Oxadiazole grafts in peptide macrocycles

Journal name:
Nature Chemistry
Volume:
8,
Pages:
1105–1111
Year published:
DOI:
doi:10.1038/nchem.2636
Received
Accepted
Published online
Corrected online

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.

At a glance

Figures

  1. Synthesis and characterization of oxadiazole-containing macrocyclic peptides.
    Figure 1: Synthesis and characterization of oxadiazole-containing macrocyclic peptides.

    a, General cyclization scheme that shows the cyclization of PGLGF with propionaldehyde and (N-isocyanimino)triphenylphosphorane. The cyclization proceeds in one pot with a short reaction time (3 h). b, HPLC chromatogram of the crude cyclization reaction (top) and linear PGLGF starting material (bottom). The reaction is highly selective for the macrocyclic product with no evidence of dimerization or oligomerization. c, X-ray crystal structure of cyclo[PGLGF]odz/ethyl major diastereomer 1a. 1a is the macrocycle major diastereomer and 1b is the macrocycle minor diastereomer. r.t., room temperature.

  2. Proposed reaction mechanism for macrocycle formation via zwitterionic control.
    Figure 2: Proposed reaction mechanism for macrocycle formation via zwitterionic control.

    A reaction mechanism for (N-isocyanimino)triphenylphosphorane-mediated macrocyclization is proposed whereby attractive zwitterionic control between the carboxylate and the positively charged phosphorane drives the cyclization reaction to furnish a mixed anhydride intermediate. The pendant exocyclic amine then intercepts the mixed anhydride and undergoes an aza-Wittig-type reaction to furnish the 1,3,4-oxadiazole-containing macrocycle.

  3. Contrasting the structural features of oxadiazole-containing macrocycles and homodetic counterparts.
    Figure 3: Contrasting the structural features of oxadiazole-containing macrocycles and homodetic counterparts.

    a,b, Hydrogen-bonding profile and temperature-chemical shift coefficients (Tcoeff) of oxadiazole (a) and homodetic peptide (b) macrocycles, based on the PGLGF sequence, as measured by variable-temperature 1H NMR spectroscopy. Hydrogen atoms engaged in intramolecular hydrogen bonding and their corresponding NMR signals are highlighted. The oxadiazole-containing macrocycle exhibits an alternative hydrogen-bonding pattern and displays increased conformational rigidity as compared with the homodetic variant.

  4. Structural properties of oxadiazole-containing macrocycles.
    Figure 4: Structural properties of oxadiazole-containing macrocycles.

    a, An overlay of the X-ray crystal structure (green) and NMR solution structure (grey) of compound 1 shows a close overlap between the solid- and solution-phase structures. b, NMR solution structure of compound 24 (hydrogen bonds are shown in yellow). c, Overlay of the NMR solution structures of 1 (grey) and 24 (green). d, Energetic contribution of hydrogen bonds to conformational stabilization in oxadiazole-containing macrocycles. Hydrogen bond distances (Å): 1, 2.18; 2, 2.60; 3, 2.15. Calculated perturbative two-electron stabilization energies (kcal mol–1): 1, 4.08; 2, 1.05, 3, 4.13. e, The orbital interaction of the Pro1 lone pair with Gly2–NH is shown using NBO. f, The NBO interaction of the oxadiazole oxygen lone pair with Gly2–NH.

