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Metal complexes of S-based ligands as anti-cancer and anti-parasitic agents

thesis
posted on 22.02.2017, 03:00 authored by Trinh, Iman
This project aimed to synthesise and characterise a range of new metal complexes of S-based ligands as pharmaceutical leads and imaging agents. Of particular interest was the chemistry of bifunctional S- and O-based compounds with various biologically-relevant metals. After synthesising a range of mercaptocarboxylic acids, the chemistry and structure-activity relationship of these molecules with bismuth, ruthenium and rhenium was explored. The effect of changing the metal in S-based dithiocarbamate compounds on biological activity was also investigated. The production and characterisation of six new mercaptocarboxylic acids including 2-mercapto-3-methylbutanoic acid (MMA-H2), 2-mercaptro-3-phenylpropanoic acid (MPA-H2), 3-mercaptobutanoic acid (MBA-H2), 3-mercapto-3-phenylpropanoic acid (MMP-H2), 3-mercapto-3-(thiophenyl-2-yl)propanoic acid (MTP-H2) and 3-mercapto-3-(4-methoxyphenyl)propanoic acid (MMPA-H2) is reported. The synthetic routes to obtaining α- and β-substituted mercaptocarboxylic acids were optimised and resulted in the isolation of analytically pure compounds. α-mercaptocarboxylic acids were synthesised using a three-step functional group interconversion process while β-acids were synthesised via a two-step reaction. The synthesis of bismuth(III) sulfidocarboxylate complexes was investigated using a range of bismuth precursors. Compounds with the general formula Bi2L3 were obtained using the triphenylbismuth solvent-free method (L = TLA, MBA, MMP), bismuth t-butoxide method (L = MMA, MPA, MMPA) and the bismuth nitrate pentahydrate reaction (L = MTP). The stability of these compounds were studied, analysed by X-ray powder diffraction (XRD) and the implications discussed. To study the biological activity of ruthenium(II) p-cymene (pcy) complexes, seven new compounds with the general formula {[Ru(pcy)L]2} were successfully synthesised and the structure of four of these compounds were characterised by X-ray crystallography. These were all isostructural and had features consistent with previous structural reports. To increase yield, HPLC purification was utilised and resulted in the separation of isomers. This was confirmed by nuclear magnetic resonance (NMR) spectroscopy and circular dichroism (CD) studies. The cytotoxicity and anti-invasive properties of these compounds were tested through MTT assays and real-time collagen migration assays and compared with other ruthenium compound currently in clinical trials. Several complexes were found to be active with IC50 values as low as 33 µM and selectivity was observed for the different cell lines. The reactions of mercaptocarboxylic acids with rhenium(I) precursors showed that mixed products were formed. The carboxylic acid (COOH) group was protected through esterification to control product formation. Reactions with [Re(bpy)(CO)3DCM]SO3CF3 (bpy = 2,2-bypyridine) resulted in the formation of neutral products with the general formula [Re(bpy)(CO)3L]. These compounds were characterised and their photophysical properties explored. Finally, a range of n-methylcyclohexyl dithiocarbamate (DTC) compounds with the formula M(DTC)X (M = Li, Na, K, Sb, Bi, Mg, Fe, Zn) were synthesised via salt metathesis and direct synthetic methods and characterised. The effect of metal on biological activity was explored against the Leishmania major promastigote and human fibroblasts. Complexes with a more ionic character showed selective toxicity against the parasite and were non-toxic to fibroblasts. Despite being in the same chemical group the bismuth and antimony compounds had opposite effects while other compounds were found to be selective to the parasite with a narrow therapeutic index.

History

Campus location

Australia

Principal supervisor

Philip C. Andrews

Additional supervisor 1

Peter C. Junk

Year of Award

2015

Department, School or Centre

Chemistry

Course

Doctor of Philosophy

Degree Type

DOCTORATE

Faculty

Faculty of Science