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This thesis describes the preparation of a various NHC ligands with five and six-membered rings, different fused aromatic cores and the subsequent synthetic development of their complexation of with Ag, Ru and Pd. The investigation and preparation of these compunds was with the intention of exploring their chemical and physical properties. The synthesis of the NHC ligands proved to be difficult, but analysis and characterisation of the side products from the reactions helped to establish successful synthetic methodologies. In both the five and six-membered research conducted a common attribute was established of a pyrid-2-yl substituent at the 1 position or both the 1 and 3 positions, thus providing new NHC ligands to investigate. The organic syntheis of the research focused on two NHC ligand functionalites, five and six membered rings. The six memerbered rings focused on 1H-perimidine as the core unit and the design of both bidentate and tridentate NHC ligands to mimic the structural binding relationship of 2,2’- bipyridine (bpy) and 2,2’:6’2”-terpyridine (tpy) with various metal salts. The synthesis of the bpy analogues was achieved in good overall yields with minimal synthetic challenges. However, the tpy analogue was unable to be realised due to time constraints and problems associated with its synthesis. The five membered NHC ligands synthesised were to investigate the physical effects of systematically increasing the size of its aromatic core. The main focus of the research was on the phenanthrene imidazole NHC ligands. This was investigated due to the minimal research that has been conducted on this core unit and NHC-complexes. Synthesis of the two-bidentate NHC ligands with an imidazole head group and fused phenanthrene backbone were completed, but this was with a picolyl substituent at the 1 position rather than the pyrid-2-yl substituent. This failure to isolate this product was attributed to steric influences. Pyrene-fused-imidazole NHC ligands were also investigated and pyrene offers a NHC core that hasn’t been investigated previously. However, synthesis and isolation of the NHC ligands proved to be difficult and was associated with the poor solubility of the NHC ligands. The organometallic NHC synthesis was studied extensively with the main focus on establishing appropriate conditions to give a NHC complex. The main metal investigated was ruthenium as subsequent NHC complexes were expected to have potentially interesting properties such as luminescence. The synthesis of a perimidine and phenanthrene NHC ruthenium complexes have not been isolated before, thus giving new NHC complexes. Many different synthetic routes were attempted to synthesise a perimidine NHC ruthenium complex. However, this proved difficult due to associated higher reactivity of the carbene carbon of perimidine with a new side product as a result of this research. The phenanthrene NHC complex synthesis suffered due to time constraints but potential methodology for their synthesis is stated.

Human tumor cell progression and metastasis is partially dependent on the ability of tumor cells to adhere to the proteins of the extracellular matrix and migrate to distant locations. Using a combinatorial screening approach, six novel D-amino acid containing peptides were identified and analyzed for their ability to adhere to human prostate tumor cells, support tumor cell adhesion and inhibit tumor cell adhesion to ECM proteins. Two peptides, RZ-3 (kmviywkag) and HYD1 (kikmviswkg) bound to tumor cell surfaces. A scrambled peptide derivative of HYD1, HYDS (wiksmkivkg) is not active. As immobilized ligands, RZ-3 and HYD1 can support prostate tumor cell adhesion. Prostate tumor cell adhesion to immobilized RZ-3 and HYD1 is integrin dependent. Soluble RZ-3 and HYD1 inhibits tumor cell adhesion to extracellular matrix proteins in a concentration dependent manner. These results indicate that RZ-3 and HYD1 are biologically active D-amino acid containing peptides that can support tumor cell adhesion and can inhibit tumor cell adhesion to immobilized extracellular matrix proteins.Cell migration is dependent on adhesive interactions with the extracelluar matrix. These interactions induce signaling and cytoskeletal responses necessary for migration. HYD1 completely blocks random haptotactic migration and inhibits invasion of prostate carcinoma cells on laminin-5. This effect is adhesion independent and reversible. The inhibition of migration by HYD1 involves a dramatic remodeling of the actin cytoskeleton resulting in increased stress fiber formation and actin colocalization with cortactin at the cell membrane. HYD1 interacts with a6 and a3 integrin subunits and elevates laminin-5 dependent intracellular signals including focal adhesion kinase, mitogen activated protein kinase kinase, and extracellular signal-regulated kinase. The scrambled derivative of HYD1, HYDS, does not interact with the a6 or a3 integrin subunits and is not biologically active. The minimal element for bioactivity of HYD1 was determined using alanine-substituted analogs of HYD1 and N- and C-terminal deletion mutants of HYD1. The minimal element necessary to block cell migration on laminin-5 and activate cell signaling through ERK is xikmviswxx. Taken together, these results indicate that HYD1 is a biologically active integrin-targeting peptide that reversibly inhibits tumor cell migration on laminin-5 and uncouples phosphotyrosine signaling from cytoskeletal dependent migration.

