Synthesis and biological evaluation of JAHAs: ferrocene-based histone deacetylase inhibitors

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), 358-362. (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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Contributors

Author: Graham J. Tizzard

Author: Simon J. Coles

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