Thomson, Phillip (2016) The design and synthesis of compounds that moderate nitric oxide levels. Doctoral thesis, Keele University.

[img] Text
ThomsonPhD2016.pdf
Restricted to Repository staff only until 27 May 2017.

Download (7MB)

Abstract

Nitric oxide (NO) is a potent biological messenger known to play key roles in many biological processes. Medical conditions such as angina, cancer and some neurodegenerative diseases have been shown to benefit from nitric oxide related therapy. The moderation of in vivo levels of nitric oxide is important when considering any lead compounds that exploit NO pathways. It has been theorised that conditions such as Alzheimer’s and Parkinson’s disease may benefit from a reduction in the levels of NO present in the brain. By inhibiting the nNOS enzyme in brain tissue it is possible to reduce the levels of NO and produce an effective way of treating a number of different neurodegenerative diseases. A series of novel, and chemically simple NOS inhibitors were sought out, building upon evidence alluded from three-dimensional structural docking studies performed using pymol and a 3D virtual environment facility.

In conditions that could benefit from a higher concentration of NO, such as angina and arteriosclerosis, the use of NO-donors is an attractive option. The synthesis of a series of novel NO-donors, based on a furoxan scaffold, of sufficient stability was achieved allowing NO release and vasodilatory studies to be conducted. Compound 94 induced 100% reversal of contraction in rat aortic, renal and pulmonary vessels and was able to release NO under both photochemical and oxidative conditions with an IC50 0.25μM. The vasodilatory effect of compound 94 and other compounds in the series was found to be reproducible and reversible. When compared to the BNF listed NO donor, sodium nitroprusside (SNP, 9), compound 94 produced a more sustainable relaxation with no fluctuations in vascular tone.

Mechanistically NO release was confirmed using mass spectroscopy and a nitric oxide analyser (NOA) through the application of ozone based chemiluminescence and provided interesting evidence towards the decomposition of this novel furoxan. In addition, a second series of novel NO donors based on the diazeniumdiolates was successfully synthesised alongside X-ray crystallography data, which is pertinent to the debate surrounding the reactivity of both the internal and terminal oxygens in the NONO moiety. These diazeniumdiolate based donors were also investigated using the NOA to identify the bet conditions for NO release, which were found to be light at 254nm.

Item Type: Thesis (Doctoral)
Subjects: Q Science > QD Chemistry
Divisions: Faculty of Natural Sciences > School of Chemical and Physical Sciences
Depositing User: Lisa Bailey
Date Deposited: 13 Apr 2017 08:46
Last Modified: 13 Apr 2017 08:46
URI: http://eprints.keele.ac.uk/id/eprint/3270

Actions (login required)

View Item View Item