Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Oxadiazole grafts in peptide macrocycles

Nature Chemistry volume 8, pages 1105–1111 (2016)Cite this article

Subjects

This article has been updated

Abstract

Synthetic methods that provide control over macrocycle conformation and, at the same time, mitigate the polarity of peptide bonds represent valuable tools for the discovery of new bioactive molecules. Here, we report a macrocyclization reaction between a linear peptide, an aldehyde and (N-isocyanimino)triphenylphosphorane. This process generates head-to-tail cyclic peptidomimetics in a single step. This method is tolerant to variation in the peptide and aldehyde components and has been applied for the synthesis of 15-, 18-, 21- and 24-membered rings. The resulting peptide macrocycles feature a 1,3,4-oxadiazole and a tertiary amine in their scaffolds. This non-canonical backbone region acts as an endocyclic control element that promotes and stabilizes a unique intramolecular hydrogen-bond network and can lead to macrocycles with conformationally rigid turn structures. Oxadiazole-containing macrocycles can also display a high passive membrane permeability, an important property for the development of bioavailable peptide-based therapeutics.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Synthesis and characterization of oxadiazole-containing macrocyclic peptides.
Figure 2: Proposed reaction mechanism for macrocycle formation via zwitterionic control.
Figure 3: Contrasting the structural features of oxadiazole-containing macrocycles and homodetic counterparts.
Figure 4: Structural properties of oxadiazole-containing macrocycles.

Similar content being viewed by others

Change history

  • 04 November 2016

    In the version of this Article originally published the label 'Gly2' was mistakenly omitted from Fig. 3a. This has now been corrected online.

References

  1. Wessjohann, L. A., Ruijter, E., Garcia-Rivera, D. & Brandt, W. What can a chemist learn from nature's macrocycles? A brief, conceptual view. Mol. Divers. 9, 171–186 (2005).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  3. 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 

  4. Nolan, E. M. & Walsh, C. T. How nature morphs peptide scaffolds into antibiotics. ChemBioChem 10, 34–53 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Angelini, A. et al. Bicyclic peptide inhibitor reveals large contact interface with a protease target. ACS Chem. Biol. 7, 817–821 (2012).

    Article  CAS  PubMed  Google Scholar 

  6. Smith, J. M., Frost, J. R. & Fasan, R. Designer macrocyclic organo-peptide hybrids inhibit the interaction between p53 and HDM2/X by accommodating a functional α-helix. Chem. Commun. 50, 5027–5030 (2014).

    Article  CAS  Google Scholar 

  7. Bullock, B. N., Jochim, A. L. & Arora, P. S. Assessing helical protein interfaces for inhibitor design. J. Am. Chem. Soc. 133, 14220–14223 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Robinson, J. A. β-hairpin peptidomimetics: design, structures and biological activities. Acc. Chem. Res. 41, 1278–1288 (2008).

    Article  CAS  PubMed  Google Scholar 

  9. Patgiri, A., Jochim, A. L. & Arora, P. S. A hydrogen bond surrogate approach for stabilization of short peptide sequences in α-helical conformation. Acc. Chem. Res. 41, 1289–1300 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Hilinski, G. J. et al. Stitched α-helical peptides via bis ring-closing metathesis. J. Am. Chem. Soc. 136, 12314–12322 (2014).

    Article  CAS  PubMed  Google Scholar 

  11. Kutchukian, P. S., Yang, J. S., Verdine, G. L. & Shakhnovich, E. I. All-atom model for stabilization of α-helical structure in peptides by hydrocarbon staples. J. Am. Chem. Soc. 131, 4622–4627 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Horne, W. S., Olsen, C. A., Beierle, J. M., Montero, A. & Ghadiri, M. R. Probing the bioactive conformation of an archetypal natural product HDAC inhibitor with conformationally homogeneous triazole-modified cyclic tetrapeptides. Angew. Chem. Int. Ed. 48, 4718–4724 (2009).

