Zap-Pano: a Photocaged Prodrug of the KDAC Inhibitor Panobinostat

Kathrin S. Troelsen; Ewen D.D. Calder; Anna Skwarska; Deborah Sneddon; Ester M. Hammond; Stuart J. Conway

doi:10.1002/cmdc.202100403

Zap-Pano: a Photocaged Prodrug of the KDAC Inhibitor Panobinostat

Kathrin S. Troelsen, Ewen D.D. Calder, Anna Skwarska, Deborah Sneddon, Ester M. Hammond^*, Stuart J. Conway^*

^*Corresponding author af dette arbejde

Biologiske lægemidler

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

7 Citationer (Scopus)

16 Downloads (Pure)

Abstract

We report the synthesis and biological evaluation of a light-activated (caged) prodrug of the KDAC inhibitor panobinostat (Zap-Pano). We demonstrate that addition of the 4,5-dimethoxy-2-nitrobenzyl group to the hydroxamic acid oxygen results in an inactive prodrug. In two cancer cell lines we show that photolysis of this compound releases panobinostat and an unexpected carboxamide analogue of panobinostat. Photolysis of Zap-Pano causes an increase in H3K9Ac and H3K18Ac, consistent with KDAC inhibition, in an oesophageal cancer cell line (OE21). Irradiation of OE21 cells in the presence of Zap-Pano results in apoptotic cell death. This compound is a useful research tool, allowing spatial and temporal control over release of panobinostat.

Originalsprog	Engelsk
Tidsskrift	ChemMedChem
Vol/bind	16
Udgave nummer	24
Sider (fra-til)	3691-3700
ISSN	1860-7179
DOI	https://doi.org/10.1002/cmdc.202100403
Status	Udgivet - 2021

Bibliografisk note

Funding Information:
K.S.T. thanks the Lundbeck foundation for a PhD Fellowship grant (R218‐2016‐1277). E.D.D.C. and A.S. thank the MRC for funding through the award of a project grant to E.M.H. and S.J.C. (MR/N009460/1). D.S. thanks the EPSRC for funding through the award of a programme grant to E.M.H. and S.J.C. (EP/S019901/1). S.J.C. thanks St Hugh's College, Oxford, for research support. We thank Dr Lisa Folkes for analytical assistance.

Publisher Copyright:
© 2021 The Authors. ChemMedChem published by Wiley-VCH GmbH

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title = "Zap-Pano: a Photocaged Prodrug of the KDAC Inhibitor Panobinostat",

abstract = "We report the synthesis and biological evaluation of a light-activated (caged) prodrug of the KDAC inhibitor panobinostat (Zap-Pano). We demonstrate that addition of the 4,5-dimethoxy-2-nitrobenzyl group to the hydroxamic acid oxygen results in an inactive prodrug. In two cancer cell lines we show that photolysis of this compound releases panobinostat and an unexpected carboxamide analogue of panobinostat. Photolysis of Zap-Pano causes an increase in H3K9Ac and H3K18Ac, consistent with KDAC inhibition, in an oesophageal cancer cell line (OE21). Irradiation of OE21 cells in the presence of Zap-Pano results in apoptotic cell death. This compound is a useful research tool, allowing spatial and temporal control over release of panobinostat.",

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author = "Troelsen, {Kathrin S.} and Calder, {Ewen D.D.} and Anna Skwarska and Deborah Sneddon and Hammond, {Ester M.} and Conway, {Stuart J.}",

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year = "2021",

doi = "10.1002/cmdc.202100403",

language = "English",

volume = "16",

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TY - JOUR

T1 - Zap-Pano

T2 - a Photocaged Prodrug of the KDAC Inhibitor Panobinostat

AU - Troelsen, Kathrin S.

AU - Calder, Ewen D.D.

AU - Skwarska, Anna

AU - Sneddon, Deborah

AU - Hammond, Ester M.

AU - Conway, Stuart J.

PY - 2021

Y1 - 2021

N2 - We report the synthesis and biological evaluation of a light-activated (caged) prodrug of the KDAC inhibitor panobinostat (Zap-Pano). We demonstrate that addition of the 4,5-dimethoxy-2-nitrobenzyl group to the hydroxamic acid oxygen results in an inactive prodrug. In two cancer cell lines we show that photolysis of this compound releases panobinostat and an unexpected carboxamide analogue of panobinostat. Photolysis of Zap-Pano causes an increase in H3K9Ac and H3K18Ac, consistent with KDAC inhibition, in an oesophageal cancer cell line (OE21). Irradiation of OE21 cells in the presence of Zap-Pano results in apoptotic cell death. This compound is a useful research tool, allowing spatial and temporal control over release of panobinostat.

AB - We report the synthesis and biological evaluation of a light-activated (caged) prodrug of the KDAC inhibitor panobinostat (Zap-Pano). We demonstrate that addition of the 4,5-dimethoxy-2-nitrobenzyl group to the hydroxamic acid oxygen results in an inactive prodrug. In two cancer cell lines we show that photolysis of this compound releases panobinostat and an unexpected carboxamide analogue of panobinostat. Photolysis of Zap-Pano causes an increase in H3K9Ac and H3K18Ac, consistent with KDAC inhibition, in an oesophageal cancer cell line (OE21). Irradiation of OE21 cells in the presence of Zap-Pano results in apoptotic cell death. This compound is a useful research tool, allowing spatial and temporal control over release of panobinostat.

KW - hypoxia

KW - KDAC

KW - Panobinostat

KW - prodrugs

U2 - 10.1002/cmdc.202100403

DO - 10.1002/cmdc.202100403

M3 - Journal article

C2 - 34259396

AN - SCOPUS:85111795678

SN - 1860-7179

VL - 16

SP - 3691

EP - 3700

JO - ChemMedChem

JF - ChemMedChem

IS - 24

ER -