A SuRE way to synthesise macrocyclic peptides

A macrocycle is defined as any molecule containing a ring of 12 or atoms. Macrocycles have important applications in a number of scientific disciplines and, of particular relevance to this work, they have much potential in drug discovery. This is backed up by the existence of over 100 known macrocycle drugs (e.g. the antibiotic erythromycin) but, this number would undoubtedly be far greater if not for the simple fact that macrocycles are usually very difficult to make. Traditionally, macrocycles are made by forming a chemical bond between the two ‘ends’ of a long linear molecule, but competing dimerisation reactions and side product formation typically dominate, meaning such processes are usually inefficient. This research is based on a new system for macrocycle synthesis in which the difficult macrocyclisation step is completely avoided, and instead, macrocycles are ‘grown’ via the iterative expansion of smaller ring systems via Successive Ring Expansion (SuRE).

The SuRE concept was validated in a recent proof-of-concept study published (see W. P. Unsworth et al., Angew. Chem. Int. Ed. 2015, 54, 15794), which demonstrated that specific amino acid could be inserted directly into cyclic β-ketoester starting materials. In this project, a new SuRE reaction system for the synthesis of medicinally relevant macrocyclic peptides will be developed, based on the expansion of simple lactam starting materials. Simpler reaction conditions, improved yields and substrate scope and better medicinal properties in the products are all anticipated benefits of the new reaction systems that will be developed.

Shortlisted applicants will be invited for an interview to take place at the University of York on Wednesday 15 February 2017. Candidates will be asked to give a 5 minute presentation as part of their interview by an academic panel. Applicants shortlisted for interview will be notified by 1 February 2017. All research students follow our innovative Doctoral Training in Chemistry (iDTC): cohort-based training to support the development of scientific, transferable and employability skills

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