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Title: Manipulation of the inflammatory response in vivo using synthetic tanshinone analogues
Author: Foulkes, Matthew James
ISNI:       0000 0004 7233 9169
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2018
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During inflammation, retention of persistent neutrophils at the inflammatory site, either due to excessive neutrophil recruitment or failed spontaneous resolution of inflammation, can play a major role in many chronic inflammatory diseases, such as chronic obstructive pulmonary disease. Current treatments for dysregulated inflammation are generally ineffective, non-specific, and can exhibit undesired side effects, thus there remains a need to identify new effective clinical treatments. Tanshinones have shown promising anti-inflammatory effects by targeting neutrophils in vivo, yet are still an underexplored class of compounds in this regard. In this work, an optimised six step synthetic route was used to synthesise a series of substituted tanshinone analogues and isomeric isotanshinones. A radical decarboxylative alkylation and an intramolecular Heck reaction were key steps in this route, and optimisation of these processes was explored considerably, including the use of Design of Experiments software. Synthesis of additional tanshinones using a Diels-Alder reaction was investigated, whilst some further compounds with broad structural similarity to tanshinones were also produced. All synthesised compounds were evaluated in vivo using a zebrafish model of inflammation. Some of the compounds reduced initial neutrophil recruitment, whilst others accelerated resolution of neutrophilic inflammation, which allowed for the construction of broad structure-activity relationships and identification of compounds with promising in vivo anti-inflammatory effects. Notable differences in toxicity profiles between compound classes were also observed. In addition, to seek a greater understanding of how molecules such as tanshinones access their molecular target in vivo, analysis of the expression of drug transporter proteins in human and zebrafish neutrophils was carried out. Annotated phylogenetic trees were produced which are envisaged to provide a generally useful resource to the field in future studies.
Supervisor: Renshaw, Stephen A. ; Jones, Simon Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available