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Defining the mechanism of action and enzymatic selectivity of psammaplin A against its epigenetic targets

Defining the mechanism of action and enzymatic selectivity of psammaplin A against its epigenetic targets
Defining the mechanism of action and enzymatic selectivity of psammaplin A against its epigenetic targets
Psammaplin A (11c) is a marine metabolite previously reported to be a potent inhibitor of two classes of epigenetic enzymes: histone deacetylases and DNA methyltransferases. The design and synthesis of a focused library based on the psammaplin A core has been carried out to probe the molecular features of this molecule responsible for its activity. By direct in vitro assay of the free thiol generated upon reduction of the dimeric psammaplin scaffold, we have unambiguously demonstrated that 11c functions as a natural prodrug, with the reduced form being highly potent against HDAC1 in vitro (IC(50) 0.9 nM). Furthermore, we have shown it to have high isoform selectivity, being 360-fold selective for HDAC1 over HDAC6 and more than 1000-fold less potent against HDAC7 and HDAC8. SAR around our focused library revealed a number of features, most notably the oxime functionality to be important to this selectivity. Many of the compounds show significant cytotoxicity in A549, MCF7, and W138 cells, with the SAR of cytotoxicity correlating to HDAC inhibition. Furthermore, compound treatment causes upregulation of histone acetylation but little effect on tubulin acetylation. Finally, we have found no evidence for 11c functioning as a DNMT inhibitor.
0022-2623
1731-1750
Baud, Matthias
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Leiser, Thomas
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Haus, Patricia
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Samlal, Sharon
045f184e-aee0-49ca-a0e5-f2db017aba09
Wong, Ai Ching
45136648-8f1a-4cbe-be29-38ce0002a8a5
Wood, Robert J.
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Petrucci, Vanessa
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Gunaratnam, Mekala
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Hughes, Siobhan M.
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Buluwela, Lakjaya
dfaeaf0b-4424-4536-b217-3af102fdac67
Turlais, Fabrice
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Neidle, Stephen
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Meyer-Almes, Franz-Josef
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White, Andrew J.P.
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Fuchter, Matthew J.
a98083c4-2a98-4844-8289-5468ec472801
Baud, Matthias
8752d519-3d33-43b6-9a77-ab731d410c2e
Leiser, Thomas
0a989c0c-4a10-4fb3-95eb-e7f511229e14
Haus, Patricia
b0229be7-ae1b-4843-b7ca-70a014b03fc9
Samlal, Sharon
045f184e-aee0-49ca-a0e5-f2db017aba09
Wong, Ai Ching
45136648-8f1a-4cbe-be29-38ce0002a8a5
Wood, Robert J.
f8754320-328e-4622-ac32-ef815fdae3b6
Petrucci, Vanessa
5dd36bc4-fd12-44b3-b5b0-d10384fe22b7
Gunaratnam, Mekala
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Hughes, Siobhan M.
0f48c905-87a5-4938-89ce-0f8a4bc42127
Buluwela, Lakjaya
dfaeaf0b-4424-4536-b217-3af102fdac67
Turlais, Fabrice
045fcdf6-0b9c-470a-9b42-1b43890d4d75
Neidle, Stephen
edf2d7ee-a257-4d4c-a3ea-b3c9c42b5ff3
Meyer-Almes, Franz-Josef
9f252633-80d9-4a9b-bcc7-96c0891a2dcf
White, Andrew J.P.
09c64321-ac83-40be-a22c-3d62e4b19a7e
Fuchter, Matthew J.
a98083c4-2a98-4844-8289-5468ec472801

Baud, Matthias, Leiser, Thomas, Haus, Patricia, Samlal, Sharon, Wong, Ai Ching, Wood, Robert J., Petrucci, Vanessa, Gunaratnam, Mekala, Hughes, Siobhan M., Buluwela, Lakjaya, Turlais, Fabrice, Neidle, Stephen, Meyer-Almes, Franz-Josef, White, Andrew J.P. and Fuchter, Matthew J. (2012) Defining the mechanism of action and enzymatic selectivity of psammaplin A against its epigenetic targets. Journal of Medicinal Chemistry, 55 (4), 1731-1750. (doi:10.1021/jm2016182). (PMID:22280363 )

Record type: Article

Abstract

Psammaplin A (11c) is a marine metabolite previously reported to be a potent inhibitor of two classes of epigenetic enzymes: histone deacetylases and DNA methyltransferases. The design and synthesis of a focused library based on the psammaplin A core has been carried out to probe the molecular features of this molecule responsible for its activity. By direct in vitro assay of the free thiol generated upon reduction of the dimeric psammaplin scaffold, we have unambiguously demonstrated that 11c functions as a natural prodrug, with the reduced form being highly potent against HDAC1 in vitro (IC(50) 0.9 nM). Furthermore, we have shown it to have high isoform selectivity, being 360-fold selective for HDAC1 over HDAC6 and more than 1000-fold less potent against HDAC7 and HDAC8. SAR around our focused library revealed a number of features, most notably the oxime functionality to be important to this selectivity. Many of the compounds show significant cytotoxicity in A549, MCF7, and W138 cells, with the SAR of cytotoxicity correlating to HDAC inhibition. Furthermore, compound treatment causes upregulation of histone acetylation but little effect on tubulin acetylation. Finally, we have found no evidence for 11c functioning as a DNMT inhibitor.

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Published date: 26 January 2012

Identifiers

Local EPrints ID: 400516
URI: https://eprints.soton.ac.uk/id/eprint/400516
ISSN: 0022-2623
PURE UUID: 79aff198-2011-4338-8e19-97ef0502ad06
ORCID for Matthias Baud: ORCID iD orcid.org/0000-0003-3714-4350

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Date deposited: 16 Sep 2016 16:02
Last modified: 14 Jul 2018 00:28

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Contributors

Author: Matthias Baud ORCID iD
Author: Thomas Leiser
Author: Patricia Haus
Author: Sharon Samlal
Author: Ai Ching Wong
Author: Robert J. Wood
Author: Vanessa Petrucci
Author: Mekala Gunaratnam
Author: Siobhan M. Hughes
Author: Lakjaya Buluwela
Author: Fabrice Turlais
Author: Stephen Neidle
Author: Franz-Josef Meyer-Almes
Author: Andrew J.P. White
Author: Matthew J. Fuchter

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