Smiles Rearrangement Bioorthogonal Reaction

Project ID: 2228cd1367 (You will need this ID for your application)

UCL Lead department: Chemistry

Lead Supervisor: Jamie Baker

Project Summary:

Bioorthogonal reactions represent a powerful class of reactions, and a rapid growth area in chemical biology research, as they enable selective chemistries even in complex biological contexts (leading to the award of the 2022 Nobel Prize in Chemistry)[1]. They are being exploited widely in applications ranging from the selective labelling of biomolecules, controlling the properties of bio-responsive materials and even the precision activation of drugs in vivo. In this PhD a completely new class of bioorthogonal click reactions will be investigated, based on preliminary recent discoveries within our laboratory. The Smiles rearrangement is an intramolecular nucleophilic aromatic substitution (SNAr) reaction involving heteroatom migration. It was discovered in 1930, by Warren and Smiles[2] and has been widely explored and applied within organic synthesis. It is notable that whilst SNAr reactions have been widely used in thiol bioconjugation,[3,4] the Smiles rearrangement has not been exploited yet in this area. In this project, the student will design, synthesise, and apply suitable electron-poor heteroaromatics for reaction with thiol containing bis-nucleophiles, with the aim of discovering highly selective, rapid and high yielding Smiles rearrangements. The reaction will need to be efficient under buffered reaction conditions, in the presence of a range of competing nucleophiles and biologically relevant species. Key prospective applications will include a ‘click-and-release’ reaction, which could allow the controlled activation of drug molecules in specific situations, and the construction of antibody-drug conjugates as a leading new class of targeted anti-cancer therapeutics. We are looking to recruit a highly motivated and creative organic chemist with an interest in chemical biology. This project will provide a thorough training in synthesis, bioconjugation as well as in a series of transferable skills. The student will join a friendly, supportive, and highly collaborative team of researchers working on innovative bioconjugation methodologies.