published_or_final_version / Chemistry / Doctoral / Doctor of Philosophy

published_or_final_version / Chemistry / Doctoral / Doctor of Philosophy

Prompted by the successful clinical application of cisplatin in cancer therapy, worldwide efforts have been devoted to develop new metal-based drugs for anticancer treatment. Gold(III) complexes at first received attention as anti-cancer drug candidates because of their square-planar geometry which resembles that of platinum(II) complexes. Subsequent studies revealed that various gold(III) complexes displayed promising anti-cancer activities with different biological mechanisms. Although some achievements have been obtained in the development of anti-cancer gold(III) complexes, challenges including the improvement of bioavailability, stability and selectivity, elucidation of the action mechanisms, and the development of novel delivery approaches of gold(III) complexes to reduce systematic toxicity, remain to be exploited. A panel of anti-cancer complexes [AuIII(R-C^N)(L)]n+ (wherein HC^N is 2-phenylpyridine, L is biguanide or biuret) have been identified and described in Chapter 3. Biguanide or biuret have been employed to improve the solubility of the complexes in aqueous solutions. Meanwhile, the lipophilicity could readily be adjusted by varying the R group to obtain a balance between lipophilicity and aqueous solubility. Among the synthesized complexes, the cationic complexes, [AuIII(butyl-C^N)biguanide]Cl (3.1) and [AuIII(C^N)biguanide]Cl (3.2) are soluble in aqueous solutions with solubility over 5 mg/mL. Besides, introduction of butyl groups to 3.1 and [AuIII(butyl-C^N)biuret] (3.3) resulted in higher cellular uptake of gold, which might enhance their cytotoxic activities (IC50 values: 1.5–17 μM) compared with 3.2 and [AuIII(C^N)biuret] (3.4) (IC50 values: 9.4–47.3 μM). Moreover, 3.1 was also found to induce cell cycle arrest in S-phase and endoplasmic reticulum (ER) damage in human cervical epithelial carcinoma (HeLa) cells, and display significant anti-angiogenic activity at its sub-cytotoxic concentrations. In Chapter 4, a series of gold(III) complexes with dithiocarbamate and 2-phenylpyridine ligands to target deubiquitinases (DUBs), have been designed. These complexes achieved significant inhibition on purified DUBs. Notably, [AuIII(2-(4-nbutylphenyl) pyridyl)(diethyldithiocarbamate)]PF6 (4.1) inhibited both the purified (IC50 values: 46–223 nM) and cell-based DUBs activities with high efficiency. Its interaction with DUB UCHL1 and peptides which are present in several types of DUBs and contain active cysteine residue were confirmed by mass spectrometric analysis. All complexes displayed significant cytotoxicities, and those containing diethyldithiocarbamate ligand displayed specific cytotoxicity on breast cancer cells. Accumulation of a tumor suppressor p53, cell-cycle arrest, and apoptotic cell death were induced in breast cancer cells by 4.1. Besides, 4.1 also showed anti-angiogenic effects. These biological activities might be related with DUBs inhibition. In Chapter 5, a cytotoxic complex [AuIII(C^N^C)(4-dpt)](CF3SO3) (5.1, HC^N^CH = 2,6-diphenylpyridine; 4-dpt = 2,4-diamino-6-(4-pyridyl)-1,3,5-triazine) has been designed to self-assemble into supramolecular polymers (5.1-SP) in acetonitrile. In physiologically relevant solutions, 5.1-SP displayed a sustained-release property of the anti-angiogenic ligand 4-dpt, and in the presence of glutathione (GSH), [AuIII(C^N^C)-GSH] adduct(s) were also gradually released. The supramolecular polymers 5.1-SP also showed selective cytotoxicity toward cancerous cells, and could act as drug-carriers of other cytotoxic agents to achieve sustained-release behavior. / published_or_final_version / Chemistry / Doctoral / Doctor of Philosophy

Includes bibliographical references. / 249 leaves : ill. ; 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 Physical and Inorganic Chemistry, 1991

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

Thesis (Ph. D.)--University of Hong Kong, 2008. / Also available online.

Thesis (Ph. D.)--University of Missouri-Columbia, 1996. / Typescript. Vita. Includes bibliographical references (leaves 137-148). Also available on the Internet.

Thesis (MSc.(Pharmacology)--Faculty of Health Sciences)-University of Pretoria, 2008. / Includes bibliographical references.

Thesis (Ph. D.)--University of Missouri-Columbia, 1996. / Typescript. Vita. Includes bibliographical references (leaves 137-148). Also available on the Internet.

Gold has emerged as valuable tool for chemists. The physico-chemical properties of the metal centre make it exceptionally prone to activate multiple bonds, such as alkynes and alkenes. Thus, its utility in catalysis has been exploited together with the synthesis of suitable catalysts to allow new, efficient transformations, and the understanding of their intrinsic mechanisms. Reported in this thesis are efforts to this goal, such as the design and study of new Au(I) and Au(III) complexes towards functionalisation of alkynes. The development of new catalytic systems is tackled in Chapter 2. An efficient method for the intermolecular hydrocarboxylation of alkynes catalysed by dinuclear Au-NHC species to access diverse vinyl esters in excellent yield and stereoselectivity is described. The successful methodology is followed by the straightforward intramolecular hydrocarboxylation of alkynoic acids to allow the stereoselective and regioselective synthesis of γ-, δ- and ε-lactones in high yield. Initial mechanistic studies into the hydrocarboxylation of alkynes are shown in Chapter 3. The discovery and characterisation of novel dinuclear gold carboxylates species is described, and their role in the catalytic inter- and intramolecular process is investigated. Chapter 4 highlights the synthesis of novel Au complexes bearing chiral isothiourea ligands. Neutral and heteroleptic Au(I) and Au(III) species are obtained in excellent yield, and their solution and solid-state behaviour studied, together with their electronic and steric properties. Further testing towards activation and functionalisation of alkynes and propargylic derivatives are shown. Dual catalytic processes involving Au and isothiourea catalysts are presented in Chapter 5. Attempts towards Lewis acid/Lewis base activation of multiple bond derivatives and activated esters towards the formation of new C-C bonds is described. The synthesis of organogold compounds, bearing NHC ligands, is described in Chapter 6. Through deprotonation of C(sp3 )-H bonds, a series of stable gold(I) complexes was synthesised and found to be suitable synthons to different gold species. Finally, the redox chemistry of organogold species is explored.