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Applications of Aqueous Olefin Metathesis in Chemical Biology and Drug Discovery

Sabatino, Valerio. Applications of Aqueous Olefin Metathesis in Chemical Biology and Drug Discovery. 2020, Doctoral Thesis, University of Basel, Faculty of Science.

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Abstract

Olefin metathesis is a Nobel prize winning reaction that can rearrange double or triple bonds with the use of transition metal catalysts. Water is a poor solvent for metathesis reactions as it triggers the premature degradation of the catalysts. However, ruthenium-based catalysts fairly tolerate water and pushed many scientists to design catalysts and substrates that can be employed in aqueous metathesis. The Ward laboratory has previously identified in olefin metathesis a useful catalytic reaction to be performed by artificial metalloenzymes (ArMs). Previously, an ArM was successfully assembled inside the periplasm of Escherichia coli, generating an “artificial metathase” able to perform an abiotic reaction such as olefin metathesis, in vivo. Herein, I discuss the opportunities to establish in vivo metathesis reactions in the context of ArMs. In metabolic engineering, such abiotic cofactors can implement metabolic pathways, for instance by generating an essential metabolite in a genetically engineered organism deprived of enzymes that synthesize that specific metabolite. To validate this hypothesis, I synthesized indole derivatives as tryptophan precursors via ring-closing metathesis with ArMs. The most relevant work of this doctoral thesis addressed the in vivo applicability of artificial metalloenzymes as bioorthogonal tools for targeted therapy. As my main goal was to enable drug discovery applications, I developed a methodology that can lead to the in vivo activation of drugs. The studies herein described led to the realization of a “close-to-release” strategy relying on aromatic intermediates which lead to spontaneous 1,4-elimination of small molecule cargoes in biological media. The close-to-release resulted in a robust approach for the release of drugs, metabolites and fluorescent probes under physiological conditions and in the periplasm of E. coli. As a follow-up on this technology, interdisciplinary studies in collaboration with Dr. Avik Samanta led to the encapsulation of an ArM inside protocellular entities based on DNA. A work that showcases new perspectives to understand how compartmentalized biomachineries emerged in a prebiotic era. In particular, how olefin metathesis activity leads to downstream morphogenetic responses with varying levels of complexity. Overall, this doctoral thesis has expanded the toolbox of transition metal mediated bioorthogonal reactions and paves the way towards ruthenium-triggered bioorthogonal catalysis for targeted therapies.
Advisors:Ward, Thomas R. R. and Gillingham, Dennis
Faculties and Departments:05 Faculty of Science > Departement Chemie > Chemie > Bioanorganische Chemie (Ward)
05 Faculty of Science > Departement Chemie > Chemie > Organische Chemie (Gillingham)
UniBasel Contributors:Gillingham, Dennis
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:14611
Thesis status:Complete
Number of Pages:v, 238
Language:English
Identification Number:
  • urn: urn:nbn:ch:bel-bau-diss146115
edoc DOI:
Last Modified:15 Feb 2022 10:51
Deposited On:10 Feb 2022 16:09

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