High resolution molecular spectroscopic techniques are useful tools to accurately probe energy differences between quantum states of molecules. These energy levels are inherently dependent on the underlying potential functions, which ultimately govern the structures and dynamics of molecules. Thus, the detailed characterization of potential energy profiles through molecular spectroscopy provides important information about molecular properties. Given the increased structural and dynamic complexity of large molecules, small compounds serve as excellent prototypes to establish quantum mechanical models that accurately characterize quantum states and ultimately potential energy functions of various molecular classes. This thesis describes the use of rotational and rovibrational spectroscopy to probe one such class: four-membered heterocycles. Rotationally-resolved vibrational spectra of four-membered rings including β-propiolactone (c-C3H4O2), 3-oxetanone (c-C3H4O2), azetidine (c-C3H6N) and silacyclobutane (c-C3H8Si) were recorded below 1200 cm-1 using a Fourier transform infrared spectrometer (FTIR) with synchrotron light at the far infrared beamline of the Canadian Light Source (CLS). Additionally, Fourier transform microwave (FTMW) spectroscopy was used to study the pure rotational spectra of β-propiolactone and silacyclobutane for the first time. This allowed the accurate characterization of the ground vibrational state and molecular structure in support of the rovibrational analysis. The far infrared vibrational modes of these four molecules were analyzed individually initially and followed by a global fit of all observed transitions of each molecule. Unique spectroscopic signatures arising from Coriolis coupling(β-propiolactone, 3-oxetanone), tunneling motions (azetidine, silacyclobutane) and the large amplitude ring puckering vibration (3-oxetanone, azetidine, silacyclobutane) were revealed and treated. The resultant Hamiltonian models used for each molecule account for the observed spectra as the spectroscopic constants are consistent across the ground state and all vibrationally excited states studied. Collectively, these studies have provided a highly effective working protocol for the treatment of high resolution rovibrational data to model the dynamic behaviour of real molecules.

The 5-HT7 receptor is the most recent addition to the 5-HT receptor family and has been linked to a variety of physiological and pathophysiological processes. Well established antide-pressant pharmaceuticals have recently been found to activate the 5-HT7 receptor, supporting the role of the 5-HT7 receptor in the antidepressant mechanism. The synthesis of potent selec-tive 5-HT7 receptor antagonists could afford a greater understanding of the 5-HT7 receptor function as well as lead to potential drug candidates. The synthesis of unfused biheteroaryl derivatives as 5-HT7 receptor ligands has been de-scribed within. These compounds have been tested for biological activity on the 5-HT6 and 5-HT7 receptors. 4-(3’-Furyl)-2-(N-substituted-piperazino)pyrimidines were found to be potent 5-HT7 receptor ligands. 4-(2’-Furyl)-2-(N-substituted-piperazino)pyrimidines have shown high se-lectivity for the 5-HT7 receptor over the 5-HT6 receptor.

High resolution molecular spectroscopic techniques are useful tools to accurately probe energy differences between quantum states of molecules. These energy levels are inherently dependent on the underlying potential functions, which ultimately govern the structures and dynamics of molecules. Thus, the detailed characterization of potential energy profiles through molecular spectroscopy provides important information about molecular properties. Given the increased structural and dynamic complexity of large molecules, small compounds serve as excellent prototypes to establish quantum mechanical models that accurately characterize quantum states and ultimately potential energy functions of various molecular classes. This thesis describes the use of rotational and rovibrational spectroscopy to probe one such class: four-membered heterocycles. Rotationally-resolved vibrational spectra of four-membered rings including β-propiolactone (c-C3H4O2), 3-oxetanone (c-C3H4O2), azetidine (c-C3H6N) and silacyclobutane (c-C3H8Si) were recorded below 1200 cm-1 using a Fourier transform infrared spectrometer (FTIR) with synchrotron light at the far infrared beamline of the Canadian Light Source (CLS). Additionally, Fourier transform microwave (FTMW) spectroscopy was used to study the pure rotational spectra of β-propiolactone and silacyclobutane for the first time. This allowed the accurate characterization of the ground vibrational state and molecular structure in support of the rovibrational analysis. The far infrared vibrational modes of these four molecules were analyzed individually initially and followed by a global fit of all observed transitions of each molecule. Unique spectroscopic signatures arising from Coriolis coupling(β-propiolactone, 3-oxetanone), tunneling motions (azetidine, silacyclobutane) and the large amplitude ring puckering vibration (3-oxetanone, azetidine, silacyclobutane) were revealed and treated. The resultant Hamiltonian models used for each molecule account for the observed spectra as the spectroscopic constants are consistent across the ground state and all vibrationally excited states studied. Collectively, these studies have provided a highly effective working protocol for the treatment of high resolution rovibrational data to model the dynamic behaviour of real molecules.

