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

Nature Chemistry volume 8, pages 590–596 (2016)Cite this article

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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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References

  1. Lahlali, H., Jobe, K. & Watkinson, M. Macrocycle size matters: ‘small’ functionalized rotaxanes in excellent yield using the CuAAC active template approach. Angew. Chem. Int. Ed. 50, 4151–4155 (2011).

    Article  CAS  Google Scholar 

  2. Spence, G. T., White, N. G. & Beer, P. D. Investigating the effect of macrocycle size in anion templated imidazolium-based interpenetrated and interlocked assemblies. Org. Biomol. Chem. 10, 7282–7291 (2012).

    Article  CAS  PubMed  Google Scholar 

  3. Katagiri, K., Tohaya, T., Masu, H., Tominaga, M. & Azumaya, I. Effect of aromatic–aromatic interactions on the conformational stabilities of macrocycle and preorganized structure during macrocyclization. J. Org. Chem. 74, 2804–2810 (2009).

    Article  CAS  PubMed  Google Scholar 

  4. Driggers, E. M., Hale, S. P., Lee, J. & Terrett, N. K. The exploration of macrocycles for drug discovery—an underexploited structural class. Nature Rev. Drug. Discov. 7, 608–624 (2008).

    Article  CAS  Google Scholar 

  5. Heinis, C. Drug discovery: tools and rules for macrocycles. Nature Chem. Biol. 10, 696–698 (2014).

    Article  CAS  Google Scholar 

  6. Seebach, D. & Gardiner, J. β-peptidic peptidomimetics. Acc. Chem. Res. 41, 1366–1375 (2008).

    Article  CAS  PubMed  Google Scholar 

  7. Davies, J. S. The cyclization of peptides and depsipeptides. J. Pept. Sci. 9, 471–501 (2003).

    Article  CAS  PubMed  Google Scholar 

  8. Yoo, B., Shin, S. B. Y., Huang, M. L. & Kirshenbaum, K. Peptoid macrocycles making the rounds with peptidomimetic oligomers. Chem. Eur. J. 16, 5528–5537 (2010).

    Article  CAS  PubMed  Google Scholar 

  9. Shin, S., Yoo, B., Todaro, L. J. & Kirshenbaum, K. Cyclic peptoids. J. Am. Chem. Soc. 129, 3218–3225 (2007).

    Article  CAS  PubMed  Google Scholar 

  10. Laursen, J. S., Engel-Andreasen, J. & Olsen, C. A. β-peptoid foldamers at last. Acc. Chem. Res. 48, 2696–2704 (2015).

    Article  CAS  PubMed  Google Scholar 

  11. Zuckermann, R. N. & Kodadek, T. Peptoids as potential therapeutics. Curr. Opin. Mol. Ther. 11, 299–307 (2009).

    CAS  PubMed  Google Scholar 

  12. Niu, J., Hili, R. & Liu, D. R. Enzyme-free translation of DNA into sequence-defined synthetic polymers structurally unrelated to nucleic acids. Nature Chem. 5, 282–292 (2013).

    Article  CAS  Google Scholar 

  13. Rosenbaum, D. M. & Liu, D. R. Efficient and sequence-specific DNA-templated polymerization of peptide nucleic acid aldehydes. J. Am. Chem. Soc. 125, 13924–13925 (2003).

    Article  CAS  PubMed  Google Scholar 

  14. Lewandowski, B. et al. Sequence-specific peptide synthesis by an artificial small-molecule machine. Science 339, 189–193 (2013).

    Article  CAS  PubMed  Google Scholar 

  15. Gody, G., Maschmeyer, T., Zetterlund, P. B. & Perrier, S. Rapid and quantitative one-pot synthesis of sequence-controlled polymers by radical polymerization. Nature Commun. 4, 2505 (2013).

    Article  CAS  Google Scholar 

  16. Zhang, Q. et al. Sequence-controlled multi-block glycopolymers to inhibit DC-SIGN-gp120 binding. Angew. Chem. Int. Ed. 52, 4435–4439 (2013).

    Article  CAS  Google Scholar 

  17. Pfeifer, S. & Lutz, J.-F. A facile procedure for controlling monomer sequence distribution in radical chain polymerizations. J. Am. Chem. Soc. 129, 9542–9543 (2007).

    Article  CAS  PubMed  Google Scholar 

  18. Nakatani, K., Ogura, Y., Koda, Y., Terashima, T. & Sawamoto, M. Sequence-regulated copolymers via tandem catalysis of living radical polymerization and in situ transesterification. J. Am. Chem. Soc. 134, 4373–4383 (2012).

    Article  CAS  PubMed  Google Scholar 

  19. Solleder, S. C. & Meier, M. A. R. Sequence control in polymer chemistry through the Passerini three-component reaction. Angew. Chem. Int. Ed. 53, 711–714 (2013).

    Article  CAS  Google Scholar 

  20. Espeel, P. et al. Multifunctionalized sequence-defined oligomers from a single building block. Angew. Chem. Int. Ed. 52, 13261–13264 (2013).

    Article  CAS  Google Scholar 

  21. Roy, R. K. et al. Design and synthesis of digitally encoded polymers that can be decoded and erased. Nature Commun. 6, 7237 (2015).

