Amino Acids

, Volume 41, Issue 3, pp 663–672 | Cite as

Cyclic α,β-peptoid octamers with differing side chain patterns: synthesis and conformational investigation

  • Emiliana De Santis
  • Thomas Hjelmgaard
  • Sophie Faure
  • Olivier Roy
  • Claude Didierjean
  • Bruce D. Alexander
  • Giuliano Siligardi
  • Rohanah Hussain
  • Tamás Jávorfi
  • Alison A. Edwards
  • Claude Taillefumier
Original Article

Abstract

The solution-phase synthesis and cyclisation of three α,β-peptoid octamers with differing side chain patterns is reported. One of these, compound C, showed a significantly greater resolution by NMR relative to the other two structurally related octamers. This observation was studied in detail by circular dichroism at a synchrotron light source to facilitate the correlation between the side chain patterns and conformational preference of these three peptoids. The X-ray crystal structure of cyclic octamer C, the first high-resolution structure for the α,β-peptoid backbone, was also obtained from methanol. Combined solid- and solution-phase studies allowed the identification of the N-2-(benzyloxy)ethyl side chain on the β-residue of the heterogeneous backbone as a key structural feature driving the increased conformational stability for octamer C.

Keywords

Peptidomimetics α,β-peptoids Circular dichroism X-ray crystallography 

Abbreviations

CD

Circular dichroism

COSY

Proton–proton correlation experiment

DMAP

4-Dimethylaminopyridine

DMF

N,N-Dimethylformamide

EDC

1-(3-Dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride

HATU

O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate

HFIP

1,1,1,3,3,3-Hexafluoroisopropanol

HMBC

Heteronuclear multiple bond correlation experiment

HRMS

High-resolution mass spectroscopy

HSQC

Heteronuclear single quantum correlation experiment

IR

Infrared

NMR

Nuclear magnetic resonance

rt

Room temperature

SI

Supporting information

SRCD

Synchrotron radiation circular dichroism

TFA

Trifluoroacetic acid

TFE

2,2,2-trifluoroethanol

THF

Tetrahydrofuran

TLC

Thin layer chromatography

UV

Ultraviolet

Supplementary material

726_2011_887_MOESM1_ESM.pdf (1.5 mb)
Supplementary material 1 (PDF 1.54 MB)

