Structural studies of peptides has relevance for various applications, like, in de novo design of proteins, in designing better catalysts for organic synthesis, in structure based drug design, in the design and construction of synthetic protein mimics and in building novel materials via supramolecular self assembly. Crystal structure determination of peptides is expected to provide information about their static structure, mode of aggregation, solvation and hydrogen bond interactions of the sequences in the solid state. Comparison and analysis of the related structures from the database analysis could provide information about sequence dependent conformational features, which eventually would act as precursor for de novo protein design. Self assembling processes are common throughout nature and technology. Living cells self assemble, and understanding life will therefore require an understanding of self assembly. Supramolecular chemistry has become an area of intense research, partly inspired by biological ensembles in nature, such as collagen and enzymes or protein assemblies in general. Understanding, inducing, and directing such self assembling processes are key to unraveling the progressive emergence of complex matter. Most of the drugs available today have a broad spectrum of action in that they can act on more than one receptor and the mechanism of action of these drugs are poorly understood. Homology modeling of receptors and docking studies with drug molecules (both peptides and non-peptides) would result in a better understanding of the mechanism of drug-receptor binding thus resulting in the design of more specific and effective drugs. This thesis reports the results of X-ray crystallographic studies of ten molecules listed below (Ter: terephthalic acid) and the molecular model of cholecystokinin type 1 receptor (CCK1R). The abbreviations used for the sequences are given in parenthesis. Boc-Gly-Dpg-Gly-Leu-OMe (GDGL), C24H44N4O7 Boc-Val-Ala-Leu-Dpg-Val-Ala-Leu-Val-Ala-Leu-Dpg-Val-Ala-Leu-OMe (VAL14), C78H14 2N14O17 MeO-Leu-Ter-Leu-OMe (LTeL), C22H32N2O6 MeO-DLeu-Ter-DLeu-OMe (DLTeDL), C22H32N2O6 MeO-Ile-Ter-Ile-OMe (ITeI), C22H32N2O6 MeO-Aib-Ter-Aib-OMe (UTeU), C18H24N2O6 Tyr-Aib-Tyr-Val (YUYV), C27H36N4O7 Tyr-Aib-Ala (YUA), C16H23N3O5 Z-Gly-Gly-Val (ZGGV), C17 H23 N3 O6 DL-4-benzamido-N, N-dipropylglutaramic acid (proglumide), C18 H26 N2 O4 Results from the Dpg containing peptide sequences helped to further the understanding of conformational preferences of this residue. The crystallographic studies on the peptide sequence, which forms a supramolecular triple helix and four pseudopeptide sequences, which adopt supramolecular ladder conformations has provided substantial information on the role of non covalent interactions in supramolecular self assembly. Crystal structure of a Gly-Gly containing tripeptide and database analysis has provided insights into the conformations adopted by this segment in peptides and proteins. The docking of the crystal structure of proglumide, an antagonist of CCK1R has led to the understanding of the mechanism of its interaction with CCK1R.

Une série de peptides présentant un ou deux motifs hydroxamate a été synthétisée, l'étape clé étant la N-acylation sélective de N-hydroxy-dipeptides terminaux. L'atome d'oxygène du groupe hydroxyle peut servir de point d'ancrage pour une autre chaîne et donne ainsi accès à de nouveaux pseudopeptides. D'une part, l'acylation de N-hydroxy-peptides a été réalisée dans différentes conditions permettant l'introduction de groupements variés, en particulier des acides aminés. Il est possible d'allonger ces N-acyloxy-peptides dans toutes les directions, même si dans certains cas des réarrangements intéressants peuvent avoir lieu. D'autre part, une réaction d'alkylation dans les conditions de Mitsunobu a permis de greffer des groupements allyle et homoallyle sur des N-hydroxy-tripeptides, conduisant notamment à la préparation d'un hexapeptide bis insaturé qui peut être cyclisé via une réaction de métathèse.