    Article  CAS  Google Scholar 

  13. Beierle, J. M. et al. Conformationally homogeneous heterocyclic pseudotetrapeptides as three-dimensional scaffolds for rational drug design: receptor-selective somatostatin analogues. Angew. Chem. Int. Ed. 48, 4725–4729 (2009).

    Article  CAS  Google Scholar 

  14. Favre, M., Moehle, K., Jiang, L. Y., Pfeiffer, B. & Robinson, J. A. Structural mimicry of canonical conformations in antibody hypervariable loops using cyclic peptides containing a heterochiral diproline template. J. Am. Chem. Soc. 121, 2679–2685 (1999).

    Article  CAS  Google Scholar 

  15. Bhat, A., Roberts, L. R. & Dwyer, J. J. Lead discovery and optimization strategies for peptide macrocycles. Eur. J. Med. Chem. 94, 471–479 (2015).

    Article  CAS  PubMed  Google Scholar 

  16. Craik, D. J., Fairlie, D. P., Liras, S. & Price, D. The future of peptide-based drugs. Chem. Biol. Drug Des. 81, 136–147 (2013).

    Article  CAS  PubMed  Google Scholar 

  17. Schwochert, J. et al. Peptide to peptoid substitutions increase cell permeability in cyclic hexapeptides. Org. Lett. 17, 2928–2931 (2015).

    Article  CAS  PubMed  Google Scholar 

  18. Rezai, T., Yu, B., Millhauser, G. L., Jacobson, M. P. & Lokey, R. S. Testing the conformational hypothesis of passive membrane permeability using synthetic cyclic peptide diastereomers. J. Am. Chem. Soc. 128, 2510–2511 (2006).

    Article  CAS  PubMed  Google Scholar 

  19. Hili, R., Rai, V. & Yudin, A. K. Macrocyclization of linear peptides enabled by amphoteric molecules. J. Am. Chem. Soc. 132, 2889–2891 (2010).

    Article  CAS  PubMed  Google Scholar 

  20. Zaretsky, S., Scully, C. C., Lough, A. J. & Yudin, A. K. Exocyclic control of turn induction in macrocyclic peptide scaffolds. Chem. Eur. J. 19, 17668–17672 (2013).

    Article  CAS  PubMed  Google Scholar 

  21. Hili, R. & Yudin, A. K. Readily available unprotected amino aldehydes. J. Am. Chem. Soc. 128, 14772–14773 (2006).

    Article  CAS  PubMed  Google Scholar 

  22. Assem, N. et al. Role of reversible dimerization in reactions of amphoteric aziridine aldehydes. J. Org. Chem. 77, 5613–5623 (2012).

    Article  CAS  PubMed  Google Scholar 

  23. Weinberger, B. & Fehlhammer, W. P. N-Isocyanoiminotriphenylphosphorane: synthesis, coordination chemistry, and reactions at the metal. Angew. Chem. Int. Ed. 19, 480–481 (1980).

    Article  Google Scholar 

  24. Stolzenberg, H., Weinberger, B., Fehlhammer, W. P., Pühlhofer, F. G. & Weiss, R. Free and metal-coordinated (N-isocyanimino)triphenylphosphorane: X-ray structures and selected reactions. Eur. J. Inorg. Chem. 4263–4271 (2005).

  25. Souldozi, A. & Ramazani, A. The reaction of (N-isocyanimino)triphenylphosphorane with benzoic acid derivatives: a novel synthesis of 2-aryl-1,3,4-oxadiazole derivatives. Tetrahedron Lett. 48, 1549–1551 (2007).

    Article  CAS  Google Scholar 

  26. Ramazani, A. & Rezaei, A. Novel one-pot, four-component condensation reaction: an efficient approach for the synthesis of 2,5-disubstituted 1,3,4-oxadiazole derivatives by a Ugi-4CR/aza-Wittig sequence. Org. Lett. 12, 2852–2855 (2010).