    Article  CAS  Google Scholar 

  22. Ouahabi, Al, A., Charles, L. & Lutz, J.-F. Synthesis of non-natural sequence-encoded polymers using phosphoramidite chemistry. J. Am. Chem. Soc. 137, 5629–5635 (2015).

  23. Porel, M. & Alabi, C. A. Sequence-defined polymers via orthogonal allyl acrylamide building blocks. J. Am. Chem. Soc. 136, 13162–13165 (2014).

    Article  CAS  PubMed  Google Scholar 

  24. Porel, M., Brown, J. & Alabi, C. Sequence-defined oligothioetheramides. Synlett 26, 565–571 (2015).

    Article  CAS  Google Scholar 

  25. Marsault, E. & Peterson, M. L. Macrocycles are great cycles: applications, opportunities, and challenges of synthetic macrocycles in drug discovery. J. Med. Chem. 54, 1961–2004 (2011).

    Article  CAS  PubMed  Google Scholar 

  26. White, C. J. & Yudin, A. K. Contemporary strategies for peptide macrocyclization. Nature Chem. 3, 509–524 (2011).

    Article  CAS  Google Scholar 

  27. Chen, S. et al. Bicyclic peptide ligands pulled out of cysteine-rich peptide libraries. J. Am. Chem. Soc. 135, 6562–6569 (2013).

    Article  CAS  PubMed  Google Scholar 

  28. Forget, D., Renaudet, O., Defrancq, E. & Dumy, P. Efficient preparation of carbohydrate–oligonucleotide conjugates (COCs) using oxime bond formation. Tetrahedron Lett. 42, 7829–7832 (2001).

    Article  CAS  Google Scholar 

  29. Villien, M. et al. The oxime bond formation as an efficient tool for the conjugation of ruthenium complexes to oligonucleotides and peptides. Tetrahedron 63, 11299–11306 (2007).

    Article  CAS  Google Scholar 

  30. Edupuganti, O. P., Renaudet, O., Defrancq, E. & Dumy, P. The oxime bond formation as an efficient chemical tool for the preparation of 3′,5′-bifunctionalised oligodeoxyribonucleotides. Bioorg. Med. Chem. Lett. 14, 2839–2842 (2004).

    Article  CAS  PubMed  Google Scholar 

  31. Mittermaier, A. K. & Kay, L. E. Observing biological dynamics at atomic resolution using NMR. Trends Biochem. Sci. 34, 601–611 (2009).

    Article  CAS  PubMed  Google Scholar 

  32. Palmer, A. G. NMR characterization of the dynamics of biomacromolecules. Chem. Rev. 104, 3623–3640 (2004).

    Article  CAS  PubMed  Google Scholar 

  33. Sprangers, R., Gribun, A., Hwang, P. M., Houry, W. A. & Kay, L. E. Quantitative NMR spectroscopy of supramolecular complexes: dynamic side pores in ClpP are important for product release. Proc. Natl Acad. Sci. USA 102, 16678–16683 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Cobas, J. C. & Martin-Pastor, M. EXSYCalc v. 1.0 (Mestrelab Research S.L., A Coruna, 2007).

  35. Spellberg, B. Race against time to develop new antibiotics. Bull. World Health Organ. 89, 88–89 (2011).

    Article  Google Scholar 

  36. Bartlett, J. G. A call to arms: the imperative for antimicrobial stewardship. Clin. Inf. Dis. 53, S4–S7 (2011).

    Article  Google Scholar 

  37. Zasloff, M. Antimicrobial peptides of multicellular organisms. Nature 415, 389–395 (2002).

    Article  CAS  PubMed  Google Scholar 

  38. Tew, G. N., Scott, R. W., Klein, M. L. & DeGrado, W. F. De novo design of antimicrobial polymers, foldamers, and small molecules: from discovery to practical applications. Acc. Chem. Res. 43, 30–39 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Huang, M. L., Shin, S. B. Y., Benson, M. A., Torres, V. J. & Kirshenbaum, K. A comparison of linear and cyclic peptoid oligomers as potent antimicrobial agents. ChemMedChem 7, 114–122 (2012).

    Article  CAS  PubMed  Google Scholar 

  40. Porter, E. A., Weisblum, B. & Gellman, S. H. Mimicry of host–defense peptides by unnatural oligomers: antimicrobial beta-peptides. J. Am. Chem. Soc. 124, 7324–7330 (2002).

    Article  CAS  PubMed  Google Scholar 

  41. Patch, J. A. & Barron, A. E. Helical peptoid mimics of magainin-2 amide. J. Am. Chem. Soc. 125, 12092–12093 (2003).

    Article  CAS  PubMed  Google Scholar 

  42. Liu, D. et al. Nontoxic membrane-active antimicrobial arylamide oligomers. Angew. Chem. Int. Ed. 43, 1158–1162 (2004).

    Article  CAS  Google Scholar 

  43. Ge, Y. et al. In vitro antibacterial properties of pexiganan, an analog of magainin. Antimicrob. Agents Chemother. 43, 782–788 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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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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  1. School of Chemical and Biomolecular Engineering, Cornell University, 120 Olin Hall, Ithaca, 14850, New York, USA

    Mintu Porel, Dana N. Thornlow, Ngoc N. Phan & Christopher A. Alabi

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  1. Mintu Porel
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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.

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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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