Skip to main content
SpringerLink
Log in

Synthesis and structural study of highly constrained hybrid cyclobutane-proline γ,γ-peptides

  • Original Article
  • Published:
Amino Acids Aims and scope Submit manuscript

Abstract

Two diastereomeric series of hybrid γ,γ-peptides derived from conveniently protected derivatives of (1R,2S)- and (1S,2R)-3-amino-2,2-dimethylcyclobutane-1-carboxylic acid and cis-4-amino-l-proline joined in alternation have efficiently been prepared through convergent synthesis. High-resolution NMR experiments show that these compounds present defined conformations in solution affording very compact structures as the result of intra and inter residue hydrogen-bonded ring formation. (R,S)-cyclobutane containing peptides adopt more twisted conformations than (S,R) diastereomers. In addition, all these γ-peptides have high tendency to aggregation providing vesicles of nanometric size, which were stable when allowed to stand for several days, as verified by transmission electron microscopy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Scheme 1
Scheme 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10

Similar content being viewed by others

Abbreviations

Boc:

t-Butoxycarbonyl

tBu:

t-Butyl

tBuOH:

t-Butanol

CD:

Circular dichroism

Cbz:

Benzyl carbamate

DIPEA:

N,N-Diisopropylethylamine

DMAP:

4-Dimethylaminopyridine

EDAC:

1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide

GABA:

γ-Aminobutyric acid

HMBC:

Heteronuclear multiple bond correlation

HSQC:

Heteronuclear single quantum correlation

Hz:

Hertz

Me:

Methyl

MeOH:

Methanol

NMR:

Nuclear magnetic resonance

NOE:

Nuclear overhauser effect

NOESY:

Nuclear overhauser effect spectroscopy

ppm:

Parts per million

PyBOP:

Benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate

ROESY:

Rotational nuclear overhauser effect spectroscopy

TEM:

Transmission electron microscopy

TFA:

Trifluoroacetic acid

THF:

Tetrahydrofuran

TOCSY:

Total correlation spectroscopy

References

  • Aguilera J, Moglioni AG, Moltrasio GY, Ortuño RM (2008) Stereodivergent and efficient synthesis of the first bis(cyclobutane) gamma-dipeptides. Tetrahedron Asymmetry 19:302–308

    Article  CAS  Google Scholar 

  • Brenner M, Seebach D (2001) Design, synthesis, NMR-solution and X-ray crystal structure of N-acyl-γ-dipeptide amides that form a βII′-type turn. Helv Chim Acta 84:2155–2166

    Article  CAS  Google Scholar 

  • Cheng RP, Gellman SH, DeGrado WF (2001) β-Peptides: from structure to function. Chem Rev 101:3219–3232

    Article  PubMed  CAS  Google Scholar 

  • DePol S, Zorn C, Klein CD, Zerbe O, Reiser O (2004) Surprisingly stable helical conformations in α/β-peptides by Incorporation of cis β-aminocyclopropane carboxylic acids. Angew Chem Int Ed 43:511–514

    Article  CAS  Google Scholar 

  • Farrera-Sinfreu J, Zaccaro L, Vidal D, Salvatella X, Giralt E, Pons M, Albericio F, Royo M (2004) A new class of foldamers based on cis-γ-amino-l-proline. J Am Chem Soc 126:6048–6057

    Article  PubMed  CAS  Google Scholar 

  • Farrera-Sinfreu J, Giralt E, Castel S, Albericio F, Royo M (2005) Cell-penetrating cis-γ-amino-l-proline-derived peptides. J Am Chem Soc 127:9459–9468

    Google Scholar 

  • Fernández D, Torres E, Avilés FX, Ortuño RM, Vendrell J (2009) Cyclobutane-containing peptides: evaluation as novel metallocarboxypeptidase inhibitors and modelling of their mode of action. Bioorg Med Chem 17:3824–3828

