Iron is the most abundant trace mineral in the body and an essential element in all living systems. In humans, iron is found at the active site of a number of key proteins involved in oxygen transport, metabolism, respiration and DNA synthesis. The development of agents that inhibit the iron dependent enzyme ribonucleotide reductase (RR) is an established strategy in cancer therapy. Hydroxyurea is the first agent to target RR by inactivating the nonheme iron centre, but its efficacy appears to be limited to myeloproliferative disorders. Currently, Triapine™ (3-aminopyridine-2-carboxaldehyde thiosemicarbazone) is a successful iron chelator, which inhibits enzyme activity and cell growth in vitro at 100 to 1000 fold lower concentrations than hydroxyurea. Preclinical studies suggested that Triapine™ may be an attractive agent to move into clinical development in patients with cancer. Therefore, heterocyclic thiosemicarbazones as well as their iron complexes are an important series of compounds, which may show promising anticancer properties. Thiosemicarbazone derivatives of the HDpT (di-2-pyridyl ketone-3-thiosemicarbazone), HBpT (2-benzoylpyridine-3-thiosemicarbazone), HNBpT (2-(3΄-nitrobenzoyl)pyridine-3-thiosemicarbazone) and HApT (2-acetylpyridine-3-thiosemicarbazone) series and their FeII and FeIII complexes were synthesised and characterised by elemental analyses, UV-vis spectroscopy, NMR spectroscopy, IR (ATR, attenuated total reflectance), EPR spectroscopy, electrochemistry, and X-ray crystallography. To further understand their physical and chemical properties, other transition metal Mn, Co, Ni, Cu and Zn complexes of the HDpT and HBpT analogues were synthesised and characterised. The X-ray crystal structure of trivalent Fe complexes and divalent (Mn, Ni, Cu and Zn) complexes were determined. The HDpT, HBpT, HNBpT and HApT analogues of thiosemicarbazone class of iron chelators have the capability to bind metal ions as tridentate (N,N,S) ligands, forming 2:1 ligand:Fe complexes with an N4S2 octahedral coordination sphere. During the course of investigation, the formation constants of MnII, NiII, CuII and ZnII complexes of these series were determined by spectrophotometric competition titration with nitrilotriacetic acid (NTA). Several interesting aspects of the coordination chemistry of these iron chelators have also been discovered To better understand the biological activities of these ligands, the chemical and the physical properties of these ligands and their iron and other transition metal complexes have been studied. Chiefly, we are concerned with their ability to cross the cell membrane (lipophilicity) as well as the redox chemistry of their metal complexes. The lipophilicity of the ligands was determined by direct partitioning between 1-octanol and water at pH 7.4. The Fe complexes of the HApT series exhibit lower redox potentials than their corresponding HDpT, HBpT and HNBpT complexes and higher anticancer activity indicating a link between their Fe redox reactivity and their biological properties.
| Identifer | oai:union.ndltd.org:ADTP/286019 |
| Creators | Mohammad Islam |
| Source Sets | Australiasian Digital Theses Program |
| Detected Language | English |
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