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Title: Design and synthesis of novel compounds to inhibit CSF-1R & evaluation of novel substrates and reactivities in NHC catalysis
Author: Davidson, Robert Wen Ming
ISNI:       0000 0004 6348 0136
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2015
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Chapter I describes work undertaken on a Medicinal Chemistry project studying the small molecule inhibition of the protein CSF-1R. Initial computational work, using the Cresset software package, involved modeling the key steric and electrostatic properties of compounds known to bind to the active site of the target enzyme, CSF-1R. The subsequent use of a virtual (computational) screen, provided new chemotypic scaffolds, which were used as starting points for structure activity relationship (SAR) exploration. Synthetic chemistry routes were designed and optimised towards analogues of promising compound “hits” focusing on the potential to introduce diversified structural features and the diminution of synthetic steps. This included the construction of an uncommon heterocyclic core motif and efforts to understand and control the regioselectivity of its formation. Chapter II concerns a synthetic methodology project in the area of N-heterocyclic carbene (NHC) catalysis. Work on this project included the development of a novel methodology for the formation of amide bonds using an internal redox approach. This involved the activation of an α-reducible aldehyde with an NHC to form an acyl azolium and subsequent trapping of this intermediate with amine nucleophiles. The hypothesis to be studied was that previous attempts at performing similar transformations with these substrates had been hampered by incompatibility of the aldehyde and amine reagents leading to unwanted condensation side reactivity; thus the main focus of this work was to provide an in situ slow release of the amine nucleophile by masking it as a carbamate that would gradually extrude CO2 under the reaction conditions releasing the amine. The other project discussed in this chapter involves the use of hemiacetals as masked aldehydes, in particular within carbohydrates, due to their natural abundance, making them a cheap source of fixed stereocentres.
Supervisor: Fuchter, Matthew Sponsor: Cancer Research UK
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral