Design and synthesis of small molecule probes for metabolic processes

Cairns, Andrew G. (2013) Design and synthesis of small molecule probes for metabolic processes. PhD thesis, University of Glasgow.

Abstract

Synthesis of a photoactivated uncoupler I was completed and subsequently used by collaborators to demonstrate mitochondria uptake.

The synthesis of a ratiometric, targetable calcium sensor was completed up to intermediate II (9 steps), alongside a thiohydantoin heterocycle III synthesised in 5 steps. A co-worker has subsequently completed the probe synthesis based on this route, with the resulting probe showing good binding and optical responses in testing.

Numerous routes to 5,6-disubstituted phenanthridinium salts were investigated towards the synthesis of a mitochondrially targeted superoxide probe and hydroxylated standards. In the course of this work a novel cyclisation was developed based on intramolecular SNAr giving access to 9-benzyloxyphenanthridinium salt V.

Rapid and high-yielding access to 5,6-disubstituted phenanthridinium salts IX was then achieved through forming benzophenones VIII via Suzuki coupling and converting these to imines with the alkylamine. The nitrogen atom of the imine then undergoes cyclisation onto the aryl fluoride in an intramolecular SNAr upon heating. This transformation was shown to have good steric and electronic tolerance in the synthesis of 13 phenanthridinium analogues with 6 structural diversification points. Subsequent DFT calculations by a colleague showed this reaction proceeds in a concerted fashion and as such represents a considerable mechanistic novelty.

Efforts towards a new probe for mitochondrial superoxide led to the synthesis of 3-tertbutyl-dihydrophenanthridine X, which does not intercalate into DNA upon oxidation. This concept was refined and lead to the development of neopentyl ethidium XI and the targeted analogue MitoBNH XII and its deuterated analogue XIII.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Keywords: synthetic chemistry, metabolic probes
• Subjects: Q Science > QD Chemistry
• Colleges/Schools: College of Science and Engineering > School of Chemistry
• Supervisor's Name: Richard, Dr. Hartley
• Date of Award: 2013
• Depositing User: Mr Andrew Gerard Cairns
• Unique ID: glathesis:2013-4897
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 04 Feb 2014 09:30
• Last Modified: 17 Feb 2017 08:18
• URI: https://theses.gla.ac.uk/id/eprint/4897