Chemotherapy is widely used to treat various forms of cancer. However, some chemotherapeutic drugs, due to their antineoplastic properties, also act upon healthy cells which normally replicate rapidly causing a plethora of undesirable side effects. One rising and promising therapeutic strategy is the development of prodrugs. Prodrugs are derivatives of the pharmaceutically active drugs but require an enzymatic or biochemical transformation within a certain biological space in order for it to become activated and capable of exerting the desired pharmacological effect. As a novel prodrug approach, this thesis describes the pioneering use of a bioorthogonal organometallic (BOOM) activation strategy to develop spatially-controlled anticancer treatments. Bioorthogonal reactions are selective chemical processes between two abiotic reagents in a biological system that do not interfere with the system’s biotic components. In BOOM reactions, one of the reagents is a metal catalyst, which if immobilized, could in principle allow for the local transformation of a continuous flow of a bioorthogonal chemo-substrate indefinitely. To exploit the benefits of this paradigm in anticancer therapy, this thesis reports the design, synthesis and screening of a set of prodrugs masked with bioorthogonal protecting groups sensitive to activation by a catalysts-based “activating device”. Specifically, it describes the synthesis of palladium (Pd0) functionalized resins (the activating device) capable of activating cytotoxic pyrimidine analogue prodrugs masked with Pd0-labile protecting groups. Both the Pd0 functionalized resins and the BOOM-activated prodrugs are independently non-cytotoxic. However, once in combination together, the Pd0 is capable of mediating the removal of the masking groups in situ and rendering the drugs in their cytotoxic state with comparable antiproliferative properties to the unmodified parental drugs in vitro. The Pd0 resins also display biocompatibility and local catalytic activity inside zebrafish embryos. This approach is intended to generate a more targeted therapeutic treatment regime while minimizing harm to normal healthy tissues through the local generation of prodrugs which are not dependent on intrinsic biological activators but by an external activating device, thus reducing the systemic presence of the drug.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:691146 |
| Date | January 2015 |
| Creators | Weiss, Jason Thomas |
| Contributors | Unciti-Broceta, Asier |
| Publisher | University of Edinburgh |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://hdl.handle.net/1842/15957 |
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