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Title: Tunable radical cyclisations : a novel approach towards biologically active heterocycles and effects on microglia
Author: Saviolaki, G.
ISNI:       0000 0004 8502 1782
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2015
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Microglial cells are key cells of the CNS that play crucial role in immunity but have been associated with the pathology of several neurological diseases such as Alzheimer's and Parkinson's diseases and multiple sclerosis. Microglial activation by bacterial LPS leads to activation of TLR-4 which in turns leads to neurological disorders. In this present thesis we have successfully synthesized TLR-4 antagonists that could potentially act as protective agents against the development of such diseases. Our methodology is based on a novel common precursor approach towards the synthesis of both tricyclic and spirocyclic heterocycles. All cyclisations are based on thiyl radical/ isocyanide methodology and avoid the use of tin. This methodology has found application to a range of analogues and the results will be described. The obtained tricyclic structures were subject to in-vitro testing, initially on cerebellum granule cells to determine their toxity, then on BV-2 cell lines and finally on microglial cell cultures where they showed a promising glioprotective role against neurological disorders. To conclude, we have successfully synthesized tricyclic ring systems 235, 293, 212 and 341 shown below using our radical cyclisation approach and after carrying out toxicity assays on primary microglia cell cultures which include LPS induced radical and cytokine production we can conclude that these compounds do not induce inflammatory cascades and might serve as protective agents.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available