Synthesis and biological evaluation of JAHAs: ferrocene-based histone deacetylase inhibitors
Synthesis and biological evaluation of JAHAs: ferrocene-based histone deacetylase inhibitors
N-1-Hydroxy-N-8-ferrocenyloctanediamide, JAHA (7), an organometallic analogue of SAHA containing a ferrocenyl group as a phenyl bioisostere, displays nanomolar inhibition of class I HDACs, excellent selectivity over class ha HDACs, and anticancer action in intact cells (IC50 = 2.4 mu M, MCF7 cell line). Molecular docking studies of 7 in HDAC8 (a,b) suggested that the ferrocenyl moiety in 7 can overlap with the aryl cap of SAHA and should display similar HDAC inhibition, which was borne out in an in vitro assay (IC50 values against HDAC8 (mu M, SD in parentheses): SAHA, 1.41 (0.15); 7, 1.36 (0.16). Thereafter, a small library of related JAHA analogues has been synthesized, and preliminary SAR studies are presented. IC50 values as low as 90 pM toward HDAC6 (class IIb) have been determined, highlighting the excellent potential of JAHAs as bioinorganic probes.
ferrocene, hdac inhibitor, bioinorganic, anticancer, hydroxamic acid
358-362
Spencer, John
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Amin, Jahangir
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Wang, Minghua
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Packham, Graham
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Alwi, Sharifah S. Syed
570a1312-d332-4522-ada4-968a68d38666
Tizzard, Graham J.
8474c0fa-40df-43a6-a662-7f3c4722dbf2
Coles, Simon J.
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Paranal, Ronald M.
665c05d6-68e3-45b9-bb9b-e650c6ffddee
Bradner, James E.
b728f11e-9cce-492c-9b53-3a875eab706d
Heightman, Tom D.
c844f4ce-0a70-41c2-b098-6e40b942322a
May 2011
Spencer, John
a3cf55cd-a4c7-4af6-b16c-96c8fb8c4cf4
Amin, Jahangir
15a45a7a-1741-45fa-9f31-9aa6ef1924ed
Wang, Minghua
68242ec4-8322-4bb5-8386-a9326f18d074
Packham, Graham
3d4f5a11-3f92-4558-9372-356001730fe0
Alwi, Sharifah S. Syed
570a1312-d332-4522-ada4-968a68d38666
Tizzard, Graham J.
8474c0fa-40df-43a6-a662-7f3c4722dbf2
Coles, Simon J.
3116f58b-c30c-48cf-bdd5-397d1c1fecf8
Paranal, Ronald M.
665c05d6-68e3-45b9-bb9b-e650c6ffddee
Bradner, James E.
b728f11e-9cce-492c-9b53-3a875eab706d
Heightman, Tom D.
c844f4ce-0a70-41c2-b098-6e40b942322a
Spencer, John, Amin, Jahangir, Wang, Minghua, Packham, Graham, Alwi, Sharifah S. Syed, Tizzard, Graham J., Coles, Simon J., Paranal, Ronald M., Bradner, James E. and Heightman, Tom D.
(2011)
Synthesis and biological evaluation of JAHAs: ferrocene-based histone deacetylase inhibitors.
ACS Medicinal Chemistry Letters, 2 (5), .
(doi:10.1021/ml100295v).
(PMID:21572592)
Abstract
N-1-Hydroxy-N-8-ferrocenyloctanediamide, JAHA (7), an organometallic analogue of SAHA containing a ferrocenyl group as a phenyl bioisostere, displays nanomolar inhibition of class I HDACs, excellent selectivity over class ha HDACs, and anticancer action in intact cells (IC50 = 2.4 mu M, MCF7 cell line). Molecular docking studies of 7 in HDAC8 (a,b) suggested that the ferrocenyl moiety in 7 can overlap with the aryl cap of SAHA and should display similar HDAC inhibition, which was borne out in an in vitro assay (IC50 values against HDAC8 (mu M, SD in parentheses): SAHA, 1.41 (0.15); 7, 1.36 (0.16). Thereafter, a small library of related JAHA analogues has been synthesized, and preliminary SAR studies are presented. IC50 values as low as 90 pM toward HDAC6 (class IIb) have been determined, highlighting the excellent potential of JAHAs as bioinorganic probes.
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e-pub ahead of print date: 18 March 2011
Published date: May 2011
Keywords:
ferrocene, hdac inhibitor, bioinorganic, anticancer, hydroxamic acid
Organisations:
Organic Chemistry: Synthesis, Catalysis and Flow
Identifiers
Local EPrints ID: 346145
URI: http://eprints.soton.ac.uk/id/eprint/346145
ISSN: 1948-5875
PURE UUID: bebdb3b3-a44f-45f7-947c-96a064acbd1e
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Date deposited: 20 Dec 2012 16:41
Last modified: 15 Mar 2024 03:10
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Contributors
Author:
John Spencer
Author:
Jahangir Amin
Author:
Minghua Wang
Author:
Graham Packham
Author:
Sharifah S. Syed Alwi
Author:
Ronald M. Paranal
Author:
James E. Bradner
Author:
Tom D. Heightman
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