Discovery of selective, antimetastatic and anti-cancer stem cell metallohelices via post-assembly modification

Hualong Song, Nicola Rogers, Simon J. Allison, Viktor Brabec, Hannah Bridgewater, Hana Kostrhunova, Lenka Markova, Roger Phillips, Emma Pinder, Samantha Shepherd, Lawrence Young, Juraj Zajac, Peter Scott

Research output: Contribution to journalArticle

Abstract

Helicates and related metallofoldamers, synthesised by dynamic self-assembly, represent an area of chemical space inaccessible by traditional organic synthesis, and yet with potential for discovery of new classes of drug. Here we report that water-soluble, optically pure Fe(II)- and even Zn(II)-based triplex metallohelices are an excellent platform for post-assembly click reactions. By these means, the in vitro anticancer activity and most importantly the selectivity of a triplex metallohelix Fe(II) system is dramatically improved. For one compound, a remarkable array of mechanistic and pharmacological behaviours is discovered: inhibition of Na+/K+ ATPase with potency comparable to the drug ouabain, antimetastatic properties (including inhibition of cell migration, re-adhesion and invasion), cancer stem cell targeting, and finally colonosphere inhibition competitive with the drug salinomycin.
LanguageEnglish
Number of pages11
JournalChemical Science
Early online date18 Jul 2019
DOIs
Publication statusE-pub ahead of print - 18 Jul 2019

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Stem cells
Pharmaceutical Preparations
Ouabain
Self assembly
Adenosine Triphosphatases
Adhesion
Cells
Water

Cite this

Song, Hualong ; Rogers, Nicola ; Allison, Simon J. ; Brabec, Viktor ; Bridgewater, Hannah ; Kostrhunova, Hana ; Markova, Lenka ; Phillips, Roger ; Pinder, Emma ; Shepherd, Samantha ; Young, Lawrence ; Zajac, Juraj ; Scott, Peter. / Discovery of selective, antimetastatic and anti-cancer stem cell metallohelices via post-assembly modification. In: Chemical Science. 2019.
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abstract = "Helicates and related metallofoldamers, synthesised by dynamic self-assembly, represent an area of chemical space inaccessible by traditional organic synthesis, and yet with potential for discovery of new classes of drug. Here we report that water-soluble, optically pure Fe(II)- and even Zn(II)-based triplex metallohelices are an excellent platform for post-assembly click reactions. By these means, the in vitro anticancer activity and most importantly the selectivity of a triplex metallohelix Fe(II) system is dramatically improved. For one compound, a remarkable array of mechanistic and pharmacological behaviours is discovered: inhibition of Na+/K+ ATPase with potency comparable to the drug ouabain, antimetastatic properties (including inhibition of cell migration, re-adhesion and invasion), cancer stem cell targeting, and finally colonosphere inhibition competitive with the drug salinomycin.",
author = "Hualong Song and Nicola Rogers and Allison, {Simon J.} and Viktor Brabec and Hannah Bridgewater and Hana Kostrhunova and Lenka Markova and Roger Phillips and Emma Pinder and Samantha Shepherd and Lawrence Young and Juraj Zajac and Peter Scott",
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Discovery of selective, antimetastatic and anti-cancer stem cell metallohelices via post-assembly modification. / Song, Hualong; Rogers, Nicola; Allison, Simon J.; Brabec, Viktor; Bridgewater, Hannah; Kostrhunova, Hana; Markova, Lenka; Phillips, Roger; Pinder, Emma; Shepherd, Samantha; Young, Lawrence; Zajac, Juraj; Scott, Peter.

In: Chemical Science, 18.07.2019.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Discovery of selective, antimetastatic and anti-cancer stem cell metallohelices via post-assembly modification

AU - Song, Hualong

AU - Rogers, Nicola

AU - Allison, Simon J.

AU - Brabec, Viktor

AU - Bridgewater, Hannah

AU - Kostrhunova, Hana

AU - Markova, Lenka

AU - Phillips, Roger

AU - Pinder, Emma

AU - Shepherd, Samantha

AU - Young, Lawrence

AU - Zajac, Juraj

AU - Scott, Peter

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AB - Helicates and related metallofoldamers, synthesised by dynamic self-assembly, represent an area of chemical space inaccessible by traditional organic synthesis, and yet with potential for discovery of new classes of drug. Here we report that water-soluble, optically pure Fe(II)- and even Zn(II)-based triplex metallohelices are an excellent platform for post-assembly click reactions. By these means, the in vitro anticancer activity and most importantly the selectivity of a triplex metallohelix Fe(II) system is dramatically improved. For one compound, a remarkable array of mechanistic and pharmacological behaviours is discovered: inhibition of Na+/K+ ATPase with potency comparable to the drug ouabain, antimetastatic properties (including inhibition of cell migration, re-adhesion and invasion), cancer stem cell targeting, and finally colonosphere inhibition competitive with the drug salinomycin.

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