A chemical approach to combatting cardiovascular reperfusion injury

Pala, Laura (2019) A chemical approach to combatting cardiovascular reperfusion injury. PhD thesis, University of Glasgow.

Due to Embargo and/or Third Party Copyright restrictions, this thesis is not available in this service.

Abstract

The research discussed in this thesis aims at combatting diseases generated by mitochondria dysfunction. Chapter 1 introduces mitochondria structure, roles and functionality, together with various strategies to improve the delivery of drugs to different targets and specifically to mitochondria. The most common strategies to target specifically mitochondria have been described, and in Chapter 2 the investigation of new strategies has been reported. This involves the synthesis of a small library of carboxylic acid and ester derivatives of phosphonium salts, in vitro results on isolated mitochondria and computational calculations. The obtained data all together support a model of uptake proposed in Chapter 2.
The research discussed in chapter 3 aims to ameliorate the effects of ischaemia/reperfusion injury, one of the deadliest cardiovascular diseases, for which no effective treatment is present in clinical practice. Previous research elucidated that the disease originates from mitochondria dysfunction and showed cardioprotection in vivo by delivering malonate as dimethyl malonate. Malonate is a known inhibitor of succinate dehydrogenase, an enzyme at the interface of the ETC and TCA cycle. The research described in this chapter presents libraries of compounds designed to improve the delivery of malonate to mitochondria. Synthesis and in vitro and in vivo results are shown, concluding with the identification of a few lead compounds.
In Chapter 4 a common feature in pathologies caused by mitochondria dysfunctions was discussed. This is the oxidative damage deriving from the production of ROS. The primary ROS is superoxide and its identification and quantification with reliable methods is crucial for the understanding of diseases. Hydroethidine is one of the best molecular probes used for the selective identification and quantification of superoxide forming a unique fluorescent species. However, hydroethidine presents some disadvantages, namely fluorescence quenching in water, which lowers the limit of detection, and intercalation to DNA, which increases the fluorescent response. The mechanism of fluorescence quenching in water is not fully understood and a few different mechanisms have been proposed in the literature. Several target compounds were designed aiming to block the DNA intercalation and the fluorescent quenching in water, in order to obtain a more suitable molecular probe for the superoxide detection for in vivo applications. The multistep synthesis of the designed targets is described together with the various routes investigated. Preliminary emission results are reported as well.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: Mitochondria, ischeamia/reperfusion injury, drug delivery, esterases, phosphonium salts, ROS, superoxide, hydroethidine.
Subjects: Q Science > QD Chemistry
Colleges/Schools: College of Science and Engineering > School of Chemistry
Supervisor's Name: Hartley, Prof. Richard C.
Date of Award: 2019
Embargo Date: 10 January 2023
Depositing User: Laura Pala
Unique ID: glathesis:2019-77869
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 13 Jan 2020 13:58
Last Modified: 28 May 2020 13:27
Thesis DOI: 10.5525/gla.thesis.77869
URI: http://theses.gla.ac.uk/id/eprint/77869
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