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dc.contributor.advisorBradley, Mark
dc.contributor.advisorCampopiano, Dominic
dc.contributor.authorJain, Sarthak
dc.date.accessioned2017-12-20T16:25:52Z
dc.date.available2017-12-20T16:25:52Z
dc.date.issued2016-11-29
dc.identifier.urihttp://hdl.handle.net/1842/25799
dc.description.abstractMany cancer drugs are inherently cytotoxic, leading to severe toxicity towards healthy tissues and organs. One effective strategy to circumvent these side effects is to mask a cytotoxic drug with a “caging group” which, once at the target tissues, releases the masked drug upon an appropriate trigger. In this study, 1,2,4,5-tetrazines which undergo bioorthogonal inverse electron demand Diels-Alder cycloadditions, were used as “chemical triggers” to unmask a “caged cargo”. The vinyl carbamate bond was successfully used as a caging group to ‘cage coumarin’ and was decaged with trigger ‘dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate’. However the trigger underwent hydrolysis under physiological conditions. Various 1,2,4,5- tetrazines were synthesized and hydrolytic stable 1,2,4,5- tetrazines were evaluated for decaging of caged coumarin but with no success. In depth stability of 1,2,4,5-tetrazines under physiological conditions was investigated before exploration alternative caging groups. The results obtained showed basic and physiological conditions had a deteriorating impact on the stability of 1,2,4,5-tetrazine with rapid degradation (t1/2 5– 50 min) in culture medium. The half-lives were significantly increased in acidic pH compared to basic pH (with up to a 187-fold increase from pH 9 to pH 5). Exploration of ketene-N,S-acetals, enamides, thioether-norbornene, enolethernorbornene and vinyl ether as caging groups was conducted. Only vinyl ethers proved to be a success with caging of two fluorophores i.e. fluorescein and resorufin. Two 1,2,4,5-tetrazines were effective in the decaging of the vinyl ether caged fluorophores in water and PBS. Bis-vinyl fluorescein was successfully decaged in HeLa cells showing the potential of vinyl ethers as a caging groups. In future, the vinyl ether would be used to cage a cytotoxic drug and its activation by 1,2,4,5-tetrazine functionalised with tumor targeting peptide or antibodies would result in localised and selective drug release.en
dc.contributor.sponsorotheren
dc.language.isoenen
dc.publisherThe University of Edinburghen
dc.relation.hasversionTetrazine as a Trigger to Release Caged Cargo (GB 1516480.9), 2015. Sarthak Jain, Kevin Neumann, Jin Geng, Elsa Valero and Mark Bradleyen
dc.relation.hasversionKevin Neumann, Sarthak Jain, Jin Geng and Mark Bradley: Nanoparticle “Switch-on” by Tetrazine Triggering, Chemical Communications, 2016, DOI: 10.1039/C6CC05118A.en
dc.relation.hasversionSarthak Jain, Kevin Neumann,Yichuan Zhang, Jin Geng, and Mark Bradley: Tetrazine-Mediated Postpolymerization Modification, Macromolecules, 2016, 49 (15), 5438–5443, DOI: 10.1021/acs.macromol.6b00867en
dc.subject1,2,4,5-tetrazinesen
dc.subjecttetrazineen
dc.subjectdecagingen
dc.subjectbioothogonal chemistryen
dc.title1,2,4,5-Tetrazine mediated decaging of biologically relevant moleculesen
dc.typeThesis or Dissertationen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD Doctor of Philosophyen
dc.rights.embargodate2100-12-31en
dcterms.accessRightsRestricted Accessen


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