids were incorporated into the synthetic peptides. Two were prepared and incorporated as a mixture of isomers and the resulting peptides were separated and purified by HPLC. The types of analogues prepared fall into three categories: analogues incorporating conformational restrictions in positions 1 and 2; bicyclic oxytocin peptides; oxytocin antagonists with changes at the Asn⁵ residue. The peptides with conformational restrictions at position 1 or 2 are: [Tic²]OT, [DTic²]OT, [DTic²,Thr⁴]OT, [β-MePhe²]OT, [ΔPhe²]OT, [Cys(CH₂)₅¹,Phe²,Thr⁴,Orn⁸]OT and [Pen¹,DPhe²,Thr⁴,Orn⁸]OT. Bicyclic peptide analogues and their monocyclic precursors include: [Mpa¹,Lys⁴,Glu⁵]OT, [Mpa¹,Lys⁴,Glu⁵]OT, [Mpa¹,Glu⁴,Lys⁸]OT, and [Mpa¹,Glu⁴,Lys⁸]OT. Antagonists with changes in the Asn⁵ residue are: [Pen¹,DPhe²,Thr⁴,Thr⁵,Orn⁸]OT; [Pen¹,DPhe²,Thr⁴,Leu⁵,Orn⁸]OT; [Pen¹,DPhe²,Thr⁴,Asp⁵,Orn⁸]OT; and [Pen¹,DPhe²,Thr⁴,Tyr⁵,Orn⁸]OT. Biological assays of these analogues for oxytocic activity in the rat uterus model have shown one of the β-MePhe²-containing peptides, [L-threo-β-MePhe²]OT, to be a very potent agonist and one bicyclic, [Mpa¹,Glu⁴,Lys⁸]OT to be an extremely potent oxytocin antagonist. Initial biophysical investigations employing 250 MHz nuclear magnetic resonance spectroscopy were also undertaken in order to determine possible solution conformations of these peptide analogues.
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Flores, Ortega Alejandra. "Conformational properties of constrained proline analogues and their application in nanobiology." Doctoral thesis, Universitat Politècnica de Catalunya, 2009. http://hdl.handle.net/10803/6477.
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This thesis is composed of two parts:We have used different computer simulation techniques to investigate the impact of different chemical modifications on the conformational preferences of proline and to examine the application of conformationally constrained proline analogues in Nanobiology.
Specifically, the first part shows the conformational study of proline derivatives that were obtained by introducing one or more double bonds in the pyrrolidine ring, by replacing the α-hydrogen atom by an alkyl group or by incorporating a polar substituent at the β- or γ-position of the pyrrolidine ring. These conformational investigations were performed using Quantum Mechanical calculations at the DFT (Density Functional Theory) levels. Furthermore, the influence of the solvent on the preferences of the different proline derivatives was examined using the Polarizable Continuum Model (PCM).
The second part of the work consists on the design of a constrained proline derive able to protect a tumor-homing peptide from the attack of proteases but retaining, or even enhancing, its intrinsic biological activity. For this purpose, the bioactive conformation of the tumor-homing peptide was determined and characterized using a computational strategy based on the combination of Simulated Annealing combined with Molecular Dynamics. After this, the designed proline was derivative was introduced in the biological peptide using a targeted replacement strategy. The efficiency of the synthetic derivative was examined in silico using classical force-field simulations.
La presente Tesis consta de dos partes:
Se han empleado distintas técnicas de simulación computacional para investigar el efecto de diferentes modificaciones químicas en las preferencias conformacionales de las prolina, así como para examinar la aplicación de análogos de prolina conformacionalmente restringidos en Nanobiología.
Concretamente, la primera parte presenta el estudio conformacional de los derivados de la prolina que se obtienen al introducir uno o más enlaces dobles en el anillo de pirrolidona, al substituir el hidrógeno α por un grupo alquilo o al incorporar un grupo polar en la posición β ó γ del anillo de pirrolidona. Estos estudios conformacionales se desarrollaron mediante métodos mecano-cuánticos basados en la Teoría del Funcional de la Densidad (DFT). Además, el efecto del disolvente en las preferencias de los diferentes derivados de prolina se investigo empleado el método PCM (Polarizable Continuum Model).
La segunda parte del trabajo consistió en el diseño de un análogo de prolina capaz de proteger un péptido que actúa como marcador tumoral del ataque de las proteasas a la vez que retiene, o incluso mejora, su actividad biológica. Para conseguir esto, inicialmente se determinó y caracterizó la conformación bioactiva del péptido empleando una estrategia computacional basada en la combinación de templado simulado y Dinámica Molecular. A continuación el derivado de prolina diseñado se incorporó en una posición específica del péptido y la eficiencia del sistema resultante fue estudiada in silico usando simulaciones basadas en potenciales clásicos.
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Chuanzheng, Zhou. "Conformationally Constrained Nucleic Acids as Potential RNA Targeting Therapeutics." Doctoral thesis, Uppsala universitet, Bioorganisk kemi, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-113680.
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Jones, Jerome Oliver. "The synthesis and application of conformationally constrained amino acids." Thesis, King's College London (University of London), 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.392153.
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Chan, Lai Chun. "Synthesis of novel heterocyclic constraints as probes for peptide bioactive conformation." Thesis, University of Bath, 1992. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.303487.
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Honcharenko, Dmytro. "Conformationally Constrained Nucleosides, Nucleotides and Oligonucleotides : Design, Synthesis and Properties." Doctoral thesis, Uppsala universitet, Bioorganisk kemi, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-8887.
