The aim of this research was to study the mechanism involved in the synthesis of deoxyhypusine, the intermediate step in the synthesis of the amino acid hypusine. Oeoxyhypusine is derived from the butylamine moiety of a spermidine molecule which is added to the famino group of one lysine in the eukaryotic initiation factor 40 (eIF-4D). Initially, a hepatoma tissue cell (HTC) lysate with a pH of 9.5 in glycine buffer and with a depleted spermidine pool supported deoxyhypusine synthesis in protein. Since CHES buffer was as efficient as glycine buffer, the synthesis of deoxyhypusine was pH dependent (optimum ∼9.2) and not buffer dependent. Next, several inhibitors were used in the cell-free system to block deoxyhypusine synthesis. Only guazatine, a plant amine oxidase inhibitor, completely inhibited deoxyhypusine synthesis. This suggested that an oxidase was involved in deoxyhypusine synthesis. In addition factors were investigated as possible allosteric stimulators of deoxyhypusine formation. NAD⁺, NADH, FAD⁺, FMN⁺, and as nicotinamide were tested for effects on deoxyhypusine formation. NAD⁺ was the most efficient stimulator, but NAOH and nicotinamide also stimulated deoxyhypusine formation. Although these factors increased the synthesis of deoxyhypusine, these assays were done in buffer with low concentrations of spermidine. When the spermidine pool was replenished, these effects were diminished. Thus, it appeared that NAD⁺ may lower the apparent K(m) for spermidine without affecting the V(max) of deoxyhypusine synthesis. The inhibition of deoxyhypusine synthesis by guazatine implied the involvement of a polyamine oxidase. Therefore, the effect of oxygen depletion on deoxyhypusine formation was investigated. The depletion of oxygen reduced the level of deoxyhypusine synthesis to 12% of the control. This activity could be restored to 85% by reoxygenation of the lysate. Thus in support of the suggestion made by the guazatine data, a spermidine oxidase in involved in deoxyhypusine formation. The most significant contribution of this work was the development of a cell free system to study deoxyhypusine. This synthesis required an unusually high pH in vitro and required polyamine depletion (Chapter 2). In addition, synthesis requires a unique spermidine oxidase that is blocked by a guazatine and is conditionally stimulated by NAD⁺ (Chapter 3).

No description available.

This thesis is concerned with the development of new synthetic routes for the asymmetric syntheses of a range of β- and γ-amino acids. Chapter 1 introduces the various biological activities displayed by cyclic β-amino acid containing compounds together with their occurrence in pharmaceutical molecules and β-peptides. Some of the most commonly used synthetic strategies for the preparation of carbocyclic β-amino acids are briefly described, with the focus on the formation and functionalisation of a five-membered carbocyclic ring. Chapter 2 describes a full investigation into a highly diastereoselective Ireland-Claisen rearrangement of stereodefined allyl β-amino esters to access enantiopure α-substituted β-amino acid products. The synthetic utility of this methodology is highlighted by its application in the asymmetric syntheses of five previously inaccessible C(5)-substituted 1,2-anti-1,5-syn-transpentacins. Chapter 3 delineates investigations into a highly diastereoselective conjugate additionelimination protocol for the preparation of a cyclic β'-amino-α,β-unsaturated ester. Subsequent chemo- and diastereoselective conjugate addition reactions of Grignard reagents and lithium amides to this substrate enabled the asymmetric syntheses of four C(5)-substituted 1,2-anti-1,5-syn-transpentacins and two five-membered β,β'-diamines. Chapter 4 details the extension of the protocol developed in Chapter 3 for the conjugate addition of Grignard reagents to a range of acyclic γ-(N,N-dibenzylamino)-substituted α,β-unsaturated esters. Elaboration of the β,γ-disubstituted γ-amino ester products culminated in the asymmetric syntheses of six β,γ-disubstituted γ-amino acids. Chapter 5 chronicles the preparation of an azabicyclic α,β-unsaturated ester, following which attempts towards the asymmetric synthesis of various substituted pyrrolizidines using a conjugate addition protocol are subsequently described. Chapter 6 contains full experimental procedures and characterisation data for all compounds synthesised in Chapters 2, 3, 4 and 5.

No description available.

Bibliography : leaves 166-183. / v, 198 leaves ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, Dept. of Chemistry, 1993?

published_or_final_version / abstract / Chemistry / Doctoral / Doctor of Philosophy

This work involved synthetic approaches to the anti-tumor agent deoxybouvardin. Numerous reactions were explored in an attempt to build an amino acid from an aromatic aldehyde under mild conditions. From these reactions new and useful synthetic methods have been discovered for making α-acylamino alcohols and unsymmetrical imides. Some dehydroamino acids were successfully prepared from aromatic aldehydes and an N-acylphosphorylglycine ester. Progress towards a synthesis of 5- η-thiodeoxybouvardin will also be discussed.

