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Title: Fragment synthesis : pharmacophore and diversity oriented approaches
Author: North, Andrew James Peter
ISNI:       0000 0004 7651 4358
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2019
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This thesis explores two approaches to fragment-based drug discovery. First, protein target CK2 was chosen due to its importance in the cancer phenotype. A literature fragment, NMR154L, proved to be a promising compound for fragment development, due to its binding at the interface site of the protein rather than the highly conserved ATP pocket. Analogues were synthesised of this fragment leading to a candidate with a better IC50. Additionally, computer modelling of the interface site suggested that a series of spirocyclic compounds would inhibit this protein. These were synthesised and tested in vitro. Results from these tests were analysed and informed the synthesis of new inhibitors with the aid of crystal structures and computer modelling. Secondly, to address the lack of spirocyclic scaffolds in fragment screening libraries a number of diversity-orientated synthetic campaigns were undertaken. The first of these utilised glycine as starting material. Two terminal alkenes were installed. The alkenes were linked and the amino and acidic residues cyclised. This allowed for the formation of a diverse range of spirocyclic scaffolds from this one starting material. Having established chemistry for linking amino and acidic residues a campaign with dehydroalanine was under taken. This would allow for the installation of the second ring by pericyclic chemistry as well as using chemistry previously established. This pericyclic chemistry was also applied to synthesising spirocycles from rings with exocyclic double bonds. These being readily installed from Wittig chemistry, this allowed utilisation of starting materials which contained a cyclic ketone. Of these azetidinone was a good candidate due to the fact it was a commercially available building block and allowed access to spirocycles containing a 4-membered ring; an underrepresented ring size. Finally, computation analysis was carried out on the library to assess it diversity and any potential biological targets which these fragments may inhibit.
Supervisor: Spring, David Sponsor: EPSRC
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
Keywords: Organic chemistry ; synthesis ; fragment based drug discovery ; diversity oriented synthesis ; CK2