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This thesis is based on six original research publications describing synthesis, structure and physicochemical and biochemical analysis of chemically modified oligonucleotides (ONs) in terms of their potential diagnostic and therapeutic applications. Synthesis of two types of bicyclic conformationally constrained nucleosides, North-East locked 1',2'-azetidine and North locked 2',4'-aza-ENA, is described. Study of the molecular structures and dynamics of bicyclic nucleosides showed that depending upon the type of fused system they fall into two distinct categories with their respective internal dynamics and type of sugar conformation. The physicochemical properties of the nucleobases in the conformationally constrained nucleosides found to be depended on the site and ring-size of the fused system. The incorporation of azetidine modified nucleotide units into 15mer ONs lowered the affinity toward the complementary RNA. However, they performed better than previously reported isosequential 1',2'-oxetane modified analogues. Whereas aza-ENA-T modification incorporated into ONs significantly enhanced affinity to the complementary RNA. To evaluate the antisense potential of azetidine-T and aza-ENA-T modified ONs, they were subjected to RNase H promoted cleavage as well as tested towards nucleolytic degradation. Kinetic experiments showed that modified ONs recruit RNase H, however with lower enzyme efficiency due to decreased enzyme-substrate binding affinity, but with enhanced turnover number. Both, azetidine-T and aza-ENA-T modified ONs demonstrated improved 3'-exonuclease stability in the presence of snake venom phosphodiesterase and human serum compared to the unmodified sequence. Oligodeoxynucleotides (ODNs) containing pyrene-functionalized azetidine-T (Aze-pyr X) and aza-ENA-T (Aza-ENA-pyr Y) modifications showed different fluorescence properties. The X modified ODNs hybridized to the complementary DNA and RNA showed variable increase in the fluorescence intensity depending upon the nearest-neighbor at the 3'-end to X modification (dA > dG > dT > dC) with high fluorescence quantum yield. However, the Y modified ODNs showed a sensible enhancement of the fluorescence intensity only with complementary DNA. Also, the X modified ODN showed decrease (~37-fold) in the fluorescence intensity upon duplex formation with RNA containing a G nucleobase mismatch opposite to the modification site, whereas a ~3-fold increase was observed for the Y modified probe.
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Tusa, Girolamo. "Synthesis and biological activity of conformationally constrained nucleosides and nucleotides." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp01/MQ34032.pdf.
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Pugh, Darren Charles. "The synthesis of conformationally constrained peptides and novel assymetric catalysts." Thesis, King's College London (University of London), 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.401641.
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McCary, Jason Lee. "Thionucleic acids as covalent constraints of DNA conformation : methods and computationanl studies /." The Ohio State University, 2000. http://rave.ohiolink.edu/etdc/view?acc_num=osu1488195633521574.
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Tsuji, Hayato. "Syntheses and Photophysical Properties of Oligosilanes Conformationally Constrained by Methylene Tethers." 京都大学 (Kyoto University), 2001. http://hdl.handle.net/2433/150690.
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Varghese, Oommen P. "Conformationally Constrained Nucleosides : Design, Synthesis, and Biochemical Evaluation of Modified Antisense Oligonucleotides." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis, 2007. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-8266.
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Billson, Jeremy Paul. "The design, synthesis, and evaluation of some conformationally constrained matrix metalloprotease inhibitors." Thesis, University of Exeter, 1997. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.535965.
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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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McKiernan, Mary Joyce. "Synthesis and conformational studies of 2,3-,3,4- and β,β- cyclised chi constrained tryptophan mimetics." Thesis, University of Cambridge, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.624745.
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Davidson, James Prentice. "Calorimetric and structural studies of 1,2,3-trisubstituted cyclopropanes as conformationally constrained peptide mimics /." Full text (PDF) from UMI/Dissertation Abstracts International, 2001. http://wwwlib.umi.com/cr/utexas/fullcit?p3008309.
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Chien, Tran Van [Verfasser]. "Design, Synthesis and Biological Evaluation of Conformationally Constrained Helicokinin I Analogues / Tran Van Chien." Wuppertal : Universitätsbibliothek Wuppertal, 2014. http://d-nb.info/1065197195/34.
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Anderson, Kelly Helen. "The Synthesis and Surface Studies of β-Amino Acids & β-Peptides." Thesis, University of Canterbury. Chemistry, 2007. http://hdl.handle.net/10092/1441.
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This thesis examines the synthesis of conformationally constrained β-amino acids and β- peptides, and the electron transfer properties of the latter when immobilised on gold. Additionally, cross metathesis on gold was investigated as a method for surface functionalisation. Chapter One introduces the concepts of electron transfer in nature, how it is facilitated by the secondary structure in α-peptides, and why β-peptides might be useful for studying electron transfer. This is followed by a discussion of the properties of β-peptides, including the enhanced stability and variety of helical secondary structures and the greater potential for functionalisation of the peptide backbone when compared to α-peptides. Finally, the conformational constraints of ring-systems on cyclic amino acids is discussed, with reference to the stabilising effect of these compounds on peptide secondary structures. Chapter Two describes the electrochemical analysis of β-hexapeptides immobilised on gold. The chapter is prefaced by a discussion of the important electron transfer mechanisms for peptides, the fabrication of peptide-gold self-assembled monolayer (SAM) interfaces, and the electron transfer in helical α-peptides. β-Peptides containing an electroactive ferrocene moeity were immobilised on gold and studied using cyclic voltammetry and chronoamperometry. The latter method was used to examine the dependence of the electron transfer rate on overpotential, thereby determining the likely mode of electron transfer through the β-peptides SSβ₆Fc, Fcβ₆SS and SC₁₅β₆Fc. These peptides exhibited very weak dependence on overpotential, characteristic of