Amino acids are important building blocks for the synthesis of a large number of biologically active compounds and drugs. Amino acids with the pentacyclo-undecane (1) and trishomocubane (2) frameworks fall into the class of conformationally constrained non-natural amino acids. Conformationally constrained amino acids are found in many naturally occurring, biologically active compounds. It was found that incorporating cage structures into drugs induces a range of positive effects: promotes transport across the cell membrane, drugs can be designed to target the central nervous system, increased receptor site specificity, and retards metabolic degradation. In the light of this, it was decided to investigate the incorporation of cage amino acids into peptides. A synthetic route has been established for the efficient synthesis of amino acids 1 and 2, and for their incorporation into peptides. Several chiral macrocyclic crown ethers and related analogues have been shown to be capable of forming complexes enantioselectively with chiral organic ammonium salts. The design and synthesis of host chiral macrocycles which are able to distinguish between the enantiomers of guest organic ammonium salts is of interest in the areas that include synthesis of enzymes, electrodes for specific ions or molecules, drugs targeted for specific sites, and enantiomer separation. A synthetic procedure has been established for the synthesis of cage annulated chiral crown ethers derived from amino acids. The advantage of using cage compounds in crown ethers is due to increased rigidity, increased solubility in non-polar solvents and increased chirality. Various techniques for the determination of enantiomeric recognition have been studied and include NMR spectroscopy, fluorescence emission spectroscopy and computational methods. The cage crown ether 3 represents a typical example of these new cage annulated, chiral crown ethers. / Thesis (M.Sc.)-University of Natal, Durban, 2001.

Cage compounds have attracted pharmaceutical and biological interest amongst others as anti-Parkinson agents. The serendipitous observation of the activity of 1-aminoadamantane 1 in Parkinsonian patients against selected viruses i.e. Herpes simplex Type I & II and Influenza A2-Asian viruses/Taiwan has increased the interest in cage compounds. This study involves the synthesis of the cage amino acid 14. Due to the insolubility of pentacyclo-[6.3.0.02,6.03,10.05,9]-undecane (trishomocubane) amino acid 14 in both polar and nonpolar solvents, including DMSO (d6), the synthesis of Fmoc-tris amino acid 50 was required for analysis. The Fmoc derivative of trishomocubane amino acid was also useful for controlled* coupling of the cage amino acid 14 to short peptides. The synthesis of the Fmoc-tris amino acid fluoride derivative is described as well as that of the tri-peptide (Ala-Ala-Ala). The incorporation of the Fmoc-tris amino acid fluoride in a tetra-peptide Ala-Ala-Ala-tris and in a hepta-peptide Ala-Ala-Ala-tris-Ala-Ala-Ala will also be presented. A computational chemistry project was undertaken using density functional theory (B3LYP) at the 6-31+G(d) level of theory, so as to enhance the understanding of the mechanism of esterification. Methanol, acetyl chloride and acetic acid were used in the model for simplicity. Four membered ring transition states were obtained with both acetyl chloride and acetic acid. A six membered ring transition state is facilitated by the selective use of one methanol molecule from the solvent. Both a concerted and step-wise mechanism are presented. / Thesis (M.Sc.)-University of KwaZulu-Natal, Durban, 2006.