References

  1. Altomare A, Cascarano G, Giacovazzo C, Guagliardi A (1993) Completion and refinement of crystal structure with SIR92. J Appl Cryst 26:343–350CrossRefGoogle Scholar
  2. Armand P, Kirshenbaum K, Falicov A, Dunbrack RL, Dill KA, Zuckermann RN, Cohen FE (1997) Chiral N-substituted glycines can form stable helical conformations. Fold Des 2:369–375PubMedCrossRefGoogle Scholar
  3. Astle JM, Udugamasooriya DG, Smallshaw JE, Kodadek TA (2008) VEGFR2 Antagonist and other peptoids evade immune recognition. Int J Pept Res Ther 14:223–227CrossRefGoogle Scholar
  4. Campbell F, Plante JP, Edwards TA, Warriner SL, Wilson AJ (2010) N-alkylated oligoamide α-helical proteomimetics. Org. Biomol Chem 8:2344–2351PubMedCrossRefGoogle Scholar
  5. Caumes C, Hjelmgaard T, Remuson R, Faure S, Taillefumier C (2010) Highly convenient gram-scale solution-phase peptoid synthesis and orthogonal side-chain post-modification. Synthesis:257–264Google Scholar
  6. Cecioni S, Faure S, Darbost U, Bonnamour I, Parrot-Lopez H, Roy O, Taillefumier C, Wimmerová M, Praly J-P, Imberty A, Vidal S (2010) Selectivity among two lectins: probing the effect of topology, multivalency and flexibility of “clicked” multivalent glycoclusters. Chem Eur J 17:2146–2159Google Scholar
  7. Clarke DT, Jones G (2004) CD12: a new high flux beamline for ultraviolet and vacuum-ultraviolet circular dichroism on the SRS Daresbury. J. Synchrotron Rad 11:142–149CrossRefGoogle Scholar
  8. Combs DJ, Lokey RS (2007) Extended peptoids: a new class of oligomers based on aromatic building blocks. Tetrahedron Lett 48:2679–2682PubMedCrossRefGoogle Scholar
  9. Flack HD, Schwarzenbach D (1988) On the use of least-square restraint for origin fixing in polar space groups. Acta Cryst A44:499–506Google Scholar
  10. Fowler SA, Blackwell HE (2009) Structure–function relationships in peptoids: recent advances toward deciphering the structural requirements for biological function. Org Biomol Chem 7:1508–1524PubMedCrossRefGoogle Scholar
  11. Fowler SA, Luechapanichkul R, Blackwell HE (2009) Synthesis and characterization of nitroaromatic peptoids: fine tuning peptoid secondary structure through monomer position and functionality. J Org Chem 74:1440–1449PubMedCrossRefGoogle Scholar
  12. Gorske BC, Blackwell HE (2006) Tuning peptoid secondary structure with pentafluoroaromatic functionality: a new design paradigm for the construction of discretely folded peptoid structures. J Am Chem Soc 128:14378–14387PubMedCrossRefGoogle Scholar
  13. Gorske BC, Bastian BL, Geske GD, Blackwell HE (2007) Local and tunable n → pi* interactions regulate amide isomerism in the peptoid backbone. J Am Chem Soc 129:8928–8929PubMedCrossRefGoogle Scholar
  14. Gorske BC, Stringer JR, Bastian BL, Fowler SA, Blackwell HE (2009) New strategies for the design of folded peptoids revealed by a survey of noncovalent interactions in model systems. J Am Chem Soc 131:16555–16567PubMedCrossRefGoogle Scholar
  15. Hamper BC, Kolodziej SA, Scates AM, Smith RG, Cortez E (1998) Solid-phase synthesis of β-peptoids: N-Substituted β-aminopropionic acid oligomers. J Org Chem 63:708–718PubMedCrossRefGoogle Scholar
  16. Hill DJ, Mio MJ, Prince RB, Hughes TS, Moore JS et al (2001) A field guide to foldamers. Chem Rev 101:3893–4012PubMedCrossRefGoogle Scholar
  17. Hioki H, Kinami H, Yoshida A, Kojima A, Kodama M, Takaoka S, Ueda K, Katsu T (2004) Synthesis of N-substituted cyclic triglycines and their response to metal ions. Tetrahedron Lett 45:1091–1094CrossRefGoogle Scholar