Compounds

33 compounds View all compounds
  1. (32S,2S,9S,15S)-15-benzyl-2-ethyl-9-isobutyl-5,8,11,14-tetraaza-1(2,5)-oxadiazola-3(1,2)-pyrrolidinacyclopentadecaphane-4,7,10,13-tetraone
    Compound 1a (32S,2S,9S,15S)-15-benzyl-2-ethyl-9-isobutyl-5,8,11,14-tetraaza-1(2,5)-oxadiazola-3(1,2)-pyrrolidinacyclopentadecaphane-4,7,10,13-tetraone
  2. (32S,2R,9S,15S)-15-benzyl-2-ethyl-9-isobutyl-5,8,11,14-tetraaza-1(2,5)-oxadiazola-3(1,2)-pyrrolidinacyclopentadecaphane-4,7,10,13-tetraone
    Compound 1b (32S,2R,9S,15S)-15-benzyl-2-ethyl-9-isobutyl-5,8,11,14-tetraaza-1(2,5)-oxadiazola-3(1,2)-pyrrolidinacyclopentadecaphane-4,7,10,13-tetraone
  3. 2-((32S,6S,9S,12S)-12-((1H-indol-3-yl)methyl)-2-ethyl-9-methyl-4,7,10,13-tetraoxo-5,8,11,14-tetraaza-1(2,5)-oxadiazola-3(1,2)-pyrrolidinacyclopentadecaphane-6-yl)acetic acid
    Compound 2 2-((32S,6S,9S,12S)-12-((1H-indol-3-yl)methyl)-2-ethyl-9-methyl-4,7,10,13-tetraoxo-5,8,11,14-tetraaza-1(2,5)-oxadiazola-3(1,2)-pyrrolidinacyclopentadecaphane-6-yl)acetic acid
  4. (32S,6S,9S,12S)-6-((1H-indol-2-yl)methyl)-2-ethyl-12-(hydroxymethyl)-9-methyl-5,8,11,14-tetraaza-1(2,5)-oxadiazola-3(1,2)-pyrrolidinacyclopentadecaphane-4,7,10,13-tetraone
    Compound 3 (32S,6S,9S,12S)-6-((1H-indol-2-yl)methyl)-2-ethyl-12-(hydroxymethyl)-9-methyl-5,8,11,14-tetraaza-1(2,5)-oxadiazola-3(1,2)-pyrrolidinacyclopentadecaphane-4,7,10,13-tetraone
  5. (32S,6S,9S,12S,15S)-2-ethyl-12-(4-hydroxybenzyl)-6-(hydroxymethyl)-9-isobutyl-15-methyl-5,8,11,14-tetraaza-1(2,5)-oxadiazola-3(1,2)-pyrrolidinacyclopentadecaphane-4,7,10,13-tetraone
    Compound 4 (32S,6S,9S,12S,15S)-2-ethyl-12-(4-hydroxybenzyl)-6-(hydroxymethyl)-9-isobutyl-15-methyl-5,8,11,14-tetraaza-1(2,5)-oxadiazola-3(1,2)-pyrrolidinacyclopentadecaphane-4,7,10,13-tetraone
  6. 2-((32S,6S,9S,12S,15S)-12-benzyl-2-ethyl-6-isobutyl-15-methyl-4,7,10,13-tetraoxo-5,8,11,14-tetraaza-1(2,5)-oxadiazola-3(1,2)-pyrrolidinacyclopentadecaphane-9-yl)acetic acid
    Compound 5 2-((32S,6S,9S,12S,15S)-12-benzyl-2-ethyl-6-isobutyl-15-methyl-4,7,10,13-tetraoxo-5,8,11,14-tetraaza-1(2,5)-oxadiazola-3(1,2)-pyrrolidinacyclopentadecaphane-9-yl)acetic acid
  7. 2-((32S,6S,9S,12S,15S)-9-benzyl-2-ethyl-12-isobutyl-15-methyl-4,7,10,13-tetraoxo-5,8,11,14-tetraaza-1(2,5)-oxadiazola-3(1,2)-pyrrolidinacyclopentadecaphane-6-yl)acetic acid
    Compound 6 2-((32S,6S,9S,12S,15S)-9-benzyl-2-ethyl-12-isobutyl-15-methyl-4,7,10,13-tetraoxo-5,8,11,14-tetraaza-1(2,5)-oxadiazola-3(1,2)-pyrrolidinacyclopentadecaphane-6-yl)acetic acid
  8. 2-((32S,6S,9S,12S,15S)-6-benzyl-2-ethyl-12-isobutyl-15-methyl-4,7,10,13-tetraoxo-5,8,11,14-tetraaza-1(2,5)-oxadiazola-3(1,2)-pyrrolidinacyclopentadecaphane-9-yl)acetic acid
    Compound 7 2-((32S,6S,9S,12S,15S)-6-benzyl-2-ethyl-12-isobutyl-15-methyl-4,7,10,13-tetraoxo-5,8,11,14-tetraaza-1(2,5)-oxadiazola-3(1,2)-pyrrolidinacyclopentadecaphane-9-yl)acetic acid
