Author: LAI-MING ELLA. WONG

Publisher:

Published: 2017-01-27

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ISBN-13: 9781361426647

This dissertation, "Iron and Ruthenium Complexes With Nitrogen and Oxygen Donor Ligands for Anti-cancer and Anti-viral Studies" by Lai-Ming, Ella, Wong, 黃禮明, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: Abstract of thesis entitled IRON AND RUTHENIUM COMPLEXES WITH NITROGEN AND OXYGEN DONOR LIGANDS FOR ANTI-CANCER AND ANTI-VIRAL STUDIES Submitted by Ella Lai-Ming Wong For the degree of Doctor of Philosophy at The University of Hong Kong in February 2006 Development of drug resistance in cancer chemotherapy has stimulated the search for new anti-cancer drugs. Due to the versatile oxidation states and diverse coordination chemistry, iron and ruthenium compounds are potential candidates for new anti-cancer agents and metallopharmaceuticals. In this study, iron(II) complexes containing polypyridines as auxiliary ligand and ruthenium-oxo oxalato cluster were synthesized and characterized by X-ray crystallography, and their anti-cancer and anti-viral properties were examined. The iron(II) complexes, [Fe(R-qpy)(CH CN) ](ClO ) [qpy = 3 2 4 2 2,2′ 6′,2″ 6″,2′″ 6′″,2″″-quinquepyridine, R = H (1a) and Ph (1b)] and [Fe(Py -OH)(CH CN)](ClO ) (2) [Py-OH = 5 3 4 2 5 2,6-bis[hydroxybis(2-pyridyl)methyl]pyridine] were stable in physiological buffers and exhibited significant cytotoxicities against some established human cancer cell lines. According to the MTT assay, their IC values were 0.1 - 70 50 M; they exhibited more pronounced cytotoxicities against hepatocellular carcinoma cells than against other type of cancer cells. Flow cytometry studies revealed that 1a could cause cell cycle arrest of HeLa cells at the S-phase, which involved DNA synthesis. Complex 1a was found to catalyze epoxidation, aziridination and amidation of hydrocarbons with good substrate conversions and high product yields. The iron(IV)-oxo and -imido reactive intermediates were generated in situ and their formulations were verified by mass spectroscopy. By Evan''s method, the result supported the iron(IV) formulation with a low-spin d electronic configuration (S = 1). A ruthenium-oxo oxalato cluster formulated as Na [Ru ( -O) (C O ) ] (3) 7 4 3 4 2 4 6 was prepared. Structural studies and magnetic measurements revealed that the ruthenium atoms adopted the oxidation states of +III, +III, +III and +IV. Complex 3 showed anti-HIV properties on infected cells. Using the HIV-1(BaL) virus infected Hut/CCR5 cells, 3 was found to exhibit >90% inhibition on viral replication at 5 M concentration. Similar findings were obtained with other HIV-infected cell lines including GHOST/CXCR4 and PBMCs. Complex 3 was non-cytotoxic to these cells even at 50 M concentration. Relevant to anti-HIV activity, 3 was found to inhibit HIV-1 reverse transcriptase activity in vitro with IC = 2 nM. 50 III A series of ruthenium complexes, cis-[Ru (Me -tet)Cl ]ClO [Me -tet = 6 2 4 6 N, N, N′, N′-tetramethyl-3,6-dimethyl-3,6-diazaoctane-1,8-diamine], III III trans-[Ru (pyz) Cl]Cl (pyz = pyrazole), trans-[Ru (3Mepyz) Cl ]Cl 4 2 4 2 II III [3Mepyz = 3-methylpyrazole], [Ru (3Mepyz) ]Cl, [Ru (salen)(H O) ]Y 6 2 2 2 [H-salen = N, N''-bis(salicylidene)ethylenediamine, Y = Cl and PF ], 2 6 III cis-[Ru (cyclen)Cl]Cl [cyclen = 1,4,7,10-tetraazacyclododecane], 2III trans-[Ru (BiIml) Cl]Y [BiIml = biimidazole, Y = Cl and PF], and 2 2 6 II cis-[Ru (BiIml) (DMSO) ](ClO ) were examined for anti-cancer activities. 2 2 4 2 Their IC values were 4 - 100 M and their cytotoxicities could be affected by 50 the auxiliary ligands. The reduction potentials of the ruthenium compounds were +/0 in