electron transfer behaviour of an electron hopping mechanism (which is also thought to occur in helical α-peptides). Both the dipole moment of the peptides and the structure of the sulfurlinker group were found to be important in determining the rate of electron transfer. Conversely, the equivalent α-peptide SSα₆Fc exhibited electron transfer behaviour characteristic of the less efficient tunnelling mechanism, which is thought to operate in strand-like peptides. Chapter Three examines the application of cross metathesis, using a Grubbs' second generation catalyst, as a means to functionalise olefin-terminated self-assembled monolayers on gold. Abstract iv Firstly, an introduction into the limited published research on cross metathesis on both planar surfaces and nanoparticles is given. Olefin-terminated thiol 3.18, suitable for immobilisation on gold, and solution phase olefin-terminated ferrocene 3.10 were synthesised as reactants for cross metathesis studies. An analytical methodology was developed involving the cross metathesis of surface-immobilised 3.18 with ferrocene 3.10 in dichloromethane, whereby the concentration of electroactive cross metathesis product 3.22 was monitored electrochemically as a function of time. The concentration of surface-immobilised product 3.22 was determined by integration of the oxidation peak area and found to be highly dependent on both the concentration of immobilised olefin reactant 3.18 and reaction time. Furthermore, the surface concentration of ferrocenyl model disulfide 3.21 and thiol 2.18 decayed markedly upon addition of Grubb's catalyst, as revealed by the decrease in the oxidation peak area, which suggested that catalystmediated desorption was occurring. Chapter Four details the solution-phase synthesis of ferrocene- and thiol-functionalised β- hexapeptides used in both the electron transfer studies described in chapter two, and in the determination of secondary structure using circular dichroism and NMR techniques. The synthesis of simple model compounds 4.14, 4.16 and 4.18 established the incompatibility of the deprotection of methyl and benzyl ester protecting groups with protected-thiol and disulfide linkers, leading to the use of N-hydroxysuccinmide-activated sulfur-linkers 4.20 and 4.22 in further synthesis. A number of β-hexapeptides were synthesised by amide coupling of β- tripeptides functionalised at the N- and C-termini. Structural studies of the methanol soluble β- hexapeptide 4.60 suggested that the covalent attachment of ferrocene moeity to the C-terminus of a β-peptide did not disrupt the formation of a 14-helix in solution. β-peptides containing functionality at both the C- and N-termini (such as SSβ₆Fc, SSβ₆Et and acetyl-protected SC₁₅β₆Fc) were not suitable for solution phase structural studies; however, molecular modelling suggested that helical conformations are the most stable these β-peptides in solution phase. Chapter Five outlines the synthesis of novel cyclic β-amino acids by two different general synthetic routes. The first uses an efficient conjugate addition/fluorination reaction of α,β- unsaturated esters with lithiated chiral secondary amines to prepare the novel cyclopentyl- and cyclohexyl-based fluorinated β-amino acids 2.43a and 2.43b. The high diastereoselectivity of this reaction, which introduces two stereocentres into the achiral unsaturated esters, is directed by the configuration of the attacking amine. The second methodology utilizes the versatile ringclosing metathesis reaction in the synthesis of novel cyclic β-amino acids. A stereoselective Abstract v trans-alkylation of olefinic β-amino acids gave the required β-dienes 5.62 and 5.77. Optimised cyclisation yields were achieved with a Grubb's 2nd generation catalyst for diene 5.62 and Grubb's 1st generation catalyst for diene 5.77, to give the trans-cycloheptyl- and cyclooctylbased β-amino acids 5.63 and 5.78, respectively. The attempted synthesis of cyclononyl-based β-amino acid 5.87 using both catalysts yielded only cyclic dimer products 5.88 and 5.89. The trans configuration of the 5.62 diene was confirmed by x-ray crystallography. Chapter Six is an experimental chapter and outlines the electrochemical setup and analysis, and the synthesis, purification and characterisation of compounds described in this thesis.
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Lu, Yuanyuan. "Indolizidine and quinolizidine motifs for the synthesis of conformationally constrained smac mimetics and chloroquine conjugates." Doctoral thesis, Universitat Autònoma de Barcelona, 2014. http://hdl.handle.net/10803/283725.
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L’esquelet d’indolizidina o quinolizidina és present a molts productes naturals i sintètics, alguns del quals presenten activitats biològiques diverses. Aquesta tesi es centra en la preparació estereoselectiva de derivats quirals d’indolizidina i quinolizidina amb un doble propòsit: i) com a precursors de peptidomimètics d’Smac conformacionalment limitats i ii) per formar conjugats amb residus de cloroquina a la recerca de nous fàrmacs antimalàrics contra soques resistents.
Pel primer propòsit, s’ha aplicat una aproximació prèviament desenvolupada en el nostre grup per a la síntesi estèreo-controlada d’indolizidines i quinolizidines N-substituïdes. La primera etapa clau de la seqüència és l’al·lilació enantioselectiva de succinimida i glutarimida amb monòxid de butadiè racèmic catalitzada per pal·ladi, on la configuració absoluta del producte al·lilat ve marcada pel sentit de quiralitat del lligand del pal·ladi. Les etapes restants fins als azabicicles fusionats inclogueren la reducció regioselectiva de la imida, una al·lilació nucleòfila i una metàtesi de tancament d’anell (RCM). Eventualment, les configuracions dels intermedis i productes es varen establir mitjançant anàlisi per difracció de raigs X.
Posteriorment, aquesta estratègia es va estendre a substrats del tipus α-amino succinimida i glutarimida. Per a derivats d’indolizidina, la nova seqüència va partir de l’àcid L-aspàrtic, que es convertí en pocs passos en (3S)-3-amino-2,5-pirrolidinodiona. L’al·lilació asimètrica sobre aquest substrat va resultar satisfactòria, conduint a un únic estereoisòmer. S’aconseguí la reducció regioselectiva clau utilitzant DIBAL-H i l’al·lilació nucleòfila i RCM consecutives van portar a l’α-aminoindolizidina esperada, com a una barreja equilibrada de dos epímers, la configuració relativa dels quals es va establir mitjançant experiments de RMN, incloent espectres COSY i NOSY. Els estudis per a obtenir els peptidomimètics d’indolizidina s’estan desenvolupant actualment. Pels anàlegs de tipus α-aminoquinolizidina, es va explorar una seqüència paral·lela a partir de l’àcid L-glutàmic. Malauradament, l’al·lilació asimètrica no va portar al producte esperat i la substitució del lligand del pal·ladi per PPh3 no va resultar prou resolutiva. Els resultats d’alguns intents realitzats amb diferents grups protectors de l’àtom de nitrogen també van ser negatius i s’examinaran més detalladament en un futur.
