Synthesis and structure-activity relationships studies of novel thiosemicarbazone derivatives as potential anti-cancer agents

摘要

The primary objective of this thesis is to synthesise novel thiosemicarbazone based iron chelators and investigate their anti-proliferative activity against neoplastic cells.Traditionally, iron chelators were developed for the treatment of iron overload diseases. However, the increased requirement for iron in rapidly proliferating cells, compared with normal cells, create an opportunity to use iron as a novel target for cancer chemotherapy. Previous development of thiosemicarbazone based iron chelators created new iron chelators with potent and selective anti-tumour activity towards a wide variety of human and murine tumour xenografts such as 2-benzoylpyridine thisoemicarbazone (BpT) and 2-(3'-nitrobenzoyl)pyridine thiosemicarbazone (NBpT). In order to understand the structure-activity relationship of the thiosemicarbazone scaffold, novel BpT analogues were designed. First attempt was made by incorporating methyl substitution on the pyridine ring and mono- or di- methoxy substitutions at the phenyl ring. In addition, incorporation of electron-donating and electron-withdrawing substituents at the phenyl substituents of the N4-position of the BpT scaffold was done. Subsequently, dimerisation of BpT by forming dithiosemicarbazones using 2,6-dibenzoylpyridine were also investigated. Most of the novel thiosemicarbazone based iron chelators showed significantly higher anti-proliferative activity than the commercially available, ‘gold-standard’ chelator desferrioxamine. Structure-activity relationship study revealed that the chelators with a single methyl substitutent on the pyridine ring had the highest anti-proliferative activity. Incorporation of mono- or di- substitution at the phenyl ring resulted in lower anti-proliferation activity, while methoxy substitution at the phenyl ring enhanced iron chelation efficacy. The study also indicated that benzoylpyridine thisoemicarbazones with electron-donating substituents resulted in greater anti-proliferative activity than electron-withdrawing groups. The increased molecular weight of the chelators influences the lipophilicity of the ligands resulting in low or moderate potency of the chelators towards neoplastic cells.The new information provided by this study could assist in the design and synthesis of future development of thiosemicarbazone based iron chelators with higher anti-proliferative activity and iron efficacy.