A SuRE way to synthesise macrocyclic peptides

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Fundamentally, this project is based on the continued developed of the 'Successive Ring Expansion' (SuRE) method to make macrocycles of medicinal importance, especially cyclic peptides. Typically, macrocyclic peptides/peptide mimetics are prepared via the end-to-end cyclisation of a long linear precursor: a difficult and unpredictable process. Unwanted side reactions, especially dimerisation processes, are a major problem; macrocyclisation reactions are generally performed at high dilution to minimise such problems, but they are rarely avoided entirely, often resulting in low yielding, impractical processes, especially on large scale. SuRE is an alternative strategy in which end-to-end cyclisation is entirely avoided, validated in published work from York, in which we demonstrated that cyclic beta-keto esters can be coupled with linear acid chloride and upon protecting group cleavage, undergo cyclisation and spontaneous ring expansion in one-pot. The ring expansion reactions are designed such that the functionality present in the starter unit is replicated in the product (circled in yellow), therefore the same coupling/ring expansion sequence can be repeated: thus, rings of increasing size can effectively be 'grown', by inserting linear fragments into an existing ring system. To date, work has focused on the ring expansion of cyclic beta-keto esters with amino and hydroxy acids. The main goal of this project is to expand the SuRE reaction toolbox through the development new SuRE reaction systems, based on the successive ring expansion of simple lactams into cyclic peptides, and to then use these products in medicinally oriented applications. Specific goals are listed below: a) By utilising N,N-benzyl-Fmoc protected amino acid chlorides as linear fragments, controlled successive ring expansion should be achievable; in this method the regenerated NH-lactam serves as a handle to allow the ring expansion to be performed. The N-benzyl groups could be cleaved by hydrogenolysis at the end of the synthesis if required. b) Alternatively, primary Fmoc-protected amino acid chlorides could be used to generate ring expanded lactams with two new NH-lactam motifs. Such products could then undergo double ring expansion to generate macrocycles containing four lactam groups, which in turn could be expanded again (this time via a quadruple ring expansion!) potentially furnishing highly complex cyclic products containing 8 amino acid fragments, via this type of exponential growth remarkably quickly. Both this strategy and 'method (a)' represent a conceptually new approach for the rapid formation of medicinally important 'stapled peptides'.c) Fully peptidic macrocycles should be accessible using cyclic dipeptides (diketopiperazines) as starting materials; e.g. tetrapeptides may be formed in a single step. Furthermore, an additional expansion of these products should allow even larger rings to be generated in just one more step. Relatively small cyclic peptides have much potential in drug discovery, but they are particularly difficult to synthesise via conventional cyclisation methods. Synthesised compounds will be submitted for bioassay through links external collaborators and industry.d) If time allows, it is also planned to demonstrate that SuRE can be used to install therapeutically important amino acid sequences into macrocycles; e.g. the valine-valine-cysteine-tyrosine sequence, which has been found to be important in known cyclic peptide HIF-1 inhibitors. Countless biologically active cyclic peptide natural products and pharmaceutical agents are also known and targets that showcase the methods developed will be chosen; e.g. the synthesis of caspofungin analogues.