Pel segon propòsit, es varen considerar dues aproximacions alternatives depenent del caràcter nucleòfil o electròfil de cada reactiu. A tal fi, es van preparar varis azabicicles i derivats de cloroquina nucleòfils i electròfils. Lamentablement, en les reaccions explorades fins ara, els conjugats esperats no van ser mai detectats.The indolizidine and quinolizidine framework is present in many natural and synthetic compounds, some of which display diverse bioactivities. This thesis focuses on the stereoselective preparation of chiral indolizidine and quinolizidine derivatives with a double purpose: i) as precursors of conformationally constrained Smac peptidomimetics and ii) to form conjugates with chloroquine residues, in the search for new antimalarial drugs against resistant strains. For the first purpose, it has been applied an approach previously developed in our group for the stereocontrolled synthesis of N-substituted indolizidines and quinolizidines. The first key step of the sequence is the palladium-catalyzed enantioselective allylation of succinimide and glutarimide with racemic butadiene monoxide, wherein the absolute configuration of the allylated products is controlled by the sense of chirality of the palladium ligand. The next steps to the fused azabicyclic compounds included regioselective reduction of the imide, followed by nucleophilic allylation and then ring closing metathesis (RCM). In the event, the configurations of the intermediates and products were established by X-ray diffraction analysis. This strategy was later on extended to α-amino succinimide and glutarimide substrates. The new sequence for the indolizidine derivatives started from L-aspartic acid, which was converted into a protected (3S)-3-amino-2,5-pyrrolidinedione in a few steps. The asymmetric allylation worked well on this substrate, providing a unique stereoisomer. The key regioselective reduction was achieved by using DIBAL-H, and the subsequent nucleophilic allylation and RCM furnished the expected α-aminoindolizidine as a balanced mixture of two epimers. Their relative and absolute configuration was inferred from NMR experiments, including COSY and NOESY spectra. The conversion of these intermediates into the targeted indolizidine peptidomimetics is currently in progress. For the α-aminoquinolizidine analogs, a parallel sequence starting from L-glutamic acid was explored. Unfortunately, in this case the asymmetric allylation did not furnish the expected product and the replacement of the palladium ligand by PPh3 showed limited assistance. Several attempts with a different nitrogen protection were also negative and will be re-examined in the future. For the second purpose, two alternative approaches were considered depending of the nucleophilic or electrophilic character of each reaction partner. With this aim, several nucleophilic and electrophilic azabicycles and chloroquine derivatives were prepared. Unluckily, in the different reactions explored up to now, the expected conjugate was never detected.
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Cates, Ryan S. "Influence of Crosslink Density on Swelling and Conformation of Surface-Constrained Poly(N-Isopropylacrylamide) Hydrogels." Scholar Commons, 2010. https://scholarcommons.usf.edu/etd/1592.
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A stimuli-responsive microgel is a three-dimensional polymer network that is able to absorb and expel a solvent (commonly water). These materials are unique in the fact that their sponge-like behavior can be actuated by environmental cues, like temperature, ion concentration, pH, and light. Because of the dynamic properties of these materials they have found applications in drug-delivery systems, micro-assays, selective filtration, artificial muscle, and non-fouling surfaces. The most well-known stimuli-responsive polymer is Poly(N-isopropylacrylamide) or PNIPAAm and it experiences a switchable swelling or deswelling over a critical temperature ( Tc=~32°C). Below the critical temperature, the gel begins mixing with the surrounding solvent and swells; above this temperature, the opposite is true. The unconstrained hydrogel will continue to swell in all directions until equilibrium is established between its propensity for mixing with the surrounding solvent and the elastic restoring forces of the gel matrix. The strength of the elastic restoring forces is dependent on the interconnectedness of the polymer network and is therefore a function of crosslink density. An increase in crosslink density results in a decreased swelling and vice versa. If the hydrogel is mechanically constrained to a surface, it can experience various wrinkling and buckling conformations upon swelling, as the stresses associated with its confinement are relieved. These conformation characteristics are a strong function of geometry (aspect ratio) and extent of swelling (i.e. crosslink density). In order to capitalize on the utility of this material, it is imperative that its volume transition is well characterized and understood.
Toward this end, pNIPAAm gels have been created with 1x10-7 to 2x10-³ mol/cm³ crosslink density and characterized. This was done by first examining its bulk, unattached swelling ability and then by evaluating its microscale properties as a surfaceconfined monolithe. The latter was achieved through the use of confocal microscopy and copolymerization with a fluorescent monomer. This method allows for a detail analysis of the deformations experienced (bulk-structural bending and surface undulating) and will ultimately lend itself to the correlation between crosslink density and the onset of mechanical phenomena.
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Klanchantra, Mutita. "Design and synthesis of beta-strand conformationally constrained calpain inhibitors for cataract treatment via metathesis ring closure." Thesis, University of Canterbury. Chemistry, 2006. http://hdl.handle.net/10092/1609.
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This thesis summarises the progress made in the design and synthesis of conformationally constrained β-strand peptidomimetic compounds using ring closing metathesis methodology under microwave irridation conditions. The best macrocycle were elaborated into an inhibitor for a specific protease target. Calpain was used as an example of protease targeting cataract disease. Chapter One introduces proteases in general centring on the general context of protease inhibitor design. The significant of the β-strand 'bioactive' conformation is discussed in details in particular the exploitation of conformationally constrained to potential lock the 'bioactive' conformation. Chapter Two illustrates in silico methods used to design a series of β-strand macrocycle 2.1-2.7. The analysis of these is performed using molecular modelling software Schrodinger suite (2005). A brief discussion of ring closing metathesis methodology is also included. Chapter Three describes the synthesis of the precursor required for RCM reactions (tripeptides dienes). Various types of allylated amino acid side chains were synthesised. The tripeptides were obtained using standard peptide coupling methodology utilising reagents such as HATU, EDC and HOAT. Chapter Four describes the application of ring closing metathesis for the synthesis of β-strand macrocycles. The development of a new reaction conditions to optimise the ring closing metathesis reaction is discussed. In particular the effect of the use of a Lewis acid (chlorodicyclohexylborane) additive in RCM reactions is investigated. Chapter Five discusses the mechanism of cataract formation, cataract treatment and the potential development of calpain inhibitors. One of the macrocycles synthesised in chapter 4 is elaborated into a calpain inhibitor. The in-vitro assay result of this is presented and this compound is currently undergoing in vivo evaluation.
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Vasco, Vidal Aldrin [Verfasser], Ludger [Gutachter] Wessjohann, and Daniel G. [Gutachter] Rivera. "Multicomponent cyclization strategies to novel conformationally constrained peptides / Aldrin Vasco Vidal ; Gutachter: Ludger Wessjohann, Daniel G. Rivera." Halle (Saale) : Universitäts- und Landesbibliothek Sachsen-Anhalt, 2020. http://d-nb.info/121073172X/34.
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Qi, Jun. "Design, Syntheses and Bioactivities of Androgen Receptor Targeted Taxane Analogs, Simplified Fluorescently Labeled Discodermolide Analogs, and Conformationally Constrained Discodermolide Analogs." Diss., Virginia Tech, 2010. http://hdl.handle.net/10919/37537.
