White Rose University Consortium logo
University of Leeds logo University of Sheffield logo York University logo

Design and Synthesis of 3-D Fragments to Explore New Areas of Pharmaceutical Space

Jones, Stefan (2020) Design and Synthesis of 3-D Fragments to Explore New Areas of Pharmaceutical Space. PhD thesis, University of York.

[img]
Preview
Text
Jones_107013699_CorrectedThesisClean.pdf.pdf - Examined Thesis (PDF)
Available under License Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 UK: England & Wales.

Download (10Mb) | Preview

Abstract

The thesis is focused on the design and synthesis of 3-D fragments to explore new areas of pharmaceutical space. Chapter 1 provides an overview of fragment-based drug discovery including, fragment design, screening and synthesis. The diastereoselective synthesis of nine pyrrolidine and piperidine fragments A-I is described in Chapter 2. These fragments were identified as suitable 3-D fragments based on a 3-D shape analysis using principal moments of inertia. The key step in the synthesis of the 2,3-disubstituted pyrrolidines was the stereoselective reduction of the dihydropyrrole to afford the cis-diastereoisomer, with the trans¬-isomers accessed via epimerisation. The piperidines were synthesised via hydrogenation of the pyridine to give the cis-diastereoisomer as the major product, with the trans again access via epimerisation of the methyl ester. Chapter 3 covers of methodology for the synthesis of all 20 regio- and diastereosiomers of piperidines J. The syntheses were completed using three main types of methodology: pyridine hydrogenation, epimerisation and lithiation-trapping of N-Boc piperidines. In Chapter 4, a different approach to 3-D fragment design and synthesis was developed. Here, the focus was on the identification of synthetic methodology that would allow the incorporation of different scaffolds and a range of aromatic/heteroaromatic groups. Ester enolate α-arylation and α-alkylation were the two approaches used to design fragments K and L which had their shapes analysed, with the most 3-D fragments selected and synthesised. Finally, the entire York 3-D fragment library was compared against a set of commercial fragment libraries to evaluate their usefulness in drug discovery, with the analysis fully summarised in chapter 5.

Item Type: Thesis (PhD)
Academic Units: The University of York > Chemistry (York)
Identification Number/EthosID: uk.bl.ethos.805501
Depositing User: Mr Stefan Jones
Date Deposited: 22 May 2020 15:16
Last Modified: 21 Jun 2020 09:53
URI: http://etheses.whiterose.ac.uk/id/eprint/26241

You do not need to contact us to get a copy of this thesis. Please use the 'Download' link(s) above to get a copy.
You can contact us about this thesis. If you need to make a general enquiry, please see the Contact us page.

Actions (repository staff only: login required)