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The mutagenic activity of oxazolopyridine compounds

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Lee, HH 2018 , 'The mutagenic activity of oxazolopyridine compounds', PhD thesis, University of Tasmania.

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Abstract

Planar heterocycles such as benzoxazoles are biologically active and often used as a scaffold for drug discovery. However, due to some toxicities associated with this group of compounds, analogues of benzoxazoles such as benzothiazoles, benzimidazoles and more recently, the oxazolopyridines have been developed in medicinal chemistry programs. The oxazolopyridine is an easy and versatile scaffold to synthesise as it is stable and has many sites for the addition of functional groups. The oxazolopyridine scaffold is also highly polar, contributing to improved target interaction in biological systems. This results in the anti-bacterial, anti-fungal, anti-parasitic and anti-inflammatory activities, and in sirtuin modulation of the oxazolopyridines. In fact, oxazolopyridines are shown to be non-toxic in vitro and in vivo in some studies, making it a very suitable scaffold for drug candidates. However, the full toxicity profile of the oxazolopyridine compounds, which include mutagenicity, is unknown and needs to be investigated to determine any unwanted effects. The oxazolopyridines and imidazopyridines are structurally similar and have some similar biological activities, but more concerningly, the carcinogen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) 46 also belongs to the imidazopyridine family. In the current study, 2-(3-aminophenyl)oxazolopyridine, 60 was chosen as the lead compound given its structural similarities to PhIP 46. It was therefore hypothesised that compound 60 may be genotoxic (DNA damaging) and mutagenic, where its mode of action is similar to PhIP 46 via the amino group attached. Toxicology screens were conducted on compound 60 in vitro. Consistent with previous studies, compound 60 was found to be non-cytotoxic in the colony forming assay. However, compound 60 was genotoxic in cells in the γH2AX assay. The non-cytotoxic but genotoxic nature of compound 60 was found to be attributed by the ability of the cells to repair the DNA damage to maintain survival after 24 hours. Compound 60 was later found to be mutagenic in the Ames test indicating that the cellular repair of the DNA damage is error-prone. In fact, compound 60 is a pro-mutagen which is dependent on oxidation and enzymatic bio-activation by liver enzymes for activity. More importantly, compound 60 was also found to transform cells in the soft agar invasion assay.
Further studies were carried out to determine the genotoxic and mutagenic mode of action of compound 60. Through quantitative structural-activity relationship (QSAR) determination, the amino group of compound 60 was not the factor for activity. This was supported by the generated Hammett plot using analogues of 2-aryloxazolopyridine where it was understood that the activity of compound 60 was driven by molecular electron density and not solely by the presence of the amino group as hypothesised. This was an important turning point for this study where the focus was shifted towards studying the electron density on the oxazolopyridine core. Given that activation is oxidation dependent, selected 2-aryloxazolopyridine analogues were found to produce N-oxides at the pyridine ring of the oxazolopyridine core. The 2-phenyloxazolopyridine-N-oxides were also found to be genotoxic in cells and was thought to be the active species. However, it was found that the 2-aryloxazolopyridine-N-oxides still required further bio-activation by liver enzymes to be mutagenic in cells. This has led to further QSAR determination of the roles of the nitrogen atoms in the oxazolopyridine core. It was therefore proposed that upon the N-oxidation of the pyridine nitrogen, a second oxidation event on the oxazole nitrogen may occur to generate the active mutagen. Identification of the mutagenic species by enzymatic bio-activation of a 2-aryloxazolopyridine analogue was attempted using ultra pressure liquid chromatography and mass spectrometry (UPLC-MS). There was evidence that the 2-aryloxazolopyridine-N-oxide was formed under these conditions but more work was required to identify the mutagenic species. Therefore, the evidence presented in this thesis is the first detailing the mutagenic mode of action and liability of the oxazolopyridine compounds which has been widespread in drug development. In fact, this may have significant ramifications for the use of the oxazolopyridine scaffold in the future.

Item Type: Thesis - PhD
Authors/Creators:Lee, HH
Keywords: oxazolopyridine, DNA damage, mutation, enzymatic bio-activation, n-oxidation
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Copyright 2018 the author

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