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Prostate cancer is the most common non-skin cancer for men in America. The androgen receptor exerts transcriptional activity and plays an important role for the proliferation of prostate cancer cells. Androgen receptor ligands bind the androgen receptor and inhibit its transcriptional activity effectively. However, prostate cancer can progress to hormone refractory prostate cancer (HRPC) to avoid this effect. Chemotherapies are currently the primary treatments for HRPC. Unfortunately, none of the available chemotherapies are curative. Among them, paclitaxel and docetaxel are two of the most effective drugs for HRPC. More importantly, docetaxel is the only form of chemotherapy known to prolong survival in the HRPC patients. We hypothesized that the conjugation of paclitaxel or docetaxel with an androgen receptor ligand will overcome the resistance mechanism of HRPC. Eleven conjugates were designed, synthesized and biologically evaluated. Some of them were active against androgen-independent prostate cancer, but they were all less active than paclitaxel and docetaxel.
Discodermolide is a microtubule interactive agent, and has a similar mechanism of action to paclitaxel. Interestingly, discodermolide is active against paclitaxel-resistant cancer cells and can synergize with paclitaxel, which make it an attractive anticancer drug candidate. Understanding the bioactive conformation of discodermolide is important for drug development, but this task is difficult due to the linear and flexible structure of discodermolide. Indirect evidence for the orientation of discodermolide in the tubulin binding pocket can be obtained from fluorescence spectroscopy of the discodermolide tubulin complex. For this purpose, we designed and synthesized a simplified fluorescently labeled discodermolide analog, and it was active in the tubulin assembly bioassay. In addition, a conformationally constrained discodermolide was designed to mimic the bioactive conformation according to computational modeling. The synthetic effort was made, but failed during one of the final steps.Ph. D.
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Meyer, Gordon Joel. "Synthesis, Characterization, and Mixed-Valence Studies of Conformationally Constrained Bisferrocenyl Complexes for the Study of Through-Space S***π; Interactions." Diss., The University of Arizona, 2014. http://hdl.handle.net/10150/337289.
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A series of conformationally constrained 2,6-bisferrocenylphenyl thioethers were synthesized via Suzuki-Miyaura cross coupling reactions. Structural information was obtained using X-ray crystallography and dynamic ¹H NMR spectroscopic studies, showing highly constrained m-terphenyl systems. Interaction of the ferrocene moieties through space mediated by the sulfur were studied by ultra-violet photoelectron spectroscopy (UPS), cyclic voltammetry, differential pulse voltammetry, UV-Vis-NIR spectroscopy and DFT computations. Electrochemical results show two, fully reversible 1e⁻ redox processes for the ferrocenes where the separation of peaks is affected by both solvent and supporting electrolyte, suggesting significant electrostatic interaction which is further confirmed in the gas phase by UPS studies. To determine if these interactions could be observed at greater distances, extended m-terphenyl complexes were shown in which 2-sulfur and 3-aromatic moieties were synthesized using a developed selective Suzuki-Miyaura monocoupling procedure in good yields. In these systems, interaction was not observed by electrochemistry or UPS. This suggests the distance between redox centers (~16 Å) is too great for electrostatic interaction, even though there is enhanced interactions observed in the truncated systems. Two new bisferrocenylphenylsulfoxides were also synthesized and studied to determine the effect of the polar sulfoxide bond on through space interaction between the ferrocene moieties. The electronic and redox properties of these compounds were studied by ultra-violet photoelectron spectroscopy, cyclic voltammetry, differential pulse voltammetry, and DFT computations. Electrochemical results for 2,6-bis(ferrocenyl) thioanisole S-oxide show two, fully reversible one electron redox processes. The initial oxidation shows a 62 mV negative shift compared to the sulfide analog 2,6-bis(ferrocenyl)thioanisole, and an increased peak separation for the oxidations of 160 mV. No peak separation is observed in the extended sulfoxide system. No intervalence charge transfer band was observed in the truncated sulfoxide complex by monitoring the UV-Vis/NIR spectroscopy of the mixed valence complex, ruling out electronic communication. Thus, the through space electrostatic interactions of the sulfoxide causes the non-equivalent ferrocenes in the truncated system to have different oxidation potentials. Synthesis was developed towards the synthesis of 1,8-bisferrocenyl-9-(alkylthio) anthracene complexes. It was observed that due to steric congestion at the C9 position of the anthracene scaffold, standard thionation reactions did not proceed as expected. Instead, the reaction of 1,8-dibromo-9-anthrone with Lawesson reagent afforded the intramolecular nucleophilic aromatic substitution cyclization product in quantitative yields. The reaction of the same anthrone under studied dithioketal formation conditions led to sulfur-rearrangement, giving the undesired 1,8-bisferrocenyl-10-(ethylthio)anthracene derivative, as confirmed by X-ray crystallography. Attempted Newman-Kwart rearrangement of 1, 8-dibromoanthracen-9-yl) dimethylcarbamothioate afforded no significant observed product formation, and decomposition of starting materials when heated for extended times. 1,8-bisferrocenyl-9-(methoxy)anthracene was synthesized and structurally characterized by dynamic X-ray crystallography to confirm connectivity. Electrochemical experiments show 2 reversible redox processes separated by 115 mV. Chemical oxidation experiments show unexpected, strong electronic coupling in the mixed valence complex. This coupling was characterized by near-IR absorption at 941 nm, indicating intervalence charge transfer (IVCT). Single electron reduction of 1,8-bisferrocenyl-9-(methoxy)anthracene, followed by quenching with various electrophiles afforded an inseparable mixture of products, one of which was identified by mass spectrometry as the desired 1,8-bisferrocenyl-9-(methylthio)anthracene product. However, this complex was not separable from the mixture and further characterization was not possible. All other routes attempted to incorporate sulfur into the system afforded no conversion of starting materials or decomposition of the reaction mixture.
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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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Spanopoulou, Anna [Verfasser], Aphrodite [Akademischer Betreuer] Kapurniotu, Horst [Gutachter] Kessler, and Aphrodite [Gutachter] Kapurniotu. "Synthesis and study of conformationally constrained peptides as inhibitors of amyloid self-assembly / Anna Spanopoulou ; Gutachter: Horst Kessler, Aphrodite Kapurniotu ; Betreuer: Aphrodite Kapurniotu." München : Universitätsbibliothek der TU München, 2019. http://d-nb.info/1213025869/34.