本論文報道了 (a) 基於1,4-二取代 1,2,3-三唑的短肽類似物的合成及表徵，和 (b)這些類肽化合物在溶液相中的自組裝及凝膠化特性研究。 / 本論文第一章簡單地介紹及槪括基於三唑的寡聚物的構象和超分子的屬性。 / 本論文第二章報告1,4-二取代 1,2,3-三唑在類肽化合物中作為聯繫單元和作為構象控制的多功能性。 / 本論文第三章敍述了一類新的包含1,2,3-三唑在分子骨幹中的類肽化合物的合成及表徵。以炔丙胺/炔丁胺和 α-疊氮酸作為雙官能團前體，不同氨基酸成分和不同C-端基的系列類肽化合物由反覆的合成過程製備而來。用炔丙醇代替炔丙胺, 相應的酯類似物也被製備用作比較研究。 / 本論文第四章敍述了這些類肽化合物的自組裝及凝膠化特性。根據一維¹H 核磁共振，二維核磁共振 (2D)，氫/氘交換核磁共振 (H/D)， 蒸汽壓力均分子量 (VPO), 圓二色譜 (CD) 和紅外光譜分析研究，基於三唑類的短肽化合物Boc-aa¹aa²***aa[superscript n]-X 被發現以頭接尾的方式自我二聚 (K[subscript dsubscript isubscript m] ~10-680 M⁻¹)。二聚常數 (K[subscript dsubscript isubscript m])隨著氨基酸單位數目的增加而增大。在相同的寡聚系列中，K[subscript dsubscript isubscript m]值受到C-端基的大小的強烈影響。三肽類似物Boc-aa¹aa²aa³-X 還是許多芳烴類溶劑的優秀有機凝膠因子。掃描電子顯微技術(SEM)形態研究顯示三維網路形成於凝膠過程中。另一方面，結果顯示，類肽化合物的連結器長度在二級結構的形成和自組裝特性上發揮重要作用。 / 爲了進一步發展頭尾二聚的概念，本論文第五章敍述頭接尾的β-髮夾類似結構可通過適當的連結器偶聯兩個基於三唑的三肽類似物來獲得，如4-羥基脯氨酸的衍生物。一維¹H 核磁共振，二維核磁共振 (2D)，氫/氘交換核磁共振 (H/D)和紅外光譜等分析方法被用來研究其自組裝特性。 / 這篇論文展示了用三唑類體系結構設計類肽分子的可行性。產品結構表徵及性質探索的結果為這些新的類肽化合物的進一步調查和應用奠定了基礎。 / This thesis reported (a) the synthesis and characterization of 1,4-disubstituted 1,2,3-triazole-based oligopeptides, and (b) the study on self assembling and gelation properties of the peptidomimetic compounds. / Chapter one gave a brief introduction and review on the click triazole-based oligomers, including their conformational and supramolecular properties. / Chapter two reviewed the versatility of 1,4-disubstituted 1,2,3-triazole unit as a linker and as a conformational controlling unit in peptidomimetics. / Chapter three disclosed the synthesis and characterization of a new class of linear peptidomimetics incorporating 1,2,3-triazoles in the backbone. Several series of click peptidomimetics, containing up to four amino acid residues and of different amino acid compositions and different C-terminal groups, were prepared by an iterative synthetic procedure, in which propargyl amine/homopropargyl amine and α-azido acids were used as bifunctional precursors. Using propargyl alcohol instead of propargyl amine, the corresponding ester analogs were also prepared for comparison studies. / In chapter four, the self-assembly and gelation properties of these peptidomimetics were illustrated. Click triazole-based oligopeptides Boc-aa¹aa²***aa[superscript n]-X (n = 2, 3 or 4) were found to self-dimerize (K[subscript dsubscript isubscript m] ~ 10-1020 M⁻¹) in a head-to-tail fashion according to ¹H NMR, two-dimensional NMR (2D), hydrogen/deuterium (H/D) exchange NMR, vapor pressure osmometry (VPO), circular dichroism (CD) and FT-IR studies. The dimerization constant (K[subscript dsubscript isubscript m]) was found to increase with increasing number of the amino acid units. Within the same oligomeric series, the K[subscript dsubscript isubscript m] value was strongly affected by the size of the C-terminal end group. The tripeptides Boc-aa¹aa²aa³-X were also excellent organogelators of many aromatic solvents. Morphological study indicated thata three-dimensional network was formed during the gelation process. On the other hand, the corresponding triester analog 98 and elongated analogs l-Boc-aa¹aa²aa³-Prg did not exhibit any self assembling properties. This revealed that the linker length and the amide units inside the click peptidomimetics played an important role in both the formation of secondary structures and the self-assembly properties. / To further develop the idea of head-to-tail dimerization, chapter five described the head-to-tail β-hairpin like structures could be obtained by conjugating two click triazole-based tripeptides through an appropriate linker such as derivatives of 4-hydroxyproline. Analytical methods, such as ¹H NMR, two-dimensional NMR, H/D exchange NMR spectroscopy, and FT-IR studies, were used to determine their self assembling properties. / This thesis has demonstrated the feasibility of designing peptidomimetic molecules with the triazole architecture. The results of the product characterization and property exploration have laid down the groundwork for further investigation and application of this new of peptidomimetic compounds. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Ke, Zhihai. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2012. / Includes bibliographical references (leaves 156-162). