This thesis describes progress towards the use of thio-maleimides as intracellular delivery vehicles. Initially, we describe efforts towards the synthesis of a Förster resonance energy transfer (FRET) maleimide for biological proof of concept experiments. We then go on to demonstrate the potential use of thio-maleimides as intracellularly cleavable moieties that can be used to deliver cargo by the development of “turn-on” reporter molecules and a pro-drug. We have synthesised a number of quenched dansyl-maleimide conjugates as “turn-on” reporter molecules. We have performed conjugate substitution reactions with the intracellular antioxidant glutathione and our quenched fluorophore-maleimide conjugates, to release the fluorophores under approximately physiological conditions. Kinetic studies of these reactions were performed. Cellular experiments confirm this reaction also occurs in biological systems, thus supporting the viability of the use of thio-maleimides as intracellular delivery vehicles. We then optimised the insertion of maleimide into small molecule disulfides. This was in order to insert maleimide into Psammaplin A, a natural product prod-drug. We thus synthesised a thio-maleimide prodrug that proved to be efficacious in biological studies.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:626799 |
| Date | January 2014 |
| Creators | Youziel, J. D. |
| Publisher | University College London (University of London) |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://discovery.ucl.ac.uk/1419510/ |
Page generated in 0.0039 seconds