Les complexes de la famille des ansa-chromocènes sont relativement peu nombreux, mais ils ont tout de même démontré des réactivités intéressantes comme la possibilité de coordonner une molécule de monoxyde de carbone au centre métallique sans être sous pression constante de gaz, ce qui n’est pas le cas pour l’homologue chromocène. L’ansa-chromocène le plus surprenant est sans doute le Me2Si(C5Me4)2Cr, car il est le seul qui ne comporte pas de ligand autre que celui de type ansa. Cependant, ce composé a été obtenu sans que le mécanisme de la réaction ne soit compris et prouvé, seul un mécanisme proposé a été publié. Au cours de cette étude, le mécanisme proposé a tout d’abord été infirmé grâce à de nombreuses expériences qui ont mené à l’élaboration d’un nouveau mécanisme. Par la suite, la réactivité du Me2Si(C5Me4)2Cr a été approfondie en le faisant réagir avec divers réactifs. Aucun produit d’addition oxydante n’a été isolé, mais la réaction avec l’isonitrile forme un complexe asymétrique avec deux isonitriles coordonnés. La détermination du moment magnétique du composé Me2Si(C5Me4)2Cr confirme la présence de deux électrons non-pairés à la température de la pièce et évoque la possibilité d’une transition à S=2 à température plus élevée. La synthèse de nouveaux complexes de type ansachromocène insaturé a été tentée avec d’autres ligands ansa, et la réaction avec [C2H4(C9H6)2]Li2 mène à un complexe dimérique avec des ligands indényles pontés. / Only a few ansa-chromocenes complexes are known but some of them have shown interesting reactivities such as the ability to coordinate a carbon monoxide molecule to the chromium center without being under continuous gas pressure, which is not the case for the chromocene analogue. The most surprising ansa-chromocene is without doubt Me2Si(C5Me4)2Cr, because it is the only example of an ansa-chromocene lacking additional ligands. However, the compound was obtained by accident and the mechanism of its formation was neither well established nor understood. Only a tentative mechanism was published. During the course of the present study, the proposed mechanism has been disproved by a series of experiments that led to the elaboration of a new mechanism. The reactivity of Me2Si(C5Me4)2Cr has been studied by reactions with various compounds. No oxidative addition product was isolated, but the reaction with isonitrile yielded an asymmetric complex with two isonitriles coordinated to chronium. The determination of the magnetic moment of this complex confirmed two unpaired electrons at room temperature and indicated the possibility of an S=2 transition at higher temperature. The synthesis of new unsaturated ansa-chromocene complexes has been attempted with other ansa ligands, and the reaction with [C2H4(C9H6)2]Li2 led to a dimeric complex with bridged indenyl ligands.

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The ligands 2-cyanocyclopentyldiphenylphosphine and 2-cyanocyclohesyldiphenylphosphine were synthesized from 1-cyanocyclopentene and 1cyanocyclohexene by addition reactions using diphenylphosphine and aqueous base as the catalyst. These ligands reacted with Pt(II) and Pd(II) salts to yield complexes of the stoichiometry MX2L2 (X = C1, Br). In these complexes the ligands were found to function as monodentate phosphines. Infrared spectroscopic evidence suggested that the platinum complex was of cis and the palladium complexes were of trans geometries.The reactions of the ligands 2-cyanocyclopentyldiphenylphosphine and 2-cyanocyclohexyldiphenylphosphine or the ligand 2-cyanoethyldiphenylphosphine with the complexes dimethyyl(cyclooctadiene)platinun(II) or methyl) (chloro) (cyclooctadiene) platinum(II) resulted in complexes of the stoichiometries Pt(CH3)2L2 and Pt(CH3)(C1)L2. In these complexes the ligands also functioned as monodentate phosphines. hmr and far infrared spectroscopic evidence suggested that the dimethylplatinuin(II) complexes were cis and the (methyl)(chloro)platinum(II) complexes were trans.A complex of the stoichiometry Pd2Cl4(Ph2PC6H10CN)2 was isolated from the reaction of a 1:1 mole ratio of PdC12 with Ph2PC6H10CN. Far infrared and Raman spectroscopic evidence 'suggested that the complex was a chlorine bridged dieter with the ligands at symmetrical positions. The nitrile groups in this complex reacted rapidly with alcohols to yield monomeric imino ether complexes.The Pt(CH3)(C1)L2 complexes reacted with AgPF6 to yield cationic salts of the stoichiometry [Pt(CH3)L2]n+n with one ligand in each [Pt(CH3)L2]+ unit presumably serving as a bridging ligand and the other as a monodentate phosphine. The coordinated nitrite groups in these complexes reacted slowly with methanol to yield amino ether complexes.

Holliday junctions are formed as an intermediate during DNA recombination as the two strands come together. Recombination occurs during meiosis, and also during DNA double strand repair. Trapping this branched intermediate could prevent DNA repair from occurring in cells which would prove beneficial during cancer treatment. There are many enzymes that cleave Holliday junctions. One such enzyme, T7 Endonuclease I, was specifically chosen to detect ligand binding at the core of the junction since its binding and cleavage of cruciforms is well documented. Specialized bifunctional ligands were studied in this project that were designed to bind DNA structures that are held in close proximity to one another. These compounds have two identical binding modules that are connected by a linker of various length and rigidity, with each module binding very weakly; however, when both modules bind the binding affinity is greatly enhanced. The interactions of these compounds with cruciforms are currently being studied.

Bibliography: leaves 123-141. / xv, 141 leaves : ill. (some col.) ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / This thesis developes specific tools to monitor receptor expression in a ligand-independent manner, demonstrates the receptor expression is not static and can be modulated by cytokines, identifies strong evidence in defining the N-terminal domain of IL-3R & chain and B'C' and F'G' loopes of domain 4 of Bc as functional domains involved in ligand binding and function and provides novel potential therapeutics. / Thesis (Ph.D.)--University of Adelaide, Dept. of Medicine, 1997