    Article  CAS  PubMed  Google Scholar 

  27. Ramazani, A., Shajari, N., Mahyari, A. & Ahmadi, Y. A novel four-component reaction for the synthesis of disubstituted 1,3,4-oxadiazole derivatives. Mol. Divers. 15, 521–527 (2011).

    Article  CAS  PubMed  Google Scholar 

  28. Rouhani, M., Ramazani, A. & Joo, S. W. Novel, fast and efficient one-pot sonochemical synthesis of 2-aryl-1,3,4-oxadiazoles. Ultrason. Sonochem. 21, 262–267 (2014).

    Article  CAS  PubMed  Google Scholar 

  29. Borg, S. et al. Synthesis of 1,2,4-oxadiazole-derived, 1,3,4-oxadiazole-derived, and 1,2,4-triazole-derived dipeptidomimetics. J. Org. Chem. 60, 3112–3120 (1995).

    Article  CAS  Google Scholar 

  30. Kumar, B. V. et al. Synthesis and biological evaluation of new tetra-aza macrocyclic scaffold constrained oxadiazole, thiadiazole and triazole rings. Arch. Pharm. 345, 250–250 (2012).

    Article  CAS  Google Scholar 

  31. Poojari, S., Parameshwar Naik, P. & Krishnamurthy, G. Synthesis of macrocycles containing 1,3,4-oxadiazole and pyridine moieties. Tetrahedron Lett. 55, 305–309 (2014).

    Article  CAS  Google Scholar 

  32. Damalanka, V. C. et al. Oxadiazole-based cell permeable macrocyclic transition state inhibitors of norovirus 3CL protease. J. Med. Chem. 59, 1899–1913 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Nielsen, D. S., Hoang, H. N., Lohman, R.-J., Diness, F. & Fairlie, D. P. Total synthesis, structure, and oral absorption of a thiazole cyclic peptide, sanguinamide A. Org. Lett. 14, 5720–5723 (2012).

    Article  CAS  PubMed  Google Scholar 

  34. Bockus, A. T. et al. Going out on a limb: delineating the effects of β-branching, N-methylation, and side chain size on the passive permeability, solubility, and flexibility of sanguinamide A analogues. J. Med. Chem. 58, 7409–7418 (2015).

    Article  CAS  PubMed  Google Scholar 

  35. Singh, Y., Stoermer, M. J., Lucke, A. J., Guthrie, T. & Fairlie, D. P. Structural mimicry of two cytochrome b562 interhelical loops using macrocycles constrained by oxazoles and thiazoles. J. Am. Chem. Soc. 127, 6563–6572 (2005).

    Article  CAS  PubMed  Google Scholar 

  36. Fairlie, D. P., Abbenante, G. & March, D. R. Macrocyclic peptidomimetics: forcing peptides into bioactive conformations. Curr. Med. Chem. 2, 654–686 (1995).

    Article  CAS  Google Scholar 

  37. McGeary, R. P. & Fairlie, D. P. Macrocyclic peptidomimetics: potential for drug development. Curr. Opin. Drug Discov. Devel. 1, 208–217 (1998).

    CAS  PubMed  Google Scholar 

  38. Zaretsky, S. et al. Mechanistic investigation of aziridine aldehyde-driven peptide macrocyclization: the imidoanhydride pathway. Chem. Sci. 6, 5446–5455 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Frank, A. T. et al. Natural macrocyclic molecules have a possible limited structural diversity. Mol. Divers. 11, 115–118 (2007).

    Article  CAS  PubMed  Google Scholar 

  40. Londregan, A. T., Farley, K. A., Limberakis, C., Mullins, P. B. & Piotrowski, D. W. A new and useful method for the macrocyclization of linear peptides. Org. Lett. 14, 2890–2893 (2012).

