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Synthesis and Biological Evaluation of JAHAs: Ferrocene-Based Histone Deacetylase Inhibitors.

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 IIa HDACs, and anticancer action in intact cells (IC(50) = 2.4 μM, 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 (IC(50) values against HDAC8 (μM, 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. IC(50) values as low as 90 pM toward HDAC6 (class IIb) have been determined, highlighting the excellent potential of JAHAs as bioinorganic probes.

SUBMITTER: Spencer J 

PROVIDER: S-EPMC3093745 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

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Synthesis and Biological Evaluation of JAHAs: Ferrocene-Based Histone Deacetylase Inhibitors.

Spencer John J   Amin Jahangir J   Wang Minghua M   Packham Graham G   Alwi Sharifah S Syed SS   Tizzard Graham J GJ   Coles Simon J SJ   Paranal Ronald M RM   Bradner James E JE   Heightman Tom D TD  

ACS medicinal chemistry letters 20110318 5

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 IIa HDACs, and anticancer action in intact cells (IC(50) = 2.4 μM, 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  ...[more]

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