  9. (32S,9S,12S,15S)-15-benzyl-2-ethyl-9-isobutyl-12-methyl-5,8,11,14-tetraaza-1(2,5)-oxadiazola-3(1,2)-pyrrolidinacyclopentadecaphane-4,7,10,13-tetraone
    Compound 8 (32S,9S,12S,15S)-15-benzyl-2-ethyl-9-isobutyl-12-methyl-5,8,11,14-tetraaza-1(2,5)-oxadiazola-3(1,2)-pyrrolidinacyclopentadecaphane-4,7,10,13-tetraone
  10. (32S,6S,9S,15S)-15-benzyl-2-ethyl-9-isobutyl-6-methyl-5,8,11,14-tetraaza-1(2,5)-oxadiazola-3(1,2)-pyrrolidinacyclopentadecaphane-4,7,10,13-tetraone
    Compound 9 (32S,6S,9S,15S)-15-benzyl-2-ethyl-9-isobutyl-6-methyl-5,8,11,14-tetraaza-1(2,5)-oxadiazola-3(1,2)-pyrrolidinacyclopentadecaphane-4,7,10,13-tetraone
  11. (32S,6S,9S,12S,15S)-15-benzyl-2-ethyl-9-isobutyl-6,12-dimethyl-5,8,11,14-tetraaza-1(2,5)-oxadiazola-3(1,2)-pyrrolidinacyclopentadecaphane-4,7,10,13-tetraone
    Compound 10 (32S,6S,9S,12S,15S)-15-benzyl-2-ethyl-9-isobutyl-6,12-dimethyl-5,8,11,14-tetraaza-1(2,5)-oxadiazola-3(1,2)-pyrrolidinacyclopentadecaphane-4,7,10,13-tetraone
  12. (32S,6S,9S,12S,15S)-6,15-dibenzyl-2-ethyl-9,12-diisobutyl-5,8,11,14-tetraaza-1(2,5)-oxadiazola-3(1,2)-pyrrolidinacyclopentadecaphane-4,7,10,13-tetraone
    Compound 11 (32S,6S,9S,12S,15S)-6,15-dibenzyl-2-ethyl-9,12-diisobutyl-5,8,11,14-tetraaza-1(2,5)-oxadiazola-3(1,2)-pyrrolidinacyclopentadecaphane-4,7,10,13-tetraone
  13. (62S,4S,9S,15S)-2-ethyl-9-isobutyl-4,15-dimethyl-3,8,11,14-tetraaza-1(2,5)-oxadiazola-6(1,2)-pyrrolidinacyclopentadecaphane-5,7,10,13-tetraone
    Compound 12 (62S,4S,9S,15S)-2-ethyl-9-isobutyl-4,15-dimethyl-3,8,11,14-tetraaza-1(2,5)-oxadiazola-6(1,2)-pyrrolidinacyclopentadecaphane-5,7,10,13-tetraone
  14. (62S,9S,15S)-2-ethyl-9-isobutyl-15-methyl-3,8,11,14-tetraaza-1(2,5)-oxadiazola-6(1,2)-pyrrolidinacyclopentadecaphane-5,7,10,13-tetraone
    Compound 13 (62S,9S,15S)-2-ethyl-9-isobutyl-15-methyl-3,8,11,14-tetraaza-1(2,5)-oxadiazola-6(1,2)-pyrrolidinacyclopentadecaphane-5,7,10,13-tetraone
  15. (32S,6S,9S,12S)-9-benzyl-2-ethyl-6,12-dimethyl-5,8,11-triaza-1(2,5)-oxadiazola-3(1,2)-pyrrolidinacyclododecaphane-4,7,10-trione
    Compound 14 (32S,6S,9S,12S)-9-benzyl-2-ethyl-6,12-dimethyl-5,8,11-triaza-1(2,5)-oxadiazola-3(1,2)-pyrrolidinacyclododecaphane-4,7,10-trione
  16. (2S,5S,8S,11S)-5-benzyl-13-ethyl-8-isobutyl-2,11-dimethyl-3,6,9,12-tetraaza-1(2,5)-oxadiazolacyclotridecaphane-4,7,10-trione
    Compound 15 (2S,5S,8S,11S)-5-benzyl-13-ethyl-8-isobutyl-2,11-dimethyl-3,6,9,12-tetraaza-1(2,5)-oxadiazolacyclotridecaphane-4,7,10-trione
  17. (2S,5S,11S)-5-benzyl-13-ethyl-2,11-dimethyl-3,6,9,12-tetraaza-1(2,5)-oxadiazolacyclotridecaphane-4,7,10-trione
    Compound 16 (2S,5S,11S)-5-benzyl-13-ethyl-2,11-dimethyl-3,6,9,12-tetraaza-1(2,5)-oxadiazolacyclotridecaphane-4,7,10-trione
  18. (32S,9S,15S,18S)-15-benzyl-2-ethyl-9-isobutyl-18-methyl-5,8,11,14,17-pentaaza-1(2,5)-oxadiazola-3(1,2)-pyrrolidinacyclooctadecaphane-4,7,10,13,16-pentaone