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Scarbath-Evers, Laura Katharina [Verfasser], Daniel [Gutachter] Sebastiani, and Arthur [Gutachter] Ernst. "Conformation and packing structure of conjugated molecules under external constraints : from solvated proteins to reconstructed surfaces / Laura Katharina Scarbath-Evers ; Gutachter: Daniel Sebastiani, Arthur Ernst." Halle (Saale) : Universitäts- und Landesbibliothek Sachsen-Anhalt, 2019. http://d-nb.info/1210727331/34.
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Alfaro-Lopez, Lorenzo Josue. "Development of new conformationally and topographically constrained p60(c-src) PTK inhibitors. Solution and solid-phase approaches for the synthesis of delta-opioid receptor peptidomimetic ligands." Diss., The University of Arizona, 1999. http://hdl.handle.net/10150/288981.
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Based on the efficient substrate for p60ᶜ⁻ˢʳᶜ protein tyrosine kinase (PTK) YIYGSFK (1) (K(m) = 55 μM) obtained by combinatorial methods, we have designed and synthesized a series of conformationally and topographically constrained substrate-based peptide inhibitors for this enzyme. The inhibitors showed IC₅₀ values in low micromolar range (0.1-3 μM). A "rotamer scan" was performed by introducing four stereoisomers of β-Me(2')Nal in the postulated interaction site of peptide inhibitor (23) Y-c[D-Pen-(2')Nal-GSFC]KR-NH₂ (IC₅₀ = 1.6 μM). We found that the χ¹ space constraints imposed by the specialized amino acids, introduced at position 3 of peptide 23, were not as important as the configuration of the Cᵅ of that residue to recognize the active site of Src and Lck PTK, as reflected on the observed selectivity ratios. Cocrystallization studies between Lck and two of our inhibitors are in progress, in a collaboration with Dr. X. Zhu (Kinetix, Pharmaceuticals, Inc.). The results obtained may serve as the basis for the design of Lck and/or Src inhibitors, either peptide or nonpeptide. SL-3111 is a high affinity (IC₅₀ = 8.4 nM) and selective (μ/δ = 2020) δ-opioid receptor peptidomimetic ligand developed in Dr. Hruby's laboratory, as the result of extensive structure-activity relationship (SAR) studies based on peptide leads. However, bioassays (GPI and MVD) and in-vivo antinociception studies on the racemic mixture and both enantiomers of this compound, have shown particular problems such as low potency and toxicity. We have shown the importance of the piperazine ring in this molecule for binding toward the δ-opioid receptor. Thus, maintaining such scaffold we have studied a series of solution and solid-phase approaches toward the synthesis of SL-3111 analogues, which explore wider functional diversity at this heterocyclic ring. Compounds 64-67 were synthesized by solution methods. Analysis of the biological data and molecular modeling studies of these compounds, revealed an interesting trend in terms of the effects of the substituent at position two of the piperazine scaffold. Three different solid-phase protocols were explored toward the development of a combinatorial library of this type of compounds, which may facilitate future SAR studies.
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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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Tucker-Kellogg, Lisa. "Systematic Conformational Search with Constraint Satisfaction." 2004. http://hdl.handle.net/1721.1/30419.
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Throughout biological, chemical, and pharmaceutical research,conformational searches are used to explore the possiblethree-dimensional configurations of molecules. This thesis describesa new systematic method for conformational search, including anapplication of the method to determining the structure of a peptidevia solid-state NMR spectroscopy. A separate portion of the thesis isabout protein-DNA binding, with a three-dimensional macromolecularstructure determined by x-ray crystallography.The search method in this thesis enumerates all conformations of amolecule (at a given level of torsion angle resolution) that satisfy aset of local geometric constraints, such as constraints derived fromNMR experiments. Systematic searches, historically used for smallmolecules, generally now use some form of divide-and-conquer forapplication to larger molecules. Our method can achieve a significantimprovement in runtime by making some major and counter-intuitivemodifications to traditional divide-and-conquer:(1) OmniMerge divides a polymer into many alternative pairs ofsubchains and searches all the pairs, instead of simply cutting inhalf and searching two subchains. Although the extra searches mayappear wasteful, the bottleneck stage of the overall search, which isto re-connect the conformations of the largest subchains, can be greatlyaccelerated by the availability of alternative pairs of sidechains.(2) Propagation of disqualified conformations acrossoverlapping subchains can disqualify infeasible conformations veryrapidly, which further offsets the cost of searching the extrasubchains of OmniMerge.(3) The search may be run in two stages, once at low-resolutionusing a side-effect of OmniMerge to determine an optimalpartitioning of the molecule into efficient subchains; then again athigh-resolution while making use of the precomputed subchains.(4) An A* function prioritizes each subchain based onestimated future search costs. Subchains with sufficiently lowpriority can be omitted from the search, which improves efficiency.A common theme of these four ideas is to make good choices about howto break the large search problem into lower-dimensional subproblems.In addition, the search method uses heuristic local searches withinthe overall systematic framework, to maintain the systematic guaranteewhile providing the empirical efficiency of stochastic search.These novel algorithms were implemented and the effectiveness of eachinnovation is demonstrated on a highly constrained peptide with 40degrees of freedom.
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Duncan, Joanna Kimberley. "Design and synthesis and testing of conformationally constrained peptidomimetics." Thesis, 2013. http://hdl.handle.net/2440/82467.
