Use this URL to cite or link to this record in EThOS:
Title: Synthesis of s-tetrazines for biomedical applications
Author: Gambardella, Alessia
ISNI:       0000 0004 8508 8741
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2019
Availability of Full Text:
Access from EThOS:
Full text unavailable from EThOS. Please try the link below.
Access from Institution:
Tetrazines are aromatic six-membered heterocycles, containing four nitrogen atoms that can react as dienes in inverse-electron-demand Diels-Alder (IEDDA) reactions leading to the formation of pyridazines. Owing to their high chemical selectivity, fast reactivity and biocompatibility, the IEDDA reaction between s-tetrazines and dienophiles has become a powerful tool in a variety of biological applications. Thus tetrazines have been exploited in applications ranging from nuclear medicine and imaging to drug delivery. The focus of my thesis has been on the design and the synthesis of new tetrazine scaffolds and their use in organic chemistry, drug activation and pre-targeting applications. In one area I successfully achieved the design and synthesis of a new orthogonal protecting group (vinyl ether benzyloxycarbonyl) that could be selectively cleaved by treatment with a tetrazine, resulting in a versatile protection strategy to temporarily mask amino functionalities in solid-phase peptide synthesis. The power of this approach was shown with the synthesis of two cyclic peptides, showing its orthogonality and compatibility with other protecting groups commonly used in Fmoc-based peptide chemistry. A new concept in drug activation chemistry was developed where tetrazines were used to design a fully traceless dual prodrug-prodrug activation strategy in which a tetrazine-masked drugs and a vinyl ether protected anti-cancer drug were coreacted via IEDDA chemistry to generate a pyridazine-based miRNA-21 inhibitor and the free anticancer drug camptothecin under biologically compatible conditions. Finally, in collaboration, an "amplification probe" was designed in which tetrazinequenched fluorophores were synthesized and used to give massive signal amplification in cell based assays upon reaction with a functionalized polymeric probe.
Supervisor: Bradley, Mark ; Vendrell Escobar, Marc Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: bioorthogonal reactions ; tetrazine chemistry ; drug activation strategy ; imaging ; fluorescence ; non-fluorescent tetrazine ; vinyl ether benzyloxycarbonyl