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

Research output: Contribution to journalArticle

56 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.

LanguageEnglish
Pages797-803
Number of pages7
JournalNature Chemistry
Volume6
Issue number9
Early online date3 Aug 2014
DOIs
Publication statusPublished - 2014
Externally publishedYes

Fingerprint

Toxicity
Cells
Peptides
Coordination Complexes
Methicillin-Resistant Staphylococcus aureus
DNA Damage
Libraries
Neoplasms
Cell Cycle
Colon
Adenocarcinoma
Breast
Methicillin
Pharmacokinetics
Head
Escherichia coli
Bacteria
Carcinoma
Scaffolds
Cell Line

Cite this

Faulkner, A. D., Kaner, R. A., Abdallah, Q. M. A., Clarkson, G., Fox, D. J., Gurnani, P., ... 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
Faulkner, Alan D. ; Kaner, Rebecca A. ; Abdallah, Qasem M A ; Clarkson, Guy ; Fox, David J. ; Gurnani, Pratik ; Howson, Suzanne E. ; Phillips, Roger M. ; Roper, David I. ; Simpson, Daniel H. ; Scott, Peter. / Asymmetric triplex metallohelices with high and selective activity against cancer cells. In: Nature Chemistry. 2014 ; Vol. 6, No. 9. pp. 797-803.
@article{4a7bb2fd3da74857a6d2300ad27862c7,
title = "Asymmetric triplex metallohelices with high and selective activity against cancer cells",
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.",
author = "Faulkner, {Alan D.} and Kaner, {Rebecca A.} and Abdallah, {Qasem M A} and Guy Clarkson and Fox, {David J.} and Pratik Gurnani and Howson, {Suzanne E.} and Phillips, {Roger M.} and Roper, {David I.} and Simpson, {Daniel H.} and Peter Scott",
note = "No full text in Eprints. HN 29/11/2017",
year = "2014",
doi = "10.1038/nchem.2024",
language = "English",
volume = "6",
pages = "797--803",
journal = "Nature Chemistry",
issn = "1755-4330",
publisher = "Nature Publishing Group",
number = "9",

}

Faulkner, AD, Kaner, RA, Abdallah, QMA, Clarkson, G, Fox, DJ, Gurnani, P, Howson, SE, Phillips, RM, Roper, DI, Simpson, DH & Scott, P 2014, 'Asymmetric triplex metallohelices with high and selective activity against cancer cells', Nature Chemistry, vol. 6, no. 9, pp. 797-803. https://doi.org/10.1038/nchem.2024

Asymmetric triplex metallohelices with high and selective activity against cancer cells. / Faulkner, Alan D.; Kaner, Rebecca A.; Abdallah, Qasem M A; Clarkson, Guy; Fox, David J.; Gurnani, Pratik; Howson, Suzanne E.; Phillips, Roger M.; Roper, David I.; Simpson, Daniel H.; Scott, Peter.

In: Nature Chemistry, Vol. 6, No. 9, 2014, p. 797-803.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Asymmetric triplex metallohelices with high and selective activity against cancer cells

AU - Faulkner, Alan D.

AU - Kaner, Rebecca A.

AU - Abdallah, Qasem M A

AU - Clarkson, Guy

AU - Fox, David J.

AU - Gurnani, Pratik

AU - Howson, Suzanne E.

AU - Phillips, Roger M.

AU - Roper, David I.

AU - Simpson, Daniel H.

AU - Scott, Peter

N1 - No full text in Eprints. HN 29/11/2017

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84906565704&partnerID=8YFLogxK

U2 - 10.1038/nchem.2024

DO - 10.1038/nchem.2024

M3 - Article

VL - 6

SP - 797

EP - 803

JO - Nature Chemistry

T2 - Nature Chemistry

JF - Nature Chemistry

SN - 1755-4330

IS - 9

ER -

Faulkner AD, Kaner RA, Abdallah QMA, Clarkson G, Fox DJ, Gurnani P et al. Asymmetric triplex metallohelices with high and selective activity against cancer cells. Nature Chemistry. 2014;6(9):797-803. https://doi.org/10.1038/nchem.2024