    Compound 17 (32S,9S,15S,18S)-15-benzyl-2-ethyl-9-isobutyl-18-methyl-5,8,11,14,17-pentaaza-1(2,5)-oxadiazola-3(1,2)-pyrrolidinacyclooctadecaphane-4,7,10,13,16-pentaone
  19. 2-((32S,6S,9S,12S,15S)-12-((1H-indol-3-yl)methyl)-2-ethyl-15-(4-hydroxybenzyl)-9-methyl-4,7,10,13,16-pentaoxo-5,8,11,14,17-pentaaza-1(2,5)-oxadiazola-3(1,2)-pyrrolidinacyclooctadecaphane-6-yl)acetic acid
    Compound 18 2-((32S,6S,9S,12S,15S)-12-((1H-indol-3-yl)methyl)-2-ethyl-15-(4-hydroxybenzyl)-9-methyl-4,7,10,13,16-pentaoxo-5,8,11,14,17-pentaaza-1(2,5)-oxadiazola-3(1,2)-pyrrolidinacyclooctadecaphane-6-yl)acetic acid
  20. 2-((32S,9S,15S,18S,21S)-18-((1H-indol-3-yl)methyl)-2-ethyl-9-(3-guanidinopropyl)-21-methyl-4,7,10,13,16,19-hexaoxo-5,8,11,14,17,20-hexaaza-1(2,5)-oxadiazola-3(1,2)-pyrrolidinacyclohenicosaphane-15-yl)acetic acid
    Compound 19 2-((32S,9S,15S,18S,21S)-18-((1H-indol-3-yl)methyl)-2-ethyl-9-(3-guanidinopropyl)-21-methyl-4,7,10,13,16,19-hexaoxo-5,8,11,14,17,20-hexaaza-1(2,5)-oxadiazola-3(1,2)-pyrrolidinacyclohenicosaphane-15-yl)acetic acid
  21. (32S,9S,15S)-15-benzyl-2-ethyl-9-isobutyl-5-methyl-5,8,11,14-tetraaza-1(2,5)-oxadiazola-3(1,2)-pyrrolidinacyclopentadecaphane-4,7,10,13-tetraone
    Compound 20 (32S,9S,15S)-15-benzyl-2-ethyl-9-isobutyl-5-methyl-5,8,11,14-tetraaza-1(2,5)-oxadiazola-3(1,2)-pyrrolidinacyclopentadecaphane-4,7,10,13-tetraone
  22. (32S,9S,15S,18S)-15-benzyl-2-ethyl-9-isobutyl-5,18-dimethyl-5,8,11,14,17-pentaaza-1(2,5)-oxadiazola-3(1,2)-pyrrolidinacyclooctadecaphane-4,7,10,13,16-pentaone
    Compound 21 (32S,9S,15S,18S)-15-benzyl-2-ethyl-9-isobutyl-5,18-dimethyl-5,8,11,14,17-pentaaza-1(2,5)-oxadiazola-3(1,2)-pyrrolidinacyclooctadecaphane-4,7,10,13,16-pentaone
  23. (32S,6S,9S,12S)-9-((1H-indol-3-yl)methyl)-2-benzyl-6-(hydroxymethyl)-12-methyl-5,8,11,14-tetraaza-1(2,5)-oxadiazola-3(1,2)-pyrrolidinacyclopentadecaphane-4,7,10,13-tetraone
    Compound 22 (32S,6S,9S,12S)-9-((1H-indol-3-yl)methyl)-2-benzyl-6-(hydroxymethyl)-12-methyl-5,8,11,14-tetraaza-1(2,5)-oxadiazola-3(1,2)-pyrrolidinacyclopentadecaphane-4,7,10,13-tetraone
  24. (32S,9S,15S)-2,15-dibenzyl-9-isobutyl-5,8,11,14-tetraaza-1(2,5)-oxadiazola-3(1,2)-pyrrolidinacyclopentadecaphane-4,7,10,13-tetraone
    Compound 23 (32S,9S,15S)-2,15-dibenzyl-9-isobutyl-5,8,11,14-tetraaza-1(2,5)-oxadiazola-3(1,2)-pyrrolidinacyclopentadecaphane-4,7,10,13-tetraone
  25. (32S,6S,9S,12S)-2-benzyl-12-(4-hydroxybenzyl)-6-(hydroxymethyl)-9-isobutyl-5,8,11,14-tetraaza-1(2,5)-oxadiazola-3(1,2)-pyrrolidinacyclopentadecaphane-4,7,10,13-tetraone
    Compound 24 (32S,6S,9S,12S)-2-benzyl-12-(4-hydroxybenzyl)-6-(hydroxymethyl)-9-isobutyl-5,8,11,14-tetraaza-1(2,5)-oxadiazola-3(1,2)-pyrrolidinacyclopentadecaphane-4,7,10,13-tetraone
  26. (62S,9S,15S)-2-benzyl-9-isobutyl-15-methyl-3,8,11,14-tetraaza-1(2,5)-oxadiazola-6(1,2)-pyrrolidinacyclopentadecaphane-5,7,10,13-tetraone
