Dial-a-macrocycle: a SuRE way to access macrocyclic peptides

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This research concerns a fundamentally new approach to make a group of molecules known as macrocycles, which are defined as any chemical species containing a ring of 12 or more 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. Indeed, it is telling that of these 100 known macrocyclic drugs, almost all are provided by Nature, with very few being made synthetically in the lab. Traditionally, macrocycles are made by forming a chemical bond between the two 'ends' of a long linear molecule, but competing reactions and side product formation typically dominate, meaning that 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 a process called Successive Ring Expansion (SuRE).In SuRE, a smaller cyclic molecule undergoes a simple chemical transformation to attach a linear molecule onto it. A reactive group built into this new postion is then used to promote a novel chemical reaction (or rearrangement) such that the linear molecule inserts itself into the original ring (which has now increased in size!). A crucial factor in the reaction design is the fact that the chemical groups present in the original ring are replicated in the enlarged product, therefore the same series of steps can then be repeated with a new linker to form an even larger ring; indeed, the sequence can theoretically be repeated indefinitely, allowing of macrocycles of virtually any ring size and composition to be made.In this work, a novel SuRE reaction system for the generation of medicinally important macrocyclic peptides (which are chemically related to proteins) will be developed. Macrocyclic peptides are of much current interest in medicinal chemistry, especially as they have proven efficacy against biological targets that are poorly treated by more traditional small molecule drugs/pharmaceutical agents. However, the fact that macrocyclic peptides are difficult to make using published methods (especially on large scale) is a major barrier to progress in this field. Preliminary results indicate that the new SuRE reaction outlined in the proposal will be high yielding and easy to perform experimentally. It is also expected that it will be broad in scope, thus allowing medicinal chemists to design and make new macrocyclic peptide drug candidates with far greater freedom than is currently possible. Furthermore, as the SuRE method is expected to be equally applicable to small and large scale synthesis, it should serve as a method to scale-up (and potentially even manufacture) biologically active pharmaceutical ingredients, if any macrocyclic peptides with promising medicinal properties are identified.