  18. Hjelmgaard T, Faure S, Caumes C, De Santis E, Edwards AA, Taillefumier C (2009) Convenient solution-phase synthesis and conformational studies of novel linear and cyclic α, β-alternating peptoids. Org Lett 11:4100–4103PubMedCrossRefGoogle Scholar
  19. Holub JM, Jang H, Kirshenbaum K (2007) Fit to be tied: conformation-directed macrocyclization of peptoid foldamers. Org Lett 9:3275–3278PubMedCrossRefGoogle Scholar
  20. Hong DP, Hoshino M, Kuboi R, Goto Y (1999) Clustering of fluorine-substituted alcohols as factor responsible for their marked effect on proteins and peptides. J Am Chem Soc 121:8427–8433CrossRefGoogle Scholar
  21. Hu XE, Cassady JM (1995) Selective O-Benzylation of aminoalkanols. Synth Commun 25:907–913CrossRefGoogle Scholar
  22. Huang K, Wu CW, Sanborn TJ, Patch JA, Kirshenbaum K, Zuckermann RN, Barron AE, Radhakrishnan I (2006) A Threaded loop conformation adopted by a family of peptoid nonamers. J Am Chem Soc 128:1733–1738PubMedCrossRefGoogle Scholar
  23. Jávorfi T, Hussain R, Myatt D, Siligardi G (2010) Measuring circular dichroism in a capillary cell using the B23 Synchrotron radiation CD beamline at diamond light source. Chirality 22:E149–E153PubMedCrossRefGoogle Scholar
  24. Kirshenbaum K, Barron AE, Goldsmith RA, Armand P, Bradley EK, Truong KTV, Dill KA, Cohen FE, Zuckerman RN (1998) Sequence-specific polypeptoids: a diverse family of heteropolymers with stable secondary structure. Proc Nat Acad Sci USA 95:4303–4308PubMedCrossRefGoogle Scholar
  25. Kwon YU, Kodadek T (2007) Quantitative evaluation of the relative cell permeability of peptoids and peptides. J Am Chem Soc 129:1508–1509PubMedCrossRefGoogle Scholar
  26. Lee BC, Zuckermann RN, Dill KA (2005) Folding a nonbiological polymer into a compact multihelical structure. J Am Chem Soc 127:10999–11009PubMedCrossRefGoogle Scholar
  27. Maulucci N, Izzo I, Bifulco G, Aliberti A, De Cola C, Comegna D, Gaeta C, Napolitano A, Pizza C, Tedesco C, Flot D, De Riccardis F (2008) Synthesis, structures, and properties of nine-, twelve-, and eighteen-membered N-benzyloxyethyl cyclic α-peptoids. Chem Commun:3927–3929Google Scholar
  28. Miller SM, Simon RJ, Ng S, Zuckermann RN, Kerr JM, Moos WH (1994) Proteolytic studies of homologous peptide and N-substituted glycine peptoid oligomers. Bioorg Med Chem Lett 4:2657–2662CrossRefGoogle Scholar
  29. Moehle K, Hofmann H-J (1996) Peptides and peptoids A quantum chemical structure comparison. Biopolymers 38:781–790PubMedCrossRefGoogle Scholar
  30. Norgren AS, Zhang SD, Arvidsson PI (2006) Synthesis and circular dichroism spectroscopic investigations of oligomeric beta-peptoids with α-chiral side chains. Org Lett 8:4533–4536PubMedCrossRefGoogle Scholar
  31. Olsen CA (2010) Peptoid-peptide hybrid backbone architectures. Chembiochem 11:152–160PubMedCrossRefGoogle Scholar
  32. Olsen CA, Lambert M, Witt M, Franzyk H, Jaroszewski JW (2008) Solid-phase peptide synthesis and circular dichroism study of chiral β-peptoid homooligomers. Amino Acids 34:465–471PubMedCrossRefGoogle Scholar
  33. Otwinowski Z, Minor W (1997) Processing of X-ray diffraction data collected in oscillation mode. Meth Enzymol 276:307–326CrossRefGoogle Scholar
  34. Patch JA, Kirshenbaum K, Seurynck SL, Zuckermann RN, Barron AE (2004) Versatile oligo(N-substituted) glycines: The many roles of peptoids in drug discovery. In: Nielsen PE (ed) Pseudopeptides in Drug Discovery. Wiley-VCH Weinheim, Germany, pp 1–31Google Scholar
  35. Roy O, Faure S, Thery V, Didierjean C, Taillefumier C (2008) Cyclic β-peptoids. Org Lett 10:921–924PubMedCrossRefGoogle Scholar
