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

Research output: Contribution to journal › Article › peer-review

5 Scopus citations

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.

Original language	English (US)
Pages (from-to)	3691-3700
Number of pages	10
Journal	ChemMedChem
Volume	16
Issue number	24
DOIs	https://doi.org/10.1002/cmdc.202100403
State	Published - Dec 14 2021
Externally published	Yes

Keywords

KDAC
Panobinostat
hypoxia
prodrugs

ASJC Scopus subject areas

Drug Discovery
General Pharmacology, Toxicology and Pharmaceutics
Molecular Medicine
Biochemistry
Pharmacology
Organic Chemistry

UN SDGs

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

Access to Document

10.1002/cmdc.202100403

Cite this

@article{641ef3b0337c492da296b90f8cba4a13,

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.",

keywords = "KDAC, Panobinostat, hypoxia, prodrugs",

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

note = "Publisher Copyright: {\textcopyright} 2021 The Authors. ChemMedChem published by Wiley-VCH GmbH",

year = "2021",

month = dec,

day = "14",

doi = "10.1002/cmdc.202100403",

language = "English (US)",

volume = "16",

pages = "3691--3700",

journal = "ChemMedChem",

issn = "1860-7179",

publisher = "John Wiley and Sons Ltd",

number = "24",

}

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 - 2021/12/14

Y1 - 2021/12/14

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 - KDAC

KW - Panobinostat

KW - hypoxia

KW - prodrugs

UR - http://www.scopus.com/inward/record.url?scp=85111795678&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85111795678&partnerID=8YFLogxK

U2 - 10.1002/cmdc.202100403

DO - 10.1002/cmdc.202100403

M3 - Article

C2 - 34259396

AN - SCOPUS:85111795678

SN - 1860-7179

VL - 16

SP - 3691

EP - 3700

JO - ChemMedChem

JF - ChemMedChem

IS - 24

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this