Inspiriert von den natürlich vorkommenden Antibiotika der Gramicidin Familie und ihrer d-(alt)-l Aminosäuresequenz, die es diesen Oligopeptiden ermöglicht, eine beta–helikale Sekundärstruktur einzunehmen, war das Hauptziel dieser Arbeit die Synthese und Charakterisierung von Peptiden und diversen Pseudopeptiden mit regulärer all-l und d-(alt)-l Sequenz und die Untersuchung des Einflusses dieser stereochemischen Variation auf die Strukturen und Eigenschaften dieser Verbindungen. Zusätzlich ergab der Austausch von Amid-Bindungen im Peptid-Rückgrat durch verschiedene Isostere diverse, teils einzigartige Pseudopeptid-Strukturen, wohingegen Verzweigung des linearen Peptid-Rückgrates zu sphärischen Molekülen führte. Alle Projekte zielten auf die Entwicklung und Synthese diskreter Oligomere für Strukturuntersuchungen, sowie auf die Einbindung der jeweiligen Strukturelemente in Polymere. Die Polymerization geeigneter Monomere zu Polymeren soll zu makro- und supramolekularen Nano-Objekten führen. Die divergent/konvergente Synthese einer Serie von Oligo-d-(alt)-l-lysinen zielte auf die Generierung hydrophiler, pH-sensitiver nanotubularer Strukturen. Schrittweiser Austausch von Amid-Bindungen des Peptid-Rückgrates durch Ester-(alt)-Urea-Einheiten führte zu all-l und d-(alt)-l Oligopseudoleucinen mit 50% und 0% Amid-Bindungs-Anteil. Design, Synthese und Polymerisation von AB-“Click”-Monomeren, basierend auf all-l and l-(alt)-d lysin Dipeptiden, ergaben hochmolekulare, Triazol-enthaltende Polypseudopeptide, deren Seitenketten mit Pyrenbuttersäure quantitativ postfunktionalisiert werden konnten. Die Einführung von Verzweigung in Glutamat-Peptide ergab chirale Dendrimere mit adressierbaren fokalen und periphären Funktionalitäten, sowie variabler Ladungsdichte. Design, Synthese und Polymerisation eines Glutamat basierenden AB2-“Click”-Monomers lieferte verwandte chirale hyperverzweigte Polypseudopeptide. / Inspired by the naturally occurring antibiotics of the Gramicidin family and their d-(alt)-l amino acid sequence, enabling these oligopeptides to adopt a beta–helical secondary structure, the work presented in this thesis targeted the syn-thesis and characterization of peptides and diverse pseudopeptides with regular all-l and d-(alt)-l sequences and the influence of this stereochemical variation on the compounds’ structures and properties. Further diversification of the struc-tures as obtained by replacing amide bonds in the peptide backbone with differ-ent isosteres, affording unique pseudopeptide structures. In addition spherical molecules were generated by introducing branching into the linear peptide scaf-fold. Throughout all projects, the aim was the design and synthesis of discrete oligomers for structural investigations and the incorporation of the respective structural elements into polymers via the polymerization of suitable monomers, in order to generate nanoscale macromolecular and supramolecular objects. The divergent/convergent synthesis of a series of oligo-d-(alt)-l-lysines targeted the generation of hydrophilic, pH-sensitive nanotubular structures. The stepwise replacement of peptide backbone amide bonds with ester-(alt)-urea moieties afforded all-l and d-(alt)-l oligopseudoleucines with 50% and 0% amide content. The design, synthesis, and polymerization of an AB-“Click”-monomer, based on all-l and l-(alt)-d lysine dipeptides afforded high molecular weight, triazole con-taining polypseudopeptides. Quantitative coupling to pyrene butyric acid afforded the respective side chain labeled polymers. The introduction of branching into glutamate peptides afforded fully chiral den-drimers with addressable focal and peripheral functionalities and variable charge density. The design, synthesis, and polymerization of a glutamate based AB2-“Click”-monomer led to related chiral hyperbranched polypseudopeptides.