Ruthenium‐Containing Linear Helicates and Mesocates with Tuneable p53‐Selective Cytotoxicity in Colorectal Cancer Cells

Simon J. Allison, David Cooke, Francesca S. Davidson, Paul I. P. Elliott, Robert A. Faulkner, Hollie B. S. Griffiths, Owen Harper, Omar Hussain, P. Jane Owen-Lynch, Roger M. Phillips, Craig R. Rice, Samantha L. Shepherd, Richard T. Wheelhouse

Research output: Contribution to journalArticle

6 Citations (Scopus)
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Abstract

The ligands L1 and L2 both form separable dinuclear double‐stranded helicate and mesocate complexes with RuII. In contrast to clinically approved platinates, the helicate isomer of [Ru2(L1)2]4+ was preferentially cytotoxic to isogenic cells (HCT116 p53−/−), which lack the critical tumour suppressor gene. The mesocate isomer shows the reverse selectivity, with the achiral isomer being preferentially cytotoxic towards HCT116 p53+/+. Other structurally similar RuII‐containing dinuclear complexes showed very little cytotoxic activity. This study demonstrates that alterations in ligand or isomer can have profound effects on cytotoxicity towards cancer cells of different p53 status and suggests that selectivity can be “tuned” to either genotype. In the search for compounds that can target difficult‐to‐treat tumours that lack the p53 tumour suppressor gene, [Ru2(L1)2]4+ is a promising compound for further development.
Original languageEnglish
Pages (from-to)9799-9804
Number of pages6
JournalAngewandte Chemie-International Edition
Volume57
Issue number31
Early online date4 Jun 2018
DOIs
Publication statusPublished - 26 Jul 2018

Cite this

Allison, S. J., Cooke, D., Davidson, F. S., Elliott, P. I. P., Faulkner, R. A., Griffiths, H. B. S., ... Wheelhouse, R. T. (2018). Ruthenium‐Containing Linear Helicates and Mesocates with Tuneable p53‐Selective Cytotoxicity in Colorectal Cancer Cells. Angewandte Chemie-International Edition, 57(31), 9799-9804. https://doi.org/10.1002/anie.201805510

Ruthenium‐Containing Linear Helicates and Mesocates with Tuneable p53‐Selective Cytotoxicity in Colorectal Cancer Cells. / Allison, Simon J.; Cooke, David; Davidson, Francesca S.; Elliott, Paul I. P.; Faulkner, Robert A.; Griffiths, Hollie B. S.; Harper, Owen; Hussain, Omar; Owen-Lynch, P. Jane; Phillips, Roger M.; Rice, Craig R.; Shepherd, Samantha L.; Wheelhouse, Richard T.

In: Angewandte Chemie-International Edition, Vol. 57, No. 31, 26.07.2018, p. 9799-9804.

Research output: Contribution to journalArticle

Allison, SJ, Cooke, D, Davidson, FS, Elliott, PIP, Faulkner, RA, Griffiths, HBS, Harper, O, Hussain, O, Owen-Lynch, PJ, Phillips, RM, Rice, CR, Shepherd, SL & Wheelhouse, RT 2018, 'Ruthenium‐Containing Linear Helicates and Mesocates with Tuneable p53‐Selective Cytotoxicity in Colorectal Cancer Cells', Angewandte Chemie-International Edition, vol. 57, no. 31, pp. 9799-9804. https://doi.org/10.1002/anie.201805510
Allison, Simon J. ; Cooke, David ; Davidson, Francesca S. ; Elliott, Paul I. P. ; Faulkner, Robert A. ; Griffiths, Hollie B. S. ; Harper, Owen ; Hussain, Omar ; Owen-Lynch, P. Jane ; Phillips, Roger M. ; Rice, Craig R. ; Shepherd, Samantha L. ; Wheelhouse, Richard T. / Ruthenium‐Containing Linear Helicates and Mesocates with Tuneable p53‐Selective Cytotoxicity in Colorectal Cancer Cells. In: Angewandte Chemie-International Edition. 2018 ; Vol. 57, No. 31. pp. 9799-9804.
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abstract = "The ligands L1 and L2 both form separable dinuclear double‐stranded helicate and mesocate complexes with RuII. In contrast to clinically approved platinates, the helicate isomer of [Ru2(L1)2]4+ was preferentially cytotoxic to isogenic cells (HCT116 p53−/−), which lack the critical tumour suppressor gene. The mesocate isomer shows the reverse selectivity, with the achiral isomer being preferentially cytotoxic towards HCT116 p53+/+. Other structurally similar RuII‐containing dinuclear complexes showed very little cytotoxic activity. This study demonstrates that alterations in ligand or isomer can have profound effects on cytotoxicity towards cancer cells of different p53 status and suggests that selectivity can be “tuned” to either genotype. In the search for compounds that can target difficult‐to‐treat tumours that lack the p53 tumour suppressor gene, [Ru2(L1)2]4+ is a promising compound for further development.",
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AU - Elliott, Paul I. P.

AU - Faulkner, Robert A.

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AU - Rice, Craig R.

AU - Shepherd, Samantha L.

AU - Wheelhouse, Richard T.

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N2 - The ligands L1 and L2 both form separable dinuclear double‐stranded helicate and mesocate complexes with RuII. In contrast to clinically approved platinates, the helicate isomer of [Ru2(L1)2]4+ was preferentially cytotoxic to isogenic cells (HCT116 p53−/−), which lack the critical tumour suppressor gene. The mesocate isomer shows the reverse selectivity, with the achiral isomer being preferentially cytotoxic towards HCT116 p53+/+. Other structurally similar RuII‐containing dinuclear complexes showed very little cytotoxic activity. This study demonstrates that alterations in ligand or isomer can have profound effects on cytotoxicity towards cancer cells of different p53 status and suggests that selectivity can be “tuned” to either genotype. In the search for compounds that can target difficult‐to‐treat tumours that lack the p53 tumour suppressor gene, [Ru2(L1)2]4+ is a promising compound for further development.

AB - The ligands L1 and L2 both form separable dinuclear double‐stranded helicate and mesocate complexes with RuII. In contrast to clinically approved platinates, the helicate isomer of [Ru2(L1)2]4+ was preferentially cytotoxic to isogenic cells (HCT116 p53−/−), which lack the critical tumour suppressor gene. The mesocate isomer shows the reverse selectivity, with the achiral isomer being preferentially cytotoxic towards HCT116 p53+/+. Other structurally similar RuII‐containing dinuclear complexes showed very little cytotoxic activity. This study demonstrates that alterations in ligand or isomer can have profound effects on cytotoxicity towards cancer cells of different p53 status and suggests that selectivity can be “tuned” to either genotype. In the search for compounds that can target difficult‐to‐treat tumours that lack the p53 tumour suppressor gene, [Ru2(L1)2]4+ is a promising compound for further development.

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