Pojamide: an HDAC3-selective ferrocene analogue with remarkably enhanced redox-triggered ferrocenium activity in cells

Cory A. Ocasio; Supojjanee Sansook; Rhiannon Jones; Justin M. Roberts; Thomas G. Scott; Nikolaos Tsoureas; Peter Coxhead; Matthew Guille; Graham J. Tizzard; Simon J. Coles; Helfrid Hochegger; James E. Bradner; John Spencer

doi:10.1021/acs.organomet.7b00437

Pojamide: an HDAC3-selective ferrocene analogue with remarkably enhanced redox-triggered ferrocenium activity in cells

Cory A. Ocasio, Supojjanee Sansook, Rhiannon Jones, Justin M. Roberts, Thomas G. Scott, Nikolaos Tsoureas, Peter Coxhead, Matthew Guille, Graham J. Tizzard, Simon J. Coles, Helfrid Hochegger, James E. Bradner, John Spencer

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Abstract

A ferrocene containing o-aminoanilide, N¹-(2-aminophenyl)-N⁸-ferrocenyloctanediamide (2b, Pojamide) displayed nanomolar potency vs HDAC3. In comparison to RGFP966, a potent and selective HDAC3 inhibitor, Pojamide displayed superior activity in HCT116 colorectal cancer cell invasion assays; however, TCH106 and romidepsin, potent HDAC1 inhibitors, outperformed Pojamide in cellular proliferation and colony formation assays. Together, these data suggest that HDAC1,3 inhibition is desirable to achieve maximum anticancer benefits. Additionally, we explored Pojamide-induced redox pharmacology. Indeed, treating HCT116 cells with Pojamide, SNP (sodium nitroprusside), and glutathione (GSH) led to greatly enhanced cytotoxicity and DNA damage, attributed to activation to an Fe(III) species.

Original language	English
Journal	Organometallics
Early online date	21 Aug 2017
DOIs	https://doi.org/10.1021/acs.organomet.7b00437
Publication status	Early online - 21 Aug 2017

Keywords

RCUK
EPSRC

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1021/acs.organomet.7b00437

Pojamide an HDAC-3-Selective Ferrocene
This document is the Accepted Manuscript version of a Published Work that appeared in final form in Organometallics, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://pubs.acs.org/doi/abs/10.1021/acs.organomet.7b00437.
Accepted author manuscript (Post-print), 1.37 MB

http://pubs.acs.org/doi/abs/10.1021/acs.organomet.7b00437

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Ocasio, C. A., Sansook, S., Jones, R., Roberts, J. M., Scott, T. G., Tsoureas, N., Coxhead, P., Guille, M., Tizzard, G. J., Coles, S. J., Hochegger, H., Bradner, J. E., & Spencer, J. (2017). Pojamide: an HDAC3-selective ferrocene analogue with remarkably enhanced redox-triggered ferrocenium activity in cells. Organometallics. Advance online publication. https://doi.org/10.1021/acs.organomet.7b00437

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title = "Pojamide: an HDAC3-selective ferrocene analogue with remarkably enhanced redox-triggered ferrocenium activity in cells",

abstract = "A ferrocene containing o-aminoanilide, N1-(2-aminophenyl)-N8-ferrocenyloctanediamide (2b, Pojamide) displayed nanomolar potency vs HDAC3. In comparison to RGFP966, a potent and selective HDAC3 inhibitor, Pojamide displayed superior activity in HCT116 colorectal cancer cell invasion assays; however, TCH106 and romidepsin, potent HDAC1 inhibitors, outperformed Pojamide in cellular proliferation and colony formation assays. Together, these data suggest that HDAC1,3 inhibition is desirable to achieve maximum anticancer benefits. Additionally, we explored Pojamide-induced redox pharmacology. Indeed, treating HCT116 cells with Pojamide, SNP (sodium nitroprusside), and glutathione (GSH) led to greatly enhanced cytotoxicity and DNA damage, attributed to activation to an Fe(III) species.",

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author = "Ocasio, {Cory A.} and Supojjanee Sansook and Rhiannon Jones and Roberts, {Justin M.} and Scott, {Thomas G.} and Nikolaos Tsoureas and Peter Coxhead and Matthew Guille and Tizzard, {Graham J.} and Coles, {Simon J.} and Helfrid Hochegger and Bradner, {James E.} and John Spencer",

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language = "English",

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T2 - an HDAC3-selective ferrocene analogue with remarkably enhanced redox-triggered ferrocenium activity in cells

AU - Ocasio, Cory A.

AU - Sansook, Supojjanee

AU - Jones, Rhiannon

AU - Roberts, Justin M.

AU - Scott, Thomas G.

AU - Tsoureas, Nikolaos

AU - Coxhead, Peter

AU - Guille, Matthew

AU - Tizzard, Graham J.

AU - Coles, Simon J.

AU - Hochegger, Helfrid

AU - Bradner, James E.

AU - Spencer, John

PY - 2017/8/21

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N2 - A ferrocene containing o-aminoanilide, N1-(2-aminophenyl)-N8-ferrocenyloctanediamide (2b, Pojamide) displayed nanomolar potency vs HDAC3. In comparison to RGFP966, a potent and selective HDAC3 inhibitor, Pojamide displayed superior activity in HCT116 colorectal cancer cell invasion assays; however, TCH106 and romidepsin, potent HDAC1 inhibitors, outperformed Pojamide in cellular proliferation and colony formation assays. Together, these data suggest that HDAC1,3 inhibition is desirable to achieve maximum anticancer benefits. Additionally, we explored Pojamide-induced redox pharmacology. Indeed, treating HCT116 cells with Pojamide, SNP (sodium nitroprusside), and glutathione (GSH) led to greatly enhanced cytotoxicity and DNA damage, attributed to activation to an Fe(III) species.

AB - A ferrocene containing o-aminoanilide, N1-(2-aminophenyl)-N8-ferrocenyloctanediamide (2b, Pojamide) displayed nanomolar potency vs HDAC3. In comparison to RGFP966, a potent and selective HDAC3 inhibitor, Pojamide displayed superior activity in HCT116 colorectal cancer cell invasion assays; however, TCH106 and romidepsin, potent HDAC1 inhibitors, outperformed Pojamide in cellular proliferation and colony formation assays. Together, these data suggest that HDAC1,3 inhibition is desirable to achieve maximum anticancer benefits. Additionally, we explored Pojamide-induced redox pharmacology. Indeed, treating HCT116 cells with Pojamide, SNP (sodium nitroprusside), and glutathione (GSH) led to greatly enhanced cytotoxicity and DNA damage, attributed to activation to an Fe(III) species.

KW - RCUK

KW - EPSRC

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DO - 10.1021/acs.organomet.7b00437

M3 - Article

SN - 0276-7333

JO - Organometallics

JF - Organometallics

ER -

Pojamide: an HDAC3-selective ferrocene analogue with remarkably enhanced redox-triggered ferrocenium activity in cells

Abstract

Keywords

UN SDGs

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