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postgraduate thesis: The anti-cancer properties of cyclometalated gold(III) complexes and organogold(III) supramolecular polymers

TitleThe anti-cancer properties of cyclometalated gold(III) complexes and organogold(III) supramolecular polymers
Authors
Issue Date2014
PublisherThe University of Hong Kong (Pokfulam, Hong Kong)
Citation
Zhang, J. [张晶晶]. (2014). The anti-cancer properties of cyclometalated gold(III) complexes and organogold(III) supramolecular polymers. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b5185919
AbstractPrompted 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.
DegreeDoctor of Philosophy
SubjectGold compounds - Therapeutic use
Organogold compounds - Therapeutic use
Dept/ProgramChemistry
Persistent Identifierhttp://hdl.handle.net/10722/208171

 

DC FieldValueLanguage
dc.contributor.authorZhang, Jingjing-
dc.contributor.author张晶晶-
dc.date.accessioned2015-02-20T23:07:00Z-
dc.date.available2015-02-20T23:07:00Z-
dc.date.issued2014-
dc.identifier.citationZhang, J. [张晶晶]. (2014). The anti-cancer properties of cyclometalated gold(III) complexes and organogold(III) supramolecular polymers. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b5185919-
dc.identifier.urihttp://hdl.handle.net/10722/208171-
dc.description.abstractPrompted 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.-
dc.languageeng-
dc.publisherThe University of Hong Kong (Pokfulam, Hong Kong)-
dc.relation.ispartofHKU Theses Online (HKUTO)-
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.rightsThe author retains all proprietary rights, (such as patent rights) and the right to use in future works.-
dc.subject.lcshGold compounds - Therapeutic use-
dc.subject.lcshOrganogold compounds - Therapeutic use-
dc.titleThe anti-cancer properties of cyclometalated gold(III) complexes and organogold(III) supramolecular polymers-
dc.typePG_Thesis-
dc.identifier.hkulb5185919-
dc.description.thesisnameDoctor of Philosophy-
dc.description.thesislevelDoctoral-
dc.description.thesisdisciplineChemistry-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.5353/th_b5185919-

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