Ruthenium-containing Linear Helicates and Mesocates with Tuneable p53 Selective Cytotoxicity in Colorectal Cancer Cells.

Simon Allison, David Cooke, Francesca S. Davidson, Paul Elliott, Robert Faulkner, Hollie Griffiths, Owen Harper, Omar Hussain, Penelope Owen-Lynch, Roger Phillips, Craig Rice, Samantha Shepherd, Richard T. Wheelhouse

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

The ligands L1 and L2 both form separable dinuclear double stranded helicate and mesocate complexes with Ru(II). 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 Ru(II)-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.
LanguageEnglish
Pages9799-9804
Number of pages6
JournalAngewandte Chemie - International Edition
Volume57
Issue number31
Early online date4 Jun 2018
DOIs
Publication statusPublished - 26 Jul 2018

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Ruthenium
Cytotoxicity
Isomers
Cells
Tumors
Genes
Ligands

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title = "Ruthenium-containing Linear Helicates and Mesocates with Tuneable p53 Selective Cytotoxicity in Colorectal Cancer Cells.",
abstract = "The ligands L1 and L2 both form separable dinuclear double stranded helicate and mesocate complexes with Ru(II). 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 Ru(II)-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.",
author = "Simon Allison and David Cooke and Davidson, {Francesca S.} and Paul Elliott and Robert Faulkner and Hollie Griffiths and Owen Harper and Omar Hussain and Penelope Owen-Lynch and Roger Phillips and Craig Rice and Samantha Shepherd and Wheelhouse, {Richard T.}",
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Ruthenium-containing Linear Helicates and Mesocates with Tuneable p53 Selective Cytotoxicity in Colorectal Cancer Cells. / Allison, Simon; Cooke, David; Davidson, Francesca S.; Elliott, Paul; Faulkner, Robert; Griffiths, Hollie; Harper, Owen; Hussain, Omar; Owen-Lynch, Penelope; Phillips, Roger; Rice, Craig; Shepherd, Samantha; Wheelhouse, Richard T.

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

Research output: Contribution to journalArticle

TY - JOUR

T1 - Ruthenium-containing Linear Helicates and Mesocates with Tuneable p53 Selective Cytotoxicity in Colorectal Cancer Cells.

AU - Allison, Simon

AU - Cooke, David

AU - Davidson, Francesca S.

AU - Elliott, Paul

AU - Faulkner, Robert

AU - Griffiths, Hollie

AU - Harper, Owen

AU - Hussain, Omar

AU - Owen-Lynch, Penelope

AU - Phillips, Roger

AU - Rice, Craig

AU - Shepherd, Samantha

AU - Wheelhouse, Richard T.

PY - 2018/7/26

Y1 - 2018/7/26

N2 - The ligands L1 and L2 both form separable dinuclear double stranded helicate and mesocate complexes with Ru(II). 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 Ru(II)-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 Ru(II). 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 Ru(II)-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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DO - 10.1002/anie.201805510

M3 - Article

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