Aldehyde oxidase catalysed oxidation of various quinolinium and related cations has been studied in vitro. Oxidation products were identified by comparison of their spectral and chromatographic characteristics with those of authentic compounds. The N-heterocyclic cations and quinolones used required synthesis. Incubation of N-methylquinolinium, N-methyl-7,8-benzoquinolinium and N-phenylquinolinium yielded the corresponding 2- and 4-quinolones simultaneously. The ratio of 2- to 4-quinolone formation was found to be species dependent; the proportion of 4-quinolone was greater with guinea pig enzyme than with rabbit enzyme. Incubation of N-methyl-4-methylquinolinium, N-methyl-4-phenylquinolinium and N-methylphenanthridinium produced the expected 2-quinolones. Cations substituted adjacent to the ring nitrogen, i. e. N-methyl-2- methylquinolinium, N-methyl-2-phenylquinolinium and N-phenyl-2-phenylquinolinium, were oxidised to the corresponding 4-quinolones. Kinetic constants were determined spectrophotometrically. The Km values obtained with rabbit enzyme ranged from 1.6 x 10-3 M for N-methylquinolinium to <10-5 M for N-phenyl-2-phenylquinolinium. Quaternary compounds were found to be better substrates than their non-quaternary counterparts, except for N-methylisoquinolinium and N-methylphenanthridinium. In general, guinea pig aldehyde oxidase was shown to have a greater affinity for N-heterocyclic cations than rabbit enzyme. The substrate binding site has been discussed in the light of the results outlined below. Oxidation of N-methyl-4-phenylquinolinium (to the 2-quinolone) was competitively inhibited by N-methyl-2-phenylquinolinium (which yields the 4-quinolone), indicating that both these cations interact at the same active site. The ratio of 2- to 4-quinolone production from N-methylquinolinium was constant under various conditions, including purification of the enzyme but changed at high pH or in the presence of N-methylphenanthridinium. Inhibition studies indicated that both quaternary and non-quaternary compounds act at the same site on the enzyme. Km and Vmax values for phthalazine, N-methyl-2-phenylquinolinium and N-methylquinolinium were determined over the pH range 5.4 to 10.2. In each case, results indicated that the enzyme has an ionisable group at the active site with a pK ca. 8. Aldehyde oxidase was shown to catalyse the dehydrogenation of the pseudobases 3,4-dihydro-4-hydroxy-3-methyl-2-quinazolinone and 3,4-dihydro- 4-hydroxy-3-methylquinazoline.

