The Synthesis and Investigation of Phenylimidazo[1,2-a]quinoline Analogues as Anti-Proliferative Agents.

Abstract

Cancer is a complex, multifarious disease among the leading causes of mortality world-wide. Mutations facilitated through errors in genomic replication can actuate development of cells with replicative immortality, resulting in cancerous tumour formation. Hormonal carcinogenesis, mediated by genotoxic oestrogen metabolite formation, in tissues exposed to high concentrations of oestrogen (such as the breast and ovaries) is catalysed by CYP1 enzymes. The observed up-regulation and over expression of certain CYP1 enzymes in oestrogen dependent cancers provides a potential therapeutic target for the development of potent, selective CYP1 enzyme inhibitors in attempts to treat oestrogen dependent cancers. A preliminary hit compound was previously identified through virtual screening and molecular docking processes. The compound, 2-phenylimidazo[1,2-α]quinoline (PIQ) was identified as a potent, selective inhibitor for CYP1 subfamily of enzymes. The aim of this project was the investigation into the synthesis and potential anti-proliferative activities of various novel PIQ analogues towards the cancer cell lines. Three different series of PIQ analogues were synthesised containing different modifications to the PIQ scaffold. The first series was the addition of substituents, ranging in size and chemical properties to the phenyl moiety. The second series consisted of PIQ analogues with imidazole modifications, including bromination, methylthiolation, Suzuki and Sonogashira coupling reactions The final series of analogues involved the methylthiolation (at the imidazole position) of the previously synthesised phenyl-substituted analogues, serving as a basis to allow for the comparison of analogues containing imidazole modifications both with and without phenyl substituents. The 2-phenylimidazo[1,2-α]pyridine analogue was also synthesised to assess the importance of the quinoline scaffold. In total, forty-five PIQ analogues were synthesised. All synthesised compounds were analysed using molecular modelling and docking techniques with the CYP1 enzyme protein structures utilising the GOLD software. These compounds also underwent biological testing at the Auckland Cancer Society Research Centre (ACSRC) to examine their anti-proliferative abilities. Results from both molecular modelling and cellular experimentation allowed for the comparison of these two processes to examine the accuracy of predicted biological activity. Most compounds showed some anti-proliferative activity towards both cell lines, however only one PIQ analogue obtained improved bioactivity over the previously reported 2-phenylimidazo[1,2-α]quinoline. These results give insight into the potential structural activity relationships of the PIQ scaffold and provide a basis for future investigation.