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This thesis describes the design, synthesis and testing of peptidomimetics pre-organised into bioactive conformations. Chapter One introduces the concept of peptidomimetics, their importance as potential pharmaceuticals. The concept of constraining a compound into a bioactive conformation (α-helix, β-turn or β-strand) by incorporation of a ring or bridge is discussed. The technique of ring closing metathesis as a strategy for cyclisation of peptidomimetics is introduced. Chapter Two surveys β-turn mimics comprised of β-amino acids. The synthesis of novel cyclic peptidomimetics comprised of β-amino acids (cyclised by ring closing metathesis) is presented. Three of the cyclic dipeptides were predicted (through in silico conformational searches) to adopt a β-turn motif. Cyclic scaffolds 2.62, 2.65 and 2.66 were each incorporated into a tri-peptide to give 2.68, 2.69 and 2.70. The propensity of each tri-peptide to adopt a β-turn motif was investigated by 1H NMR. There is strong evidence that 2.70 has a β-turn geometry based on the presence of an intra-molecular hydrogen bond between the i and i+3 residues. Chapter Three introduces cysteine protease calpain II as the primary biological target for this thesis. Calpain is implicated in cataract formation and its inhibition is a logical approach to cataract prevention. Proteases are known to, almost universally, bind substrates and inhibitors in a β-strand conformation. Four macrocycles, designed to be preorganised in a β-strand geometry, were synthesised by ring closing metathesis (compounds 3.02 – 3.05). Macrocycle 3.02 was made to investigate the suitability of an N-terminal 4-fluoro-benzyl-sulfonyl (FBS) in macrocyclic calpain inhibitors. The synthesis of 3.02 was optimised to give the required compound in 33% yield compared to a reported 1% for analogue CAT0811. Diols 3.03 and 3.04 (as a mixture with 3.03 in an 85:15 ratio) were designed to explore possible hydrophilic interactions with the active site of calpain. Macrocycle 3.05 was designed to investigate the relative importance of having an aromatic residue at P₁ for inhibition of calpain, α-chymotrypsin and the 20S proteasome. Chapter Four reports the in vitro testing of macrocycles 3.02, 3.03 and 3.04 against calpain II and discusses these results in the context of the SAR study completed by the Abell group to identify the criteria for the most potent macrocyclic calpain inhibitor. CAT0811 was confirmed as the most potent macrocyclic calpain II inhibitor to date with an IC₅₀ of 0.03 μM. Macrocycle 3.02 had an IC₅₀ of 0.045 μM against calpain II, confirming the suitability of FBS as an N-terminus in these macrocycles. Macrocycle 3.03 had an IC₅₀ of 3.7 μM against calpain II, suggesting a diol substituent is not tolerated by the enzyme at P₁. Diol 3.04 (as a mixture with 3.03 in an 85:15 ratio) was essentially inactive against calpain II (IC50 > 50 μM), presumably as 3.04 has a low propensity to adopt a β-strand conformation. Macrocycle 3.05 had an IC₅₀ of 0.15 μM against calpain II, a Ki of 686 μM against α-chymotrypsin and an IC₅₀ of 1.46 μM against the chymotrypsin-like sub-site of the 20S proteasome. CAT0811 was inactive against α-chymotrypsin and had an IC₅₀ of 1.51 μM against the chymotrypsin-like sub-site of the 20S proteasome. While modification to the P₁ and P₃ positions moderately influenced the selectivity of the macrocycles (comparing 3.05 with CAT0811), a much more dramatic affect was gain by modification of the P₂ residue (as in 4.02). Chapter Five reports the synthesis and in vivo testing of tritiated analogues of CAT0811 and 4.04 by reduction of CAT0811 with NaBT₄ to give macrocycle 5.02, and subsequent oxidation of 5.02 to give 5.03. Compounds 5.02 and 5.03 were separately formulated and administered to sheep from the cataract flock. Liquid scintillation counting was used to get a preliminary outlook on the absorption, distribution and excretion of the macrocycles and to investigate the phenomenon of les crossover of the inhibitors. Previous in vivo trials of CAT0811 have reported that when the formulated inhibitor is administered to the left lens, both lenses are equally observed to have slowing of cataract progression (p < 0.05). Levels of tritium in the treated and untreated lenses were measured. Equal amounts of 5.02 were found in both lenses 48 h after application. This supports our hypothesis that lens crossover of the macrocycles is occurring.Thesis (Ph.D.) -- University of Adelaide, School of Chemistry and Physics, 2013
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Borowski, Krzysztof. "Conformational Ensemble Generation via Constraint-based Rigid-body Dynamics Guided by the Elastic Network Model." Thesis, 2011. http://hdl.handle.net/10012/6162.
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Conformational selection is the idea that proteins traverse positions on the
conformational space represented by their potential energy landscape, and in particular positions considered as local energy minima. Conformational selection a useful concept in ligand binding studies and in exploring the
behavior of protein structures within that energy landscape. Often, research that explores protein function requires the generation of conformational ensembles, or collections of protein conformations from a single structure. We describe a method of conformational ensemble generation that uses joint-constrained rigid-body dynamics (an approach that allows for explicit consideration of rigidity) and the elastic network model (providing structurally derived directional guides for the rigid-body model). We test our model on a selection of unbound proteins and examine the structural validity of the resulting ensembles, as well as the ability of such an approach to generate conformations with structural overlaps close to the ligand-bound versions of the proteins.
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Tucker-Kellogg, Lisa, and Tomás Lozano-Pérez. "OmniMerge: A Systematic Approach to Constrained Conformational Search." 2003. http://hdl.handle.net/1721.1/3684.
Full textAbstract:
OmniMerge performs a systematic search to enumerate all conformations of a molecule (at a given level of torsion-angle resolution) that satisfy a set of local geometric constraints. Constraints would typically come from NMR experiments, but applications such as docking or homology modeling could also give rise to similar constraints. The molecule to be searched is partitioned into small subchains so that the set of possible conformations for the whole molecule may be constructed by merging the feasible conformations for the subchain parts. However, instead of using a binary tree for straightforward divide-and-conquer, OmniMerge defines a sub-problem for every possible subchain of the molecule. Searching every subchain provides a counter-intuitive advantage: with every possible subdivision available for merging, one may choose the most favorable merge for each subchain, particularly for the bottleneck chain(s). Improving the bottleneck step may therefore cause the whole search to be completed more quickly. Finally, to discard infeasible conformations more rapidly, OmniMerge filters the solution set of each subchain based on compatibility with the solutions sets of all overlapping subchains. These two innovations—choosing the most favorable merges and enforcing consistency between overlapping subchains—yield significant improvements in run time. By determining the extent of structural variability permitted by a set of constraints, OmniMerge offers the potential to aid error analysis and improve confidence for NMR results on peptides and moderate-sized molecules.Singapore-MIT Alliance (SMA)
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Shehu, Amarda. "Sampling biomolecular conformations with spatial and energetic constraints." Thesis, 2005. http://hdl.handle.net/1911/17825.