  36. Seebach D, Gardiner J (2008) β-peptidic peptidomimetics. Acc Chem Res 41:1366–1375PubMedCrossRefGoogle Scholar
  37. Seo JW, Barron AE, Zuckermann RN (2010) Novel peptoid building blocks: Synthesis of functionalized aromatic helix-inducing submonomers. Org Lett 12:492–495PubMedCrossRefGoogle Scholar
  38. Shah NH, Butterfoss GL, Nguyen K, Yoo B, Bonneau R, Rabenstein DL, Kirshenbaum K (2008) Oligo(N-aryl glycines): a new twist on structured peptoids. J Am Chem Soc 130:16622–16632PubMedCrossRefGoogle Scholar
  39. Sheldrick GM (2008) A short history of SHELX. Acta Cryst A64:112–122Google Scholar
  40. Shin SB, Yoo B, Todaro LJ, Kirshenbaum K (2007) Cyclic peptoids. J Am Chem Soc 129:3218–3225PubMedCrossRefGoogle Scholar
  41. Simon RJ, Kania RS, Zuckermann RN, Huebner VD, Jewell DA, Banville S, Ng S, Wang L, Rosenberg S, Spellmeyer DC, Tan R, Frankel AD, Santi DV, Cohen FE, Bartlett PA (1992) Peptoids: a modular approach to drug discovery. Proc Natl Acad Sci USA 89:9367–9371PubMedCrossRefGoogle Scholar
  42. Stringer JR, Crapster JA, Guzei IA, Blackwell HE (2010) Construction of peptoids with all trans-amide backbones and peptoid reverse turns via the tactical incorporation of N-aryl side chains capable of hydrogen bonding. J Org Chem 75:6068–6078PubMedCrossRefGoogle Scholar
  43. Sui Q, Borchardt D, Rabenstein DL (2007) Kinetics and equilibria of cis/trans isomerization of backbone amide bonds in peptoids. J Am Chem Soc 129:12042–12048PubMedCrossRefGoogle Scholar
  44. Wien F, Miles AJ, Lees JG, Hoffmann SV, Wallace BA (2005) VUV irradiation effects on proteins in high-flux synchrotron circular dichroism spectroscopy. J Synchrotron Rad 12:517–523CrossRefGoogle Scholar
  45. Wu CW, Sanborn TJ, Huang K, Zuckermann RN, Barron AE (2001) Peptoid oligomers with α-chiral, aromatic side chains: sequence requirements for the formation of stable peptoid helices. J Am Chem Soc 123:6778–6784PubMedCrossRefGoogle Scholar
  46. Wu CW, Kirshenbaum K, Sanborn TJ, Patch JA, Huang K, Dill KA, Zuckermann RN, Barron AE (2003) Structural and spectroscopic studies of peptoid oligomers with α-chiral aliphatic side chains. J Am Chem Soc 125:13525–13530PubMedCrossRefGoogle Scholar
  47. Yoo B, Kirshenbaum K (2008) Peptoid architectures: elaboration, actuation, and application. Curr Opin Chem Biol 12:714–721PubMedCrossRefGoogle Scholar
  48. Yoo B, Shin SBY, Huang ML, Kirshenbaum K (2010) Peptoid macrocycles: making the rounds with peptidomimetic oligomers. Chem Eur J 16:5528–5537Google Scholar
  49. Zuckermann RN, Kodadek T (2009) Peptoids as potential therapeutics. Curr Opin Mol Ther 11:299–307PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Emiliana De Santis
    • 1
  • Thomas Hjelmgaard
    • 2
    • 3
  • Sophie Faure
    • 2
    • 3
  • Olivier Roy
    • 2
    • 3
  • Claude Didierjean
    • 4
  • Bruce D. Alexander
    • 5
  • Giuliano Siligardi
    • 6
  • Rohanah Hussain
    • 6
  • Tamás Jávorfi
    • 6
  • Alison A. Edwards
    • 1
  • Claude Taillefumier
    • 2
    • 3
  1. 1.Medway School of PharmacyUniversities of Kent and Greenwich at MedwayChatham MaritimeUK
  2. 2.Clermont-Université, Université Blaise Pascal, Laboratoire SEESIBClermont-FerrandFrance
  3. 3.CNRS, UMR 6504, Laboratoire SEESIBAubière CedexFrance
  4. 4.CRM2, Equipe Biocristallographie, UMR 7036 CNRS-UHP, Faculté des Sciences et TechnologiesUniversité de LorraineVandoeuvre-lès-NancyFrance
  5. 5.School of ScienceUniversity of GreenwichChatham MaritimeUK
  6. 6.Diamond Light Source Ltd., Diamond House, Harwell Science and Innovation CampusDidcotUK

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