    Article  PubMed  Google Scholar 

  • Fisher A, Mann A, Verma V, Thomas N, Mishra RK, Johnson RL (2006) Design and synthesis of photoaffinityl-labeling ligands of the L-Prolyl-L-leucylglycinamide binding site involved in the allosteric modulation of the dopamine receptor. J Med Chem 49:307–317

    Article  PubMed  CAS  Google Scholar 

  • Gorrea E, Torres E, Nolis P, DaSilva E, Amabilino DB, Branchadell V, Ortuño RM (2011) Self-assembly of chiral trans-cyclobutane containing β-dipeptides into ordered aggregates. Chem Eur J 17:4588–4597

    Google Scholar 

  • Guo L, Chi Y, Almeida AM, Guzei IA, Parker BK, Gellman SH (2009) Stereospecific synthesis of conformationally constrained γ-amino acids: new foldamer building blocks that support helical secondary structure. J Am Chem Soc 131:16018–16020

    Article  PubMed  CAS  Google Scholar 

  • Guo L, Almeida AM, Zhang W, Reidenbach AG, Choi SH, Guzei IA, Gellman SH (2010) Helix formation in preorganized β/γ-peptide foldamers: hydrogen-bond analogy to the α-helix without α-amino acid residues. J Am Chem Soc 132:7868–7869

    Article  PubMed  CAS  Google Scholar 

  • Hecht S, Huc I (2007) Foldamers: structure, properties and applications. Wiley-VCH, Weinheim

    Google Scholar 

  • Horne WS, Gellman SH (2008) Foldamers with heterogeneous backbones. Acc Chem Res 41:1399–1408

    Article  PubMed  CAS  Google Scholar 

  • Izquierdo S, Kogan MJ, Parella T, Moglioni AG, Branchadell V, Giralt E, Ortuño RM (2004) 14-Helical folding in a cyclobutane containing β-tetrapeptide. J Org Chem 69:5093–5099

    Article  PubMed  CAS  Google Scholar 

  • Koglin N, Zorn C, Beumer R, Cabrele C, Bubert C, Sewald N, Reiser O, Beck-Sickinger AG (2003) Analogues of neuropeptide y containing β-aminocyclopropane carboxylic acids are the shortest linear peptides that are selective for the Y1 receptor. Angew Chem Int Ed 42:202–205

    Article  CAS  Google Scholar 

  • Lang M, Bufe B, DePol S, Reiser O, Meyerhof W, Beck-Sickinger AG (2006) Structural properties of orexins for activation of their receptors. J Pept Sci 12:258–266

    Article  PubMed  CAS  Google Scholar 

  • Moglioni AG, García-Expósito E, Aguado GP, Parella T, Moltrasio GY, Branchadell V, Ortuño RM (2000) Divergent routes to chiral cyclobutyl synthons from (−)-α-pinene and their use in the stereoselective synthesis of cyclobutane dehydro amino acids. J Org Chem 65:3934–3940

    Article  PubMed  CAS  Google Scholar 

  • Rodríguez-Ropero F, Canales M, Zanuy D, Zhang A, Schlüter D, Alemán C (2009) Helical dendronized polymers with chiral second-generation dendrons: atomistic view and driving forces for structure formation. J Phys Chem B 113:14868–14876

    Article  PubMed  Google Scholar 

  • Rúa F, Boussert S, Parella T, Diez-Pérez I, Branchadell V, Giralt E, Ortuño RM (2007) Self-assembly of a cyclobutane β-tetrapeptide to form nano-sized structures. Org Lett 9:3643–3645

    Article  PubMed  Google Scholar 

  • Seebach D, Brenner M, Rueping M, Jaun B (2002) γ2-, γ3-, and γ2, 3, 4-Amino acids, coupling to γ-hexapeptides: CD spectra, NMR solution and X-ray crystal structures of γ-peptides. Chem Eur J 8:573–584

