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:

Optically pure, water-stable metallo-helical ‘flexicate’ assemblies with antibiotic activity

Nature Chemistry volume 4, pages 31–36 (2012)Cite this article

Subjects

Abstract

The helicates—chiral assemblies of two or more metal atoms linked by short or relatively rigid multidentate organic ligands—may be regarded as non-peptide mimetics of α-helices because they are of comparable size and have shown some relevant biological activity. Unfortunately, these beautiful helical compounds have remained difficult to use in the medicinal arena because they contain mixtures of isomers, cannot be optimized for specific purposes, are insoluble, or are too difficult to synthesize. Instead, we have now prepared thermodynamically stable single enantiomers of monometallic units connected by organic linkers. Our highly adaptable self-assembly approach enables the rapid preparation of ranges of water-stable, helicate-like compounds with high stereochemical purity. One such iron(II) ‘flexicate’ system exhibits specific interactions with DNA, promising antimicrobial activity against a Gram-positive bacterium (methicillin-resistant Staphylococcus aureus, MRSA252), but also, unusually, a Gram-negative bacterium (Escherichia coli, MC4100), as well as low toxicity towards a non-mammalian model organism (Caenorhabditis elegans).

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: Self assembly of helical bimetallics.
Figure 2: 1H NMR spectrum of ΔFe,RC-[Fe2L1a3][ClO4]4 (Δ3a) in CD3CN (700 MHz).
Figure 3: Views of the structure of the cation unit in ΔZn,RC-[Zn2L1a3][ClO4]4 (Δ4a).
Figure 4: Self-assembly of diastereomerically pure flexicate systems ΔFe-[Fe2L23][ClO4]4 [Δ5a (X = H), Δ5b (X = OH), Δ5c (X = OCH2C≡CH)].
Figure 5: Derivation of the binding angle of the flexicate relative to the DNA helix/flow orientation axis.

Similar content being viewed by others

References

  1. Huang, Y., Huang, J. & Chen, Y. Alpha-helical cationic antimicrobial peptides: relationships of structure and function. Protein Cell 1, 143–152 (2010).

    Article  CAS  Google Scholar 

  2. Hancock, R. E. W. & Sahl, H.-G. Antimicrobial and host-defense peptides as new anti-infective therapeutic strategies. Nature Biotechnol. 24, 1551–1557 (2006).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  4. Tossi, A., Sandri, L. & Giangaspero, A. Amphipathic, alpha-helical antimicrobial peptides. Biopolymers 55, 4–30 (2000).

    Article  CAS  Google Scholar 

  5. Boyle, A. L. & Woolfson, D. N. De novo designed peptides for biological applications. Chem. Soc. Rev. 40, 4295–4306 (2011).

    Article  CAS  Google Scholar 

  6. Cummings, C. G. & Hamilton, A. D. Disrupting protein–protein interactions with non-peptidic, small molecule alpha-helix mimetics. Curr. Opin. Chem. Biol. 14, 341–346 (2010).

    Article  CAS  Google Scholar 

  7. Haridas, V. From peptides to non-peptide alpha-helix inducers and mimetics. Eur. J. Org. Chem. 2009, 5112–5128 (2009).

    Article  Google Scholar 

  8. Grauer, A. & König, B. Peptidomimetics—a versatile route to biologically active compounds. Eur. J. Org. Chem. 2009, 5099–5111 (2009).

    Article  Google Scholar 

  9. Davis, J. M., Tsou, L. K. & Hamilton, A. D. Synthetic non-peptide mimetics of alpha-helices. Chem. Soc. Rev. 36, 326–334 (2007).

    Article  CAS  Google Scholar 

  10. Lehn, J.-M. et al. Spontaneous assembly of double-stranded helicates from oligobipyridine ligands and copper(I) cations: structure of an inorganic double helix. Proc. Natl Acad. Sci. USA 84, 2565–2569 (1987).

    Article  CAS  Google Scholar 

  11. He, C., Zhao, Y., Guo, D., Lin, Z. & Duan, C. Chirality transfer through helical motifs in coordination compounds. Eur. J. Inorg. Chem. 2007, 3451–3463 (2007).

    Article  Google Scholar 

  12. Piguet, C., Borkovec, M., Hamacek, J. & Zeckert, K. Strict self-assembly of polymetallic helicates: the concepts behind the semantics. Coord. Chem. Rev. 249, 705–726 (2005).

    Article  CAS  Google Scholar 

  13. Schalley, C. A., Lützen, A. & Albrecht, M. Approaching supramolecular functionality. Chem. Eur. J. 10, 1072–1080 (2004).

    Article  CAS  Google Scholar 

  14. Hannon, M. J. & Childs, L. J. Helices and helicates: beautiful supramolecular motifs with emerging applications. Supramol. Chem. 16, 7–22 (2004).

    Article  CAS  Google Scholar 

  15. Albrecht, M. ‘Let's Twist Again’: double-stranded, triple-stranded, and circular helicates. Chem. Rev. 101, 3457–3498 (2001).

    Article  CAS  Google Scholar 

  16. Albrecht, M. How do they know? Influencing the relative stereochemistry of the complex units of dinuclear triple-stranded helicate-type complexes. Chem. Eur. J. 6, 3485–3489 (2000).

    Article  CAS  Google Scholar 

  17. Caulder, D. L. & Raymond, K. N. Supermolecules by design. Acc. Chem. Res. 32, 975–982 (1999).

    Article  CAS  Google Scholar 

  18. Constable, E. C. Oligopyridines as helicating ligands. Tetrahedron 48, 10013–10059 (1992).

    Article  CAS  Google Scholar 

  19. Glasson, C. R. K. et al. Microwave synthesis of a rare [Ru2L3]4+ triple helicate and its interaction with DNA. Chem. Eur. J. 14, 10535–10538 (2008).

    Article  CAS  Google Scholar 

  20. Yu, H., Wang, X., Fu, M., Ren, J. & Qu, X. Chiral metallo-supramolecular complexes selectively recognize human telomeric G-quadruplex DNA. Nucleic Acids Res. 36, 5695–5703 (2008).

    Article  CAS  Google Scholar 

  21. Schoentjes, B. & Lehn, J.-M. Interaction of double-helical polynuclear copper(I) complexes with double-stranded DNA. Helv. Chim. Acta 78, 1–12 (1995).

    Article  CAS  Google Scholar 

  22. Cardo, L., Sadovnikova, V., Phongtongpasuk, S., Hodges, N. J. & Hannon, M. J. Arginine conjugates of metallo-supramolecular cylinders prescribe helicity and enhance DNA junction binding and cellular activity. Chem. Commun. 47, 6575–6577 (2011).

    Article  CAS  Google Scholar 

  23. Boer, D. R. et al. Self-assembly of functionalizable two-component 3D DNA arrays through the induced formation of DNA three-way-junction branch points by supramolecular cylinders. Angew. Chem. Int. Ed. 49, 2336–2339 (2010).

    Article  CAS  Google Scholar 

  24. Richards, A. D., Rodger, A., Hannon, M. J. & Bolhuis, A. Antimicrobial activity of an iron triple helicate. Int. J. Antimicrob. Agents 33, 469–472 (2009).

    Article  CAS  Google Scholar 

  25. Parajo, Y. et al. Effect of bridging ligand structure on the thermal stability and DNA binding properties of iron(II) triple helicates. Dalton Trans. 4868–4874 (2009).

  26. Malina, J., Hannon, M. J. & Brabec, V. DNA binding of dinuclear iron(II) metallosupramolecular cylinders. DNA unwinding and sequence preference. Nucleic Acids Res. 36, 3630–3638 (2008).

    Article  CAS  Google Scholar 

  27. Malina, J., Hannon, M. J. & Brabec, V. Interaction of dinuclear ruthenium(II) supramolecular cylinders with DNA: sequence-specific binding, unwinding, and photocleavage. Chem. Eur. J. 14, 10408–10414 (2008).

    Article  CAS  Google Scholar 

  28. Hotze, A. C. G. et al. Supramolecular iron cylinder with unprecedented DNA binding is a potent cytostatic and apoptotic agent without exhibiting genotoxicity. Chem. Biol. 15, 1258–1267 (2008).

    Article  CAS  Google Scholar 

  29. Pascu, G. I., Hotze, A. C. G., Sanchez-Cano, C., Kariuki, B. M. & Hannon, M. J. Dinuclear ruthenium(II) triple-stranded helicates: luminescent supramolecular cylinders that bind and coil DNA and exhibit activity against cancer cell lines. Angew. Chem. Int. Ed. 46, 4374–4378 (2007).

    Article  CAS  Google Scholar 

  30. Malina, J., Hannon, M. J. & Brabec, V. Recognition of DNA three-way junctions by metallosupramolecular cylinders: gel electrophoresis studies. Chem. Eur. J. 13, 3871–3877 (2007).

    Article  CAS  Google Scholar 

  31. Oleksi, A. et al. Molecular recognition of a three-way DNA junction by a metallosupramolecular helicate. Angew. Chem. Int. Ed. 45, 1227–1231 (2006).

    Article  CAS  Google Scholar 

  32. Hotze, A. C. G., Kariuki, B. M. & Hannon, M. J. Dinuclear double-stranded metallosupramolecular ruthenium complexes: potential anticancer drugs. Angew. Chem. Int. Ed. 45, 4839–4842 (2006).

    Article  Google Scholar 

  33. Meistermann, I. et al. Intramolecular DNA coiling mediated by metallosupramolecular cylinders: differential binding of P and M helical enantiomers. Proc. Natl Acad. Sci. USA 99, 5069–5074 (2002).

    Article  CAS  Google Scholar 

  34. Hannon, M. J. et al. Intramolecular DNA coiling mediated by a metallo-supramolecular cylinder. Angew. Chem. Int. Ed. 40, 879–884 (2001).

    Article  Google Scholar 

  35. Howson, S. E. & Scott, P. Approaches to the synthesis of optically pure helicates. Dalton Trans. 40, 10268–10277 (2011).

    Article  CAS  Google Scholar 

  36. Howson, S. E. et al. Self-assembling optically pure Fe(A-B)3 chelates. Chem. Commun. 1727–1729 (2009).

  37. Howson, S. E. et al. Origins of stereoselectivity in optically pure phenylethaniminopyridine tris-chelates M(NN′)3n+ (M=Mn, Fe, Co, Ni and Zn). Dalton Trans. 40, 10416–10433 (2011).

    Article  CAS  Google Scholar 

  38. Telfer, S. G., Kuroda, R. & Sato, T. Stereoselective formation of dinuclear complexes with anomalous CD spectra. Chem. Commun. 1064–1065 (2003).

  39. Telfer, S. G., Sato, T., Kuroda, R., Lefebvre, J. & Leznoff, D. B. Dinuclear complexes of chiral tetradentate pyridylimine ligands: diastereoselectivity, positive cooperativity, anion selectivity, ligand self-sorting based on chirality, and magnetism. Inorg. Chem. 43, 421–429 (2004).

    Article  CAS  Google Scholar 

  40. Hohenstein, E. G. & Sherrill, C. D. Effects of heteroatoms on aromatic π–π interactions: benzene–pyridine and pyridine dimer. J. Phys. Chem. A 113, 878–886 (2009).

    Article  CAS  Google Scholar 

  41. Xu, J., Parac, T. N. & Raymond, K. N. meso myths: what drives assembly of helical versus meso-[M2L3] clusters? Angew. Chem. Int. Ed. 38, 2878–2882 (1999).

    Article  CAS  Google Scholar 

  42. Bakunova, S. M. et al. Synthesis and antiprotozoal activity of pyridyl analogues of pentamidine. J. Med. Chem. 52, 4657–4667 (2009).

    Article  CAS  Google Scholar 

  43. Hidaka, J. & Douglas, B. E. Circular dichroism of coordination compounds. II. Some metal complexes of 2,2′-dipyridyl and 1,10-phenanthroline. Inorg. Chem. 3, 1180–1184 (1964).

    Article  CAS  Google Scholar 

  44. Ziegler, M. & von Zelewsky, A. Charge-transfer excited state properties of chiral transition metal coordination compounds studied by chiroptical spectroscopy. Coord. Chem. Rev. 177, 257–300 (1998).

    Article  CAS  Google Scholar 

  45. Holden, M. T. G. et al. Complete genomes of two clinical Staphylococcus aureus strains: evidence for the rapid evolution of virulence and drug resistance. Proc. Natl Acad. Sci. USA 101, 9786–9791 (2004).

    Article  CAS  Google Scholar 

  46. Dwyer, F. P., Gyarfas, E. C., Rogers, W. P. & Koch, J. H. Biological activity of complex ions. Nature 170, 190–191 (1952).

    Article  CAS  Google Scholar 

  47. Bolhuis, A. et al. Antimicrobial activity of ruthenium-based intercalators. Eur. J. Pharm. Sci. 42, 313–317 (2011).

    Article  CAS  Google Scholar 

  48. Hancock, R. E. W. The bacterial outer membrane as a drug barrier. Trends Microbiol. 5, 37–42 (1997).

    Article  CAS  Google Scholar 

  49. Artal-Sanz, M., de Jong, L. & Tavernarakis, N. Caenorhabditis elegans: a versatile platform for drug discovery. Biotechnol. J. 1, 1405–1418 (2006).

    Article  CAS  Google Scholar 

  50. Leung, M. C. K. et al. Caenorhabditis elegans: an emerging model in biomedical and environmental toxicology. Toxicol. Sci. 106, 5–28 (2008).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors acknowledge the EPSRC and the University of Warwick for financial support. The authors thank the EPSRC National Crystallography Service (University of Southampton, UK) for data collection.

Author information

Authors and Affiliations

  1. Department of Chemistry, University of Warwick, Gibbet Hill Road, Coventry, CV4 7AL, UK

    Suzanne E. Howson, Guy J. Clarkson, Alison Rodger & Peter Scott

  2. Department of Pharmacy and Pharmacology, University of Bath, Bath, BA2 7AY, UK

    Albert Bolhuis

  3. Institute of Biophysics, Academy of Sciences of the Czech Republic, Královopolská 135, Brno, CZ-61265, Czech Republic

    Viktor Brabec & Jaroslav Malina

Authors
  1. Suzanne E. Howson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Albert Bolhuis
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Viktor Brabec
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Guy J. Clarkson
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jaroslav Malina
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Alison Rodger
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Peter Scott
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

S.E.H. synthesized the compounds, carried out the spectroscopic studies, analysed data and drafted the paper. A.B. designed and performed the antimicrobial and toxicity studies. V.B. and J.M. designed and performed the ethidium bromide displacement experiments and DNA melting studies. G.J.C. solved and refined the X-ray crystal data. A.R. designed the linear dichroism studies and assisted with analysis of the resulting data. P.S. conceived and directed the project, analysed data and wrote the paper.

Corresponding author

Correspondence to Peter Scott.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary information

Supplementary information (PDF 1013 kb)

Supplementary information

Crystallographic data for compound delta4a. (CIF 36 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Howson, S., Bolhuis, A., Brabec, V. et al. Optically pure, water-stable metallo-helical ‘flexicate’ assemblies with antibiotic activity. Nature Chem 4, 31–36 (2012). https://doi.org/10.1038/nchem.1206

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nchem.1206

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