Despite previous extensive study of the widely-employed ruthenium-catalysed olefin metathesis reaction, the finer mechanistic details have not been elucidated. An area that is noticeably lacking is spectroscopic exploration of the relevant complexes. In this work, organometallic ruthenium complexes of importance to olefin metathesis have been investigated using Ru K-edge X-ray absorption spectroscopy. The lowest energy feature in the Ru K-edge spectrum has been unambiguously assigned as due to Ru 4d←1s transitions. These electric-dipole-forbidden transitions are extremely sensitive to geometry. For centrosymmetric complexes, the pre-edge feature has very low intensity because it is limited by the weak electric quadrupole mechanism. By contrast, non-centrosymmetric complexes exhibit a substantial increase in pre-edge intensity because Ru 5p-4d mixing introduces electric-dipole-allowed character to the Ru 4d←1s transitions. The energy of the edge feature in the Ru K-edge spectrum corresponds to ionisation of 1s electrons and is a good indicator of the charge on the metal centre. Unexpectedly, we found that the first-generation (L = PCy₃) Grubbs precatalyst (1) has a higher 1s ionisation energy than the second-generation (L = H₂IMes) complex (2). This effect provides a compelling rationale for the unexplained differences in phosphine dissociation kinetics for complexes 1 and 2: the phosphine dissociation rate of 2 is slower than 1 because the metal centre is more electron-deficient in 2. Density functional theory calculations confirm the charge differences and offer some insight into the nature of bonding in these complexes, particularly with regard to the N-heterocyclic carbene and trialkylphosphine ligands. On the basis of these results, we propose that, for this system, the NHC ligand is a weaker σ-charge donor than the phosphine ligand, and that the NHC accepts significant π-electron density from the metal; both interactions function to reduce the electron density on the ruthenium centre. An ultimate goal is to investigate reactive species in the olefin metathesis mechanism; accordingly, we have made considerable progress toward collecting XAS data for a metallacyclobutane species, and we are pursuing methods to trap the four-coordinate intermediate in the metathesis cycle.

"Work carried out by the author between March 1953 and January 1957 as a member of the Biophysics Group of the Physics Department of the University of Adelaide."--Pref. / "December 1957." / Includes bibliographical references (leaves 131-135) / vii, 135 leaves : ill. ; 26 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 Physics, 1957

Src Homology 3 (SH3) domains are small protein- protein interaction domains that bind to proline-rich peptides, mediating a range of important biological processes. Because the deregulation of events involving SH3 domains forms the basis of many human diseases, the SH3 domains are appealing targets for the development of potential therapeutics. Previously in the field, no examples of entirely small-molecule ligands for the SH3 domains have been identified. However, in our research group, we have discovered a class of heterocyclic compounds that bind to the Tec SH3 domain at conserved residues in the proline-rich peptide binding site, with weak to moderate affinity. The highest affinity of these was 2- aminoquinoline (Kd = 125 mM). In this thesis, a range of approaches are described, that were intended to contribute towards development of higher affinity small-molecule ligands for the Tec SH3 domain. Preliminary experiments, involving testing a variety of compounds structurally related to 2- aminoquinoline, provided new structure activity information, and led to a better understanding of the 2-aminoquinoline/SH3 domain binding event. The major component of this thesis is a thorough investigation into the synthesis of a range of 2- aminoquinoline derivatives. N-Substituted- 2-aminoquinolines were synthesised, however these compounds bound the SH3 domain with slightly lower affinity than 2-aminoquinoline. 6- Substituted-2-aminoquinolines were subsequently prepared, and ligands were identified with up to six-fold improved affinity relative to 2-aminoquinoline, and enhanced selectivity for the Tec SH3 domain. The techniques used for the ligand binding studies were Nuclear Magnetic Resonance (NMR) chemical shift perturbation and Fluorescence Polarisation (FP) peptide displacement assays. As part of the ligand binding studies, it was intended that the 3D tructure of a 2- aminoquinoline ligand/SH3 complex would be obtained using NMR methods, provided that a ligand was identified that bound the SH3 domain in slow exchange on the NMR timescale. However, this goal was not fulfilled. Despite this, the work presented in this thesis provides a solid foundation for the development of potent 2-aminoquinoline ligands for SH3 domains, with engineered specificity. / Thesis (Ph.D.)--School of Molecular and Biomedical Science, 2005.

Thesis (M. Phil.)--University of Hong Kong, 2008. / Also available in print.

Thesis (Ph. D.)--University of Nevada, Reno, 2008. / "December, 2008." Includes bibliographical references. Online version available on the World Wide Web.

Thesis (Ph.D.(Chemistry))--University of Pretoria, 2002. / Includes bibliographical references (p. 194-195).