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Sequence-defined bioactive macrocycles via an acid-catalysed cascade reaction

Abstract

Synthetic macrocycles derived from sequence-defined oligomers are a unique structural class whose ring size, sequence and structure can be tuned via precise organization of the primary sequence. Similar to peptides and other peptidomimetics, these well-defined synthetic macromolecules become pharmacologically relevant when bioactive side chains are incorporated into their primary sequence. In this article, we report the synthesis of oligothioetheramide (oligoTEA) macrocycles via a one-pot acid-catalysed cascade reaction. The versatility of the cyclization chemistry and modularity of the assembly process was demonstrated via the synthesis of >20 diverse oligoTEA macrocycles. Structural characterization via NMR spectroscopy revealed the presence of conformational isomers, which enabled the determination of local chain dynamics within the macromolecular structure. Finally, we demonstrate the biological activity of oligoTEA macrocycles designed to mimic facially amphiphilic antimicrobial peptides. The preliminary results indicate that macrocyclic oligoTEAs with just two-to-three cationic charge centres can elicit potent antibacterial activity against Gram-positive and Gram-negative bacteria.

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Figure 1: Schematic for sequence-defined macrocycle formation.
Figure 2: Synthesis of macrocyclic oligoTEAs.
Figure 3: Characterization of the chain conformation of macrocyclic oligoTEAs.
Figure 4: HPLC traces of the purified oligoTEA macrocycles listed in Table 1.
Figure 5: Antimicrobial activity and selectivity of macrocyclic and linear oligoTEAs.

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Acknowledgements

The authors acknowledge the Army Research Office (W911NF-15-1-0179), Cornell University start-up research funds and the Nancy and Peter Meinig Investigator Fellowship for support of this work. D.N.T. acknowledges the National Science Foundation (graduate research fellowship) and the Fleming Fellowship.

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Contributions

C.A.A. conceived the oligoTEA macrocycle concept. C.A.A. and M.P. conceived the molecular design and synthetic protocols. M.P. and N.N.P. carried out the synthesis and characterization. D.N.T. performed antimicrobial and haemolysis assays. M.P. and C.A.A. analysed the data. C.A.A. wrote the paper. C.A.A., M.P., D.N.T. and N.N.P. discussed the results and edited the manuscript.

Corresponding author

Correspondence to Christopher A. Alabi.

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Porel, M., Thornlow, D., Phan, N. et al. Sequence-defined bioactive macrocycles via an acid-catalysed cascade reaction. Nature Chem 8, 590–596 (2016). https://doi.org/10.1038/nchem.2508

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