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This work extends cyclic coordinate descent to efficiently satisfy multiple spatial constraints, respect the secondary structure of proteins., and work with reduced backbone protein models. Reduced models allow us to treat large systems that are intractable under all-atom models. In addition, this thesis combines the satisfaction of multiple spatial constraints with conformational sampling and energy minimization techniques to generate spatially constrained biomolecular structures that are energetically stable under physiological conditions.
The experiments in this thesis demonstrate the relevance and robustness of our method on three areas of applications: loop closure; backbone reconstruction, and physical trajectory recovery. Addressing the problem of loop closure, we obtain ensembles of spatially constrained conformations whose energy landscape is in agreement with laboratory experimental results on the energetic stability of the proteins at hand. Our experiments on backbone reconstruction agree with results from statistical approaches to this problem, but in addition guarantee the energetic feasibility of the completed models. (Abstract shortened by UMI.)
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Miduturu, Chandrasekhar Venkataraman. "DNA constraints for rational control of macromolecular conformation /." 2006. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3223670.
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Thesis (Ph. D.)--University of Illinois at Urbana-Champaign, 2006.Source: Dissertation Abstracts International, Volume: 67-07, Section: B, page: 3805. Adviser: Scott K. Silverman. Includes bibliographical references. Available on microfilm from Pro Quest Information and Learning.
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"Conformational properties of constrained proline analogues and their application in nanobiology." Universitat Politècnica de Catalunya, 2009. http://www.tesisenxarxa.net/TDX-0417109-095127/.
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古玉鳳. "Stereoselective synthesis of conformational constrained apha-galactosylceramide analogues from exo-glycals." Thesis, 2005. http://ndltd.ncl.edu.tw/handle/74913985097229356105.
Full textAbstract:
碩士國立臺灣師範大學
化學系
93
CD1 molecules are the family of MHC-like cell surface glycoproteins presenting glycolipid antigens to lymphocytes. They recognize and bind glycolipid antigens through lipid-protein interactions and hand over the sugar moiety of the antigen to the receptor on natural killer T (NKT) cells to activate the immune system. Human CD1d and its mouse homolog are shown to provide natural kill T cells with a special glycolipid, CD1 molecules are the family of MHC-like cell surface glycoproteins presenting glycolipid antigens to lymphocytes. They recognize and bind glycolipid antigens through lipid-protein interactions and hand over the sugar moiety of the antigen to the receptor on natural killer T (NKT) cells to activate the immune system. Human CD1d and its mouse homolog are shown to provide natural kill T cells with a special glycolipid,apha-galactosylceramide (apha-GalGer),apha-GlaCer-activated NKT cells have been reported to play crucial roles in a variety of autoimmune pathologies, including multiple sclerosis, autoimmune diabetes, organ transplant repulsion and atherosclerosis. The necessary structural features of apha-GalCer have been identified necessary for antigen recognition by CD1-restricted NKT cells, such as (1) the anomeric glycosidic linkage between sugar and lipid moieties; (2) the 2-hydroxyl group on the pyranose ring; (3) the presence of 3’ and 4’-hydoxyl groups on the phytosphingosine chain. Change of the antigen structure may alter the level of stimulatory activity and switch the cytokine pattern released by NKT cells. A series of conformationally constrained C- or O-linked apha-GalCer analogues were designed and synthesized. The main skeleton was constructed by stereoselective addition of exo-glyclas and subsequent ozonolysis, reductive amination, cyclization. The new stereogenic center of these intermediates and products was determined by special NMR methods. In addition, the ELISA method was used to evaluate the immuno-activity of these synthesized molecules.apha-galactosylceramide (apha-GalGer), apha-GlaCer-activated NKT cells have been reported to play crucial roles in a variety of autoimmune pathologies, including multiple sclerosis, autoimmune diabetes, organ transplant repulsion and atherosclerosis. The necessary structural features of apha-GalCer have been identified necessary for antigen recognition by CD1-restricted NKT cells, such as (1) the anomeric glycosidic linkage between sugar and lipid moieties; (2) the 2-hydroxyl group on the pyranose ring; (3) the presence of 3’ and 4’-hydoxyl groups on the phytosphingosine chain. Change of the antigen structure may alter the level of stimulatory activity and switch the cytokine pattern released by NKT cells. A series of conformationally constrained C- or O-linked apha-GalCer analogues were designed and synthesized. The main skeleton was constructed by stereoselective addition of exo-glyclas and subsequent ozonolysis, reductive amination, cyclization. The new stereogenic center of these intermediates and products was determined by special NMR methods. In addition, the ELISA method was used to evaluate the immuno-activity of these synthesized molecules.
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Kling, Dale Lee. "Conformationally constrained aminoglycosides ribosomal binding probes and potential antibiotics /." 2006. http://etd.nd.edu/ETD-db/theses/available/etd-04112006-183339/.
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Thesis (M.S.)--University of Notre Dame, 2006.Thesis directed by Shahriar Mobashery for the Department of Chemistry and Biochemistry. "April 2006." Includes bibliographical references (leaves 63-70).
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Galan, Hurtado Maria del Carmen. "Conformationally constrained oligosaccharides as probes for carbohydrate-protein interactions." 2002. http://purl.galileo.usg.edu/uga%5Fetd/galan-hurtado%5Fmaria-del-carmen%5F200212%5Fphd.
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Thesis (Ph. D.)--University of Georgia, 2002.Directed by Geert-Jan Boons. Includes an article published in Journal of the American Chemical Society, and articles submitted to Chemistry: a European journal, and Journal of biological chemistry. Includes bibliographical references (leaves 147-164).
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Ya-Fang, kang, and 康雅芳. "Synthesis of Anti Conformationally Constrained Pyrimidine Acyclic Nucleoside Analogs." Thesis, 1996. http://ndltd.ncl.edu.tw/handle/36188406811194288889.
Full textAbstract:
碩士國防醫學院
藥學研究所
84
The objective of this sudy is to synthesize a of series anti conformationally constrained pyrimidine acyclic nucleoside analogs containing an oxazepine or oxazine ring moiety.
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Amiot, Nicolas Claude René. "Design and synthesis of conformationally constrained trisaccharides for probing carbohydrate-protein interactions." 2001. http://purl.galileo.usg.edu/uga%5Fetd/amiot%5Fnicolas%5Fc%5F200112%5Fphd.
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