    Article  CAS  PubMed  Google Scholar 

  41. Brown, H. A. & Waymouth, R. M. Zwitterionic ring-opening polymerization for the synthesis of high molecular weight cyclic polymers. Acc. Chem. Res. 46, 2585–2596 (2013).

    Article  CAS  PubMed  Google Scholar 

  42. Guo, L., Lahasky, S. H., Ghale, K. & Zhang, D. N-Heterocyclic carbene-mediated zwitterionic polymerization of N-substituted N-carboxyanhydrides toward poly(α-peptoid)s: kinetic, mechanism, and architectural control. J. Am. Chem. Soc. 134, 9163–9171 (2012).

    Article  CAS  PubMed  Google Scholar 

  43. Tyndall, J. D., Pfeiffer, B., Abbenante, G. & Fairlie, D. P. Over one hundred peptide-activated G protein-coupled receptors recognize ligands with turn structure. Chem. Rev. 105, 793–826 (2005).

    Article  CAS  PubMed  Google Scholar 

  44. Glendening, E. D., Landis, C. R. & Weinhold, F. NBO 6.0: natural bond orbital analysis program. J. Comput. Chem. 34, 1429–1437 (2013).

    Article  CAS  PubMed  Google Scholar 

  45. Weinhold, F. Natural bond orbital analysis: a critical overview of relationships to alternative bonding perspectives. J. Comput. Chem. 33, 2363–2379 (2012).

    Article  CAS  PubMed  Google Scholar 

  46. Rozas, I., Alkorta, I. & Elguero, J. Bifurcated hydrogen bonds: three-centered interactions. J. Phys. Chem. A 102, 9925–9932 (1998).

    Article  CAS  Google Scholar 

  47. Kansy, M., Senner, F. & Gubernator, K. Physicochemical high throughput screening: parallel artificial membrane permeation assay in the description of passive absorption processes. J. Med. Chem. 41, 1007–1010 (1998).

    Article  CAS  PubMed  Google Scholar 

  48. Alex, A., Millan, D. S., Perez, M., Wakenhut, F. & Whitlock, G. A. Intramolecular hydrogen bonding to improve membrane permeability and absorption in beyond rule of five chemical space. Med. Chem. Comm. 2, 669–674 (2011).

    Article  CAS  Google Scholar 

  49. Rezai, T. et al. Conformational flexibility, internal hydrogen bonding, and passive membrane permeability: successful in silico prediction of the relative permeabilities of cyclic peptides. J. Am. Chem. Soc. 128, 14073–14080 (2006).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank D. Burns and D. Pichugin for their assistance with NMR spectroscopic experiments and A. J. Lough for acquiring and solving X-ray crystal structures. A. L. Roughton (Encycle Therapeutics) is thanked for coordinating the PAMPA analysis and thoughtful discussions. This paper is dedicated to Professor G. K. Surya Prakash.

Author information

Authors and Affiliations

  1. Department of Chemistry, Davenport Research Laboratories, University of Toronto, 80 St George Street, Toronto, M5S 3H6, Ontario, Canada

    John R. Frost, Conor C. G. Scully & Andrei K. Yudin

Authors
  1. John R. Frost
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Conor C. G. Scully
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Andrei K. Yudin
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

A.K.Y. conceived the idea. J.R.F and C.C.G.S designed and performed the experiments and analysed the experimental data. J.R.F. prepared the manuscript with contributions from all the authors; all the authors contributed to discussions.

Corresponding author

Correspondence to Andrei K. Yudin.

Ethics declarations

Competing interests

A.Y. is the scientific founder of Encycle Therapeutics.

Supplementary information

Supplementary information

Supplementary information (PDF 5749 kb)

Supplementary information

Crystallographic data for compound 1a (CIF 1165 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Frost, J., Scully, C. & Yudin, A. Oxadiazole grafts in peptide macrocycles. Nature Chem 8, 1105–1111 (2016). https://doi.org/10.1038/nchem.2636

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nchem.2636

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing