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

Nature Chemistry volume 4, pages 3136 (2012) | Download Citation

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).

  • Compound C24H28N2O2

    (R,R)-1,4-Bis{(2-amino-2-phenylethoxy)methyl}benzene

  • Compound C17H18N2O4

    1,5-Bis(2-pyridinaldehyd-5-oxy)pentane

  • Compound C108H102Cl4Fe2N12O22

    ΔFe-Tris(6-((2-(4-(((R)-2-((pyridin-2-yl)methyleneamino)-2-phenylethoxy)methyl)benzyloxy)ethylimino)methyl)pyridine)diiron(II) perchlorate

  • Compound C108H102Cl4Fe2N12O28

    ΔFe-Tris(6-((2-(4-(((R)-2-((5-hydroxypyridin-2-yl)methyleneamino)-2-phenylethoxy)methyl)benzyloxy)ethylimino)methyl)pyridin-3-ol)diiron(II) perchlorate

  • Compound C126H114Cl4Fe2N12O28

    ΔFe-Tris((1R,1'R)-2,2'-(1,4-phenylenebis(methylene))bis(oxy)bis(1-phenyl-N-((5-(prop-2-ynyloxy)pyridin-2-yl)methylene)ethanamine))diiron(II) perchlorate

  • Compound C108H102Cl4N12O22Zn2

    ΔZn-Tris(6-((2-(4-(((R)-2-((pyridin-2-yl)methyleneamino)-2-phenylethoxy)methyl)benzyloxy)ethylimino)methyl)pyridine)dizinc(II) perchlorate

  • Compound C99H108Cl4Fe2N12O22

    ΔFe-Tris{(1S,1'S)-N,N'-(5,5'-(pentane-1,5-diylbis(oxy))bis(pyridine-5,2-diyl))bis(methan-1-yl-1-ylidene)bis(1-phenylethanamine)}diiron(II) perchlorate

  • Compound C99H108Cl4Fe2N12O28

    ΔFe-Tris{(1R,1'R)-N,N'-(5,5'-(pentane-1,5-diylbis(oxy))bis(pyridine-5,2-diyl))bis(methan-1-yl-1-ylidene)bis(1-phenyl-2-hydroxyethanamine)}diiron(II) perchlorate

  • Compound C117H120Cl4Fe2N12O28

    ΔFe-Tris{(1R,1'R)-N,N'-(5,5'-(pentane-1,5-diylbis(oxy))bis(pyridine-5,2-diyl))bis(methan-1-yl-1-ylidene)bis(1-phenyl-2-(prop-2-ynyloxy)ethanamine)}diiron(II) perchlorate

  • Compound C99H108Cl4N12O22Zn2

    ΔZn-Tris{(1S,1'S)-N,N'-(5,5'-(pentane-1,5-diylbis(oxy))bis(pyridine-5,2-diyl))bis(methan-1-yl-1-ylidene)bis(1-phenylethanamine)}dizinc(II) perchlorate

  • Compound C108H102Cl4Fe2N12O6

    ΔFe-Tris(6-((2-(4-(((R)-2-((pyridin-2-yl)methyleneamino)-2-phenylethoxy)methyl)benzyloxy)ethylimino)methyl)pyridine)diiron(II) chloride

  • Compound C108H102Cl4Fe2N12O6

    ΛFe-Tris(6-((2-(4-(((S)-2-((pyridin-2-yl)methyleneamino)-2-phenylethoxy)methyl)benzyloxy)ethylimino)methyl)pyridine)diiron(II) chloride

  • Compound C99H108Cl4Fe2N12O6

    ΔFe-Tris{(1S,1'S)-N,N'-(5,5'-(pentane-1,5-diylbis(oxy))bis(pyridine-5,2-diyl))bis(methan-1-yl-1-ylidene)bis(1-phenylethanamine)}diiron(II) chloride

  • Compound C99H108Cl4Fe2N12O6

    ΛFe-Tris{(1R,1'R)-N,N'-(5,5'-(pentane-1,5-diylbis(oxy))bis(pyridine-5,2-diyl))bis(methan-1-yl-1-ylidene)bis(1-phenylethanamine)}diiron(II) chloride

  • Compound C99H108Cl4Fe2N12O12

    ΔFe-Tris{(1R,1'R)-N,N'-(5,5'-(pentane-1,5-diylbis(oxy))bis(pyridine-5,2-diyl))bis(methan-1-yl-1-ylidene)bis(1-phenyl-2-hydroxyethanamine)}diiron(II) chloride

  • Compound C99H108Cl4Fe2N12O12

    ΛFe-Tris{(1S,1'S)-N,N'-(5,5'-(pentane-1,5-diylbis(oxy))bis(pyridine-5,2-diyl))bis(methan-1-yl-1-ylidene)bis(1-phenyl-2-hydroxyethanamine)}diiron(II) chloride

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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

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, CZ-61265 Brno, Czech Republic

    • Viktor Brabec
    •  & Jaroslav Malina

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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.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Peter Scott.

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    Crystallographic data for compound delta4a.

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DOI

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

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