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese. / Table of Contents --- p.i / Acknowledgements --- p.iv / Abbreviations --- p.v / Abstract --- p.vi / Publications related to this thesis --- p.x / Chapter Chapter One --- Click ChemistryA Powerful Tool to Create Supramolecular Chimeras / Chapter 1.1 --- Introduction to Click Chemistry --- p.1 / Chapter 1.2 --- General Synthetic Strategies of Acyclic Oligotriazoles --- p.6 / Chapter 1.3 --- Conformational Properties --- p.9 / Chapter 1.3.1 --- Helical Structures from Oligotriazoles --- p.9 / Chapter 1.3.2 --- Double Helical Structure from Oligotriazoles --- p.12 / Chapter 1.3.3 --- β-Strands and β-sheets derived from Oligotriazoles --- p.13 / Chapter 1.4 --- Supramolecular Properties --- p.14 / Chapter 1.4.1 --- Host-guest Binding --- p.14 / Chapter 1.4.2 --- Self Assembling Properties --- p.17 / Chapter 1.4.3 --- Chemosensing Properties --- p.19 / Chapter Chapter Two --- Click PeptidomimeticsTricks with Clicks / Chapter 2.1 --- Click ChemistryA New Ligation Tool for Peptidomimetics Synthesis --- p.20 / Chapter 2.2 --- Click Peptidomimetics --- p.22 / Chapter 2.2.1 --- Peptidepeptide --- p.23 / Chapter 2.2.2 --- Polymerpeptide --- p.25 / Chapter 2.2.3 --- Dendrimerpeptide --- p.26 / Chapter 2.2.4 --- Small moleculepeptide --- p.27 / Chapter 2.3 --- The triazole linkage as conformational control --- p.29 / Chapter 2.3.1 --- Triazole-based β-turn mimetics --- p.29 / Chapter 2.3.2 --- Cyclic turn mimetics --- p.31 / Chapter 2.3.3 --- Cis/trans-prolyl mimic --- p.33 / Chapter 2.3.4 --- Triazoles in helix bundles --- p.34 / Chapter 2.4 --- Oligotriazole peptides --- p.35 / Chapter 2.5 --- Summary and Aim of the Project --- p.36 / Chapter Chapter Three --- Design, Synthesis and Characterization of Oligotriazole-based Peptidomimetics / Chapter 3.1 --- Synthetic Design --- p.38 / Chapter 3.2 --- Choice of Reaction Conditions --- p.40 / Chapter 3.3 --- Synthesis of Linear Click Triazole-based Peptidomimetics --- p.41 / Chapter 3.3.1 --- Preparation of Click Triazole-based Peptidomimetics with Shorter Linkers --- p.42 / Chapter 3.3.2 --- Preparation of Click Triazole-based Peptidomimetics l-Boc-aa¹aa²**aa[superscript n]-X with a Longer Spacer --- p.47 / Chapter 3.3.3 --- Preparation of ester analogs and other model compounds --- p.49 / Chapter 3.4 --- Characterization of Linear Click Triazole-based Peptidomimetics --- p.51 / Chapter 3.4.1 --- Nuclear Magnetic Resonance (NMR) Spectroscopy --- p.52 / Chapter 3.4.1.1 --- ¹H NMR Spectroscopy --- p.52 / Chapter 3.4.1.2 --- ¹³C NMR Spectroscopy --- p.57 / Chapter 3.4.2 --- Mass Spectrometry Analysis --- p.59 / Chapter 3.4.3 --- High-performance Liquid Chromatography Analysis --- p.61 / Chapter 3.5 --- Conclusions --- p.62 / Chapter Chapter Four --- Self-Assembling Properties of Click Triazole-based Peptidomimetics / Chapter 4.1 --- Introduction --- p.63 / Chapter 4.2 --- Results and Discussion --- p.65 / Chapter 4.2.1 --- Nuclear Magnetic Resonance (NMR) Spectroscopy --- p.65 / Chapter 4.2.1.1 --- Variable Concentration ¹H NMR --- p.65 / Chapter 4.2.1.2 --- Two-dimensional ¹H NMR --- p.71 / Chapter 4.2.1.3 --- Hydrogen/deuterium (H/D) exchange --- p.74 / Chapter 4.2.2 --- Vapor Pressure Osmometry (VPO) --- p.77 / Chapter 4.2.3 --- Infra-red (IR) Spectroscopy --- p.78 / Chapter 4.2.4 --- Theoretical Calculation --- p.80 / Chapter 4.2.5 --- Circular Dichroism (CD) --- p.81 / Chapter 4.2.6 --- Gelation Behaviors --- p.83 / Chapter 4.2.6.1 --- General Gelation Properties --- p.83 / Chapter 4.2.6.2 --- Morphology Studies --- p.87 / Chapter 4.3 --- Conclusions --- p.90 / Chapter Chapter Five --- β-Hairpin Structure from Click Triazole-based Peptidomimetics / Chapter 5.1 --- Introduction and Design of β-hairpin --- p.91 / Chapter 5.2 --- β-Hairpin Like Click Triazole-based Peptidomimetics Based on a Bifunctional Aromatic Linker 105 --- p.92 / Chapter 5.3 --- β-Hairpin Like Click Peptidomimetics Based on a Proline Linker 113 --- p.97 / Chapter 5.4 --- Conclusions --- p.107 / Chapter Chapter Six --- Conclusion and Outlook --- p.109 / Chapter Chapter Seven --- Experimental Procedures / Chapter 7.1 --- General Information --- p.112 / Chapter 7.2 --- Experimental Procedures --- p.113 / Chapter 7.3 --- Other Experimental --- p.152 / References --- p.156 / Chapter Appendix 1 --- (Nuclear Magnetic Resonance Spectra) --- p.A1 / Appendix 2 --- p.A111