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Design and Synthesis of a 3-D Fragment Library

Downes, Thomas (2019) Design and Synthesis of a 3-D Fragment Library. PhD thesis, University of York.

[img] Text (Final Thesis)
Downes_202039166_CorrectedThesisClean.pdf - Examined Thesis (PDF)
Restricted until 31 March 2021.


This thesis describes the design and synthesis of a library of novel 3-D fragments for use in drug discovery. Chapter 1 explains the process of fragment based drug discovery in detail, as well as why the synthesis of novel 3-D fragments is needed and the previous work carried out in the group to design and select 33 initial 3-D fragments. These fragments were designed to fit industry-recommended guidelines on physicochemical properties and their 3- D shape was analysed using principal moments of inertia (PMI) plots to demonstrate that they occupied under-explored areas of 3-D space. Chapter 2 describes synthetic efforts towards four of these fragments. Chapter 3 details a new approach that was devised in order to synthesise 3-D fragments that contained greater functional group variation. This route focussed on the triflation, Suzuki- Miyaura cross-coupling, hydrogenation and derivatisation of β-ketoesters to give 3-D fragments. Using this route, 24 novel 3-D fragments were synthesised. Finally, Chapter 4 contains an analysis of both the physicochemical properties and the 3-D shapes of the 1st and 2nd generation 3-D fragments. These properties are compared to both industry-recommended guidelines and commercially available fragment libraries.

Item Type: Thesis (PhD)
Academic Units: The University of York > Chemistry (York)
Depositing User: Dr Thomas Downes
Date Deposited: 22 May 2020 17:17
Last Modified: 22 May 2020 17:17
URI: http://etheses.whiterose.ac.uk/id/eprint/26562

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