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

Lead Research Organisation: University of York
Department Name: Chemistry


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.

Planned Impact

Macrocyclic compounds are unquestionably of great scientific and societal importance, but they are generally difficult to make via known synthetic methods, which represents a major barrier when trying to develop applications of functionalised macrocycles. In this research, we aim to address this using Successive Ring Expansion (SuRE), which is an innovative strategy that allows macrocycles to be produced by expanding smaller ring systems iteratively. SuRE has the potential to significantly simplify the synthesis of complex macrocycles, which should enable the design of new technologies across a number of varied scientific fields that currently are impaired by synthetic/practical limitations.

Of particular relevance to this research, it is anticipated that SuRE will expedite the discovery and development of new pharmaceuticals and agrochemicals. Continued research and development in these industries is essential to meet the burgeoning worldwide healthcare and sustenance requirement, and thus supporting these vitally important, major UK industries is of high importance. Increasing the ease with which bioactive macrocycles can be prepared (throughout the discovery process) could ultimately lead to the development of new drugs/crop protection agents, which would enhance quality of life, making a direct societal impact. To facilitate the uptake and impact of the research in both of these industries, materials transfer agreements have been established with both Eli Lilly (pharmaceuticals) and Syngenta (agrochemicals) to perform bioassays on the produced macrocycles; in both cases this service will be provided for free as in-kind support. Planned collaborations with academic groups should also help to generate additional medicinal impact; for example, both synthesised compounds and proposal ideas produced during this project will be submitted to the EU Lead factory (ELF) program. ELF is an innovative venture designed to deliver free access to a unique industry-standard high-throughout-screening platform of up to 500,000 compounds to provide novel starting points for drug discovery. Any useful biological results arising from these activities will be of high value to medicinal researchers and also inform our group about particularly useful macrocycle scaffolds and thus direct future synthetic endeavors. It is also planned to explore the potential of our compounds as inhibitors of protein-protein interactions. Macrocycles have proven efficacy in this arena, and our involvement would support the objectives of the University of Leeds-led EPSRC program grant to develop new approaches for the inhibition of protein-protein interactions.

These collaborative activities should ensure that our efforts are directed towards the synthesis of macrocyclic compounds with the highest chance of making a genuine societal impact, either in medicinal chemistry or agrochemistry. The simplicity and versatility of the new SuRE procedures is important, as this increases the chances of the new SuRE methods being used, both by collaborators and other groups. Scalability is another key advantage, as this means that SuRE can potentially be used right through the discovery process, from lead identification to manufacture. As well as scientific benefits, we also believe that UK / EU industry will be able to gain a commercial advantage as these new methodologies are established. With involvement from the academic/industrial collaborators outlined above, we will explore and discuss any such opportunities as they arise. Any novel inventions with potentially valuable intellectual property (IP) generating during this project will have their IP protected. The University of York Research and Enterprise Office will be consulted over IP protection as appropriate, liaising with their intellectual property and legal manager.


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Stephens TC (2018) Iterative Assembly of Macrocyclic Lactones using Successive Ring Expansion Reactions. in Chemistry (Weinheim an der Bergstrasse, Germany)