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Asymmetric triplex metallohelices with high and selective activity against cancer cells

Nature Chemistry volume 6, pages 797–803 (2014)Cite this article

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Abstract

Small cationic amphiphilic α-helical peptides are emerging as agents for the treatment of cancer and infection, but they are costly and display unfavourable pharmacokinetics. Helical coordination complexes may offer a three-dimensional scaffold for the synthesis of mimetic architectures. However, the high symmetry and modest functionality of current systems offer little scope to tailor the structure to interact with specific biomolecular targets, or to create libraries for phenotypic screens. Here, we report the highly stereoselective asymmetric self-assembly of very stable, functionalized metallohelices. Their anti-parallel head-to-head-to-tail ‘triplex’ strand arrangement creates an amphipathic functional topology akin to that of the active sub-units of, for example, host-defence peptides and p53. The metallohelices display high, structure-dependent toxicity to the human colon carcinoma cell-line HCT116 p53++, causing dramatic changes in the cell cycle without DNA damage. They have lower toxicity to human breast adenocarcinoma cells (MDA-MB-468) and, most remarkably, they show no significant toxicity to the bacteria methicillin-resistant Staphylococcus aureus and Escherichia coli.

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Figure 1: Metallohelix architectures.
Figure 2: Synthesis and characterisation of triplex metallohelices.
Figure 3: Exposure of cancer cells to triplex metallohelices.

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Acknowledgements

The authors thank the EPSRC and the University of Warwick for financial support, and the National Crystallographic Service for recording the X-ray data (structure code AF20)50.

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Author notes

  1. Alan D. Faulkner and Rebecca A. Kaner: These authors contributed equally to this work

Authors and Affiliations

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

    Alan D. Faulkner, Rebecca A. Kaner, Guy Clarkson, David J. Fox, Pratik Gurnani, Suzanne E. Howson, Daniel H. Simpson & Peter Scott

  2. College of Pharmacy, Taif University, PO Box 888, Taif, 21974, Saudi Arabia

    Qasem M. A. Abdallah

  3. Institute of Cancer Therapeutics, University of Bradford, Bradford, BD7 1DP, UK

    Roger M. Phillips

  4. School of Life Sciences, Gibbet Hill Campus, University of Warwick, Coventry, CV4 7AL, UK

    David I. Roper & Daniel H. Simpson

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Contributions

A.D.F. performed computational work under the direction of D.J.F. A.D.F. and R.A.K. synthesized and characterized the compounds following early studies by S.E.H., and developed and conducted stability studies. R.A.K. and Q.M.A.A. performed the biological work under the direction of R.M.P. P.G. developed a synthesis of [Fe2(C25H20N4)3]Cl4 and performed stability studies. G.J.C. solved and refined the X-ray crystal data. D.H.S. conducted the antimicrobial experiments under the direction of D.I.R. P.S. conceived and directed the project, interpreted the data and wrote the manuscript.

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Correspondence to Peter Scott.

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The authors declare no competing financial interests.

Supplementary information

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Crystallographic data for compound RC,∆Zn,HHT-[Zn2L3a3][ClO4]4.4H2O (CIF 974 kb)

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Faulkner, A., Kaner, R., Abdallah, Q. et al. Asymmetric triplex metallohelices with high and selective activity against cancer cells. Nature Chem 6, 797–803 (2014). https://doi.org/10.1038/nchem.2024

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