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

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

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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).

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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.

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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.

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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

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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.

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Correspondence to Peter Scott.

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Crystallographic data for compound delta4a. (CIF 36 kb)

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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

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