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Title: Design, synthesis and evaluation of structurally-diverse analogues of platensimycin
Author: Fisher , Martin James
Awarding Body: University of Leeds
Current Institution: University of Leeds
Date of Award: 2011
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This thesis describes the development of a new approach to the discovery of novel bioactive small molecules in which diversity-oriented synthesis techniques are integrated with structure-based ligand design. The approach was applied to the design, synthesis and evaluation of analogues of platensimycin, a potent natural product antibiotic known to target the fatty acid biosynthesis pathway enzyme FabF. The design of analogues was achieved by the creation of a virtual library of fragments that formed part of molecules which could be synthesised using diversity oriented methods developed within the Nelson group. These fragments could then be appended in silica to the headgroup taken from platensimycin to generate new molecular scaffolds. These molecules could be subsequently decorated in silica with a range of functional groups to further improve their predicted binding affinity. The synthesis of analogues was accomplished using fluorous-tagged specialised building blocks, containing the platensimycin headgroup. Skeletal information for molecular scaffolds was pre-encoded by appending simple building blocks, to yield metathesis substrates, which could be reprogrammed by ring closing metathesis, accessing a range of heterocyclic scaffolds. Further functionalisation of the heteroatoms in the resulting products allowed all the analogues to by prepared using a common synthetic route. Finally, the ligands were assessed using an NMR-based biophysical assay which had not been used previously to test FabF inhibitors. This assay allowed a critical evaluation of the approach by comparison of predicted and observed K; values.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available