    Article  CAS  Google Scholar 

  • Torino D, Mollica A, Pinnen F, Feliciani F, Spisani S, Lucente G (2009) Novel chemotactic For-Met-Leu-Phe-OMe (fMLF-OMe) analogues based on Met residue replacement by 4-amino-proline scaffold: synthesis and bioactivity. Bioorg Med Chem 17:251–259

    Article  PubMed  CAS  Google Scholar 

  • Torres E, Gorrea E, DaSilva E, Nolis P, Branchadell V, Ortuño RM (2009) Prevalence of eight-membered hydrogen-bonded rings in some bis(cyclobutane) β-dipeptides with trans stereochemistry. Org Lett 11:2301–2304

    Article  PubMed  CAS  Google Scholar 

  • Torres E, Gorrea E, Burusco KK, DaSilva E, Nolis P, Rúa F, Boussert S, Díez-Pérez I, Dannenberg S, Izquierdo S, Giralt E, Jaime C, Branchadell V, Ortuño RM (2010) Folding and self-assembling with β-oligomers based on (1R, 2S)-2-aminocyclobutane-1-carboxylic acid. Org Biomol Chem 8:564–575

    Article  PubMed  CAS  Google Scholar 

  • Woods CR, Ishii T, Boger DL (2002) Synthesis and DNA binding properties of iminodiacetic-acid-linked polyamides: characterization of cooperative extended 2:1 side-by-side parallel binding. J Am Chem Soc 124:10676–10682

    Article  PubMed  CAS  Google Scholar 

  • Zhang A, Schlüter AD (2007) Multigram solution-phase synthesis of three diastereomeric tripeptidic second-generation dendrons based on (2S, 4S)-, (2S, 4R)-, and (2R, 4S)-4-aminoprolines. Chem Asian J 2:1540–1548

    Article  PubMed  CAS  Google Scholar 

  • Zhang A, Rodríguez-Ropero F, Zanuy D, Alemán C, Meijer EW, Schlüter AD (2008) A rigid, chiral, dendronized polymer with a thermally table, right-handed helical conformation. Chem Eur J 14:6924–6934

    Article  CAS  Google Scholar 

Download references

Acknowledgments

Authors thank financial support from Spanish Ministerio de Ciencia e Innovación (grants CTQ2007-61704/BQU, CTQ2008-00177/BQU, and CTQ2010-15408/BQU) and Generalitat de Catalunya (grant 2009SGR-733). Time allocated in the Servei de Ressonància Magnètica Nuclear and Servei de Microscòpia Electrónica (UAB) is gratefully acknowledged. R G-A thanks Ministry of Education for a predoctoral fellowship.

Author information

Authors and Affiliations

  1. Departament de Química, Universitat Autònoma de Barcelona, Bellaterra, 08193, Barcelona, Spain

    Raquel Gutiérrez-Abad, Carles Acosta-Silva, Juan A. Cobos, Ona Illa & Rosa M. Ortuño

  2. Combinatorial Chemistry Unit, Barcelona Science Park, University of Barcelona, Baldiri Reixac, 10, 08028, Barcelona, Spain

    Daniel Carbajo & Miriam Royo

  3. Servei de RMN, Universitat Autònoma de Barcelona, Bellaterra, 08193, Barcelona, Spain

    Pau Nolis

Authors
  1. Raquel Gutiérrez-Abad
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Daniel Carbajo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Pau Nolis
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Carles Acosta-Silva
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Juan A. Cobos
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ona Illa
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Miriam Royo
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Rosa M. Ortuño
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rosa M. Ortuño.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 139656 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gutiérrez-Abad, R., Carbajo, D., Nolis, P. et al. Synthesis and structural study of highly constrained hybrid cyclobutane-proline γ,γ-peptides. Amino Acids 41, 673–686 (2011). https://doi.org/10.1007/s00726-011-0912-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00726-011-0912-4

Keywords

Search

Navigation