    Compound 25 (62S,9S,15S)-2-benzyl-9-isobutyl-15-methyl-3,8,11,14-tetraaza-1(2,5)-oxadiazola-6(1,2)-pyrrolidinacyclopentadecaphane-5,7,10,13-tetraone
  27. (2S,5S,11S)-5,13-dibenzyl-2,11-dimethyl-3,6,9,12-tetraaza-1(2,5)-oxadiazolacyclotridecaphane-4,7,10-trione
    Compound 26 (2S,5S,11S)-5,13-dibenzyl-2,11-dimethyl-3,6,9,12-tetraaza-1(2,5)-oxadiazolacyclotridecaphane-4,7,10-trione
  28. (32S,9S,15S)-15-benzyl-2,9-diisobutyl-5,8,11,14-tetraaza-1(2,5)-oxadiazola-3(1,2)-pyrrolidinacyclopentadecaphane-4,7,10,13-tetraone
    Compound 27 (32S,9S,15S)-15-benzyl-2,9-diisobutyl-5,8,11,14-tetraaza-1(2,5)-oxadiazola-3(1,2)-pyrrolidinacyclopentadecaphane-4,7,10,13-tetraone
  29. (6S,12S,15S,20aS)-12-benzyl-6-isobutyl-15-methyltetradecahydropyrrolo[1,2-a][1,4,7,10,13,16]hexaazacyclooctadecine-1,4,7,10,13,16-hexaone
    Compound 28 (6S,12S,15S,20aS)-12-benzyl-6-isobutyl-15-methyltetradecahydropyrrolo[1,2-a][1,4,7,10,13,16]hexaazacyclooctadecine-1,4,7,10,13,16-hexaone
  30. (6S,9S,12S,15S,20aS)-12-benzyl-6-isobutyl-9,15-dimethyltetradecahydropyrrolo[1,2-a][1,4,7,10,13,16]hexaazacyclooctadecine-1,4,7,10,13,16-hexaone
    Compound 29 (6S,9S,12S,15S,20aS)-12-benzyl-6-isobutyl-9,15-dimethyltetradecahydropyrrolo[1,2-a][1,4,7,10,13,16]hexaazacyclooctadecine-1,4,7,10,13,16-hexaone
  31. (3S,6S,12S,15S,20aS)-12-benzyl-6-isobutyl-3,15-dimethyltetradecahydropyrrolo[1,2-a][1,4,7,10,13,16]hexaazacyclooctadecine-1,4,7,10,13,16-hexaone
    Compound 30 (3S,6S,12S,15S,20aS)-12-benzyl-6-isobutyl-3,15-dimethyltetradecahydropyrrolo[1,2-a][1,4,7,10,13,16]hexaazacyclooctadecine-1,4,7,10,13,16-hexaone
  32. (3S,6S,9S,12S,15S,20aS)-12-benzyl-6-isobutyl-3,9,15-trimethyltetradecahydropyrrolo[1,2-a][1,4,7,10,13,16]hexaazacyclooctadecine-1,4,7,10,13,16-hexaone
    Compound 31 (3S,6S,9S,12S,15S,20aS)-12-benzyl-6-isobutyl-3,9,15-trimethyltetradecahydropyrrolo[1,2-a][1,4,7,10,13,16]hexaazacyclooctadecine-1,4,7,10,13,16-hexaone
  33. (3S,6S,9S,12S,15S,20aS)-3,12-dibenzyl-6,9-diisobutyl-15-methyltetradecahydropyrrolo[1,2-a][1,4,7,10,13,16]hexaazacyclooctadecine-1,4,7,10,13,16-hexaone
    Compound 32 (3S,6S,9S,12S,15S,20aS)-3,12-dibenzyl-6,9-diisobutyl-15-methyltetradecahydropyrrolo[1,2-a][1,4,7,10,13,16]hexaazacyclooctadecine-1,4,7,10,13,16-hexaone

Change history

Corrected online 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.

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Affiliations

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

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

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.

Competing financial interests

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

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    Crystallographic data for compound 1a

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