Investigations into a palladium-catalysed heterocyclisation-allylation reaction and studies towards the validation of DPY-31 as a novel target for the treatment of parasitic nematode infections

Williams, Lewis (2015) Investigations into a palladium-catalysed heterocyclisation-allylation reaction and studies towards the validation of DPY-31 as a novel target for the treatment of parasitic nematode infections. PhD thesis, University of Glasgow.

Abstract

The opening chapter details investigations undertaken into heteroallylation methodology developed within the France group. The first section gives an overview of the existing strategies for palladiumcatalysed alkene difunctionalisation reactions which construct a new nitrogen-containing heterocycle. Particular attention is devoted to the construction of new carbon–carbon bonds and the relative lack of methods to construct new sp3–sp3 C–C bonds.

The second section details the results of a mechanistic investigation into the previously developedoxyallylation ethodology. The investigation successfully provided evidence that an isohypsicpalladium(II) catalysed mechanism was operative.

The third section discusses attempts towards the extension of the heteroallylation methodology to include the construction of nitrogen-containing heterocycles. Initial attempts focussed on the aminoallylation of tosylamides, from which four new heterocycles were synthesised. Further investigations with hydroxamates allowed the synthesis of three further heterocycles, but the results demonstrate the potential for a greater substrate scope in the future.

The fourth section details experimental procedures and compound data.

The second chapter details research undertaken towards the validation of a novel therapeutic target for the treatment of parasitic nematode infections. The first section details the current treatments and the growing levels of resistance to these treatments. Furthermore, previously published data concerning nematode astacins, the proposed new target, is presented, providing information which was utilised for the design of the new inhibitors.

The second section discusses the design and synthesis of proposed nematode astacin inhibitors, and details the biological testing results gathered by our collaborators. Two compounds, in particular, were demonstrated to be the most potent known compounds against the new therapeutic target. Taken together, the results demonstrate a start point towards to goal of a new class of nematode-infection therapeutics.

The third section details experimental procedures and compound data.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Keywords: Synthetic organic chemistry, medicinal chemistry
• Subjects: Q Science > QD Chemistry
• Colleges/Schools: College of Science and Engineering > School of Chemistry
• Supervisor's Name: France, Dr. D. J.
• Date of Award: 2015
• Depositing User: Mr Lewis Williams
• Unique ID: glathesis:2015-6797
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 03 Nov 2015 13:50
• Last Modified: 11 Nov 2015 14:55
• URI: https://theses.gla.ac.uk/id/eprint/6797