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Metal Mediated Mechanisms of Drug Release 10.17863/CAM.31775 Stenton, Benjamin James 0000000158522803 Bernardes, Goncalo 0000000165948917 In this thesis will be described research towards the development of bioorthogonal bond-cleavage reactions, and their applications in targeted drug delivery (Figure 1). The first project relates to the development of a palladium mediated bond-cleavage or “decaging” reaction which can cause a propargyl carbamate to decompose and release an amine. This was further developed by the incorporation of a protein modification handle which allowed an amine-bearing drug to be covalently ligated to a protein by a palladium-cleavable linker. This chemistry was demonstrated by the conjugation of the anticancer drug doxorubicin to a tumour targeted anti-HER2 nanobody. The drug could then be delivered to cancer cells upon addition of a palladium complex. The second project relates to the development of a platinum mediated bond-cleavage reaction. This was developed with the aim of using platinum-containing anticancer drugs – such as cisplatin – as a catalyst to cause drug release reactions in tumours. In this reaction an alkyne-containing amide can decompose to release an amine upon addition of platinum complexes, and was applied to the release of prodrugs of the cytotoxins monomethylauristatin E and 5-fluorouracil in cancer cells. A cisplatin-cleavable antibody-drug conjugate was designed and synthesised, and progress towards its biological evaluation will be discussed. University of Cambridge 2018-11-24 Thesis Doctoral Doctor of Philosophy (PhD) en EPSRC https://www.repository.cam.ac.uk/handle/1810/284402 https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/d244ea95-88b6-480e-9da4-a3fdf49165bb/download 18a3c77b2086660b3c509fb6cda26601 https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/1e3327de-029f-427c-adf6-f66f05c54c4b/download 87eda9de84448d1f82354d60eee3eb5f https://www.rioxx.net/licenses/all-rights-reserved/ Bioorthogonal decaging linker ADC antibody-drug conjugate targeted drug delivery drug delivery bifunctional linker protein modification organometallic catalysis chemotherapy cancer bioconjugation conjugation