Asymmetric triplex metallohelices with high and selective activity against cancer cells

Alan D. Faulkner, Rebecca A. Kaner, Qasem M A Abdallah, Guy Clarkson, David J. Fox, Pratik Gurnani, Suzanne E. Howson, Roger M. Phillips, David I. Roper, Daniel H. Simpson, Peter Scott

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75 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)797-803
Number of pages7
JournalNature Chemistry
Volume6
Issue number9
Early online date3 Aug 2014
DOIs
Publication statusPublished - 2014
Externally publishedYes

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    Faulkner, A. D., Kaner, R. A., Abdallah, Q. M. A., Clarkson, G., Fox, D. J., Gurnani, P., Howson, S. E., Phillips, R. M., Roper, D. I., Simpson, D. H., & Scott, P. (2014). Asymmetric triplex metallohelices with high and selective activity against cancer cells. Nature Chemistry, 6(9), 797-803. https://doi.org/10.1038/nchem.2024