Synthesis and Biological Evaluation of JAHAs: Ferrocene-Based Histone Deacetylase Inhibitors
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Abstract
<i>N</i><sup>1</sup>-Hydroxy-<i>N</i><sup>8</sup>-ferrocenyloctanediamide, JAHA (<b>7</b>), 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<sub>50</sub> = 2.4 μM, MCF7 cell line). Molecular docking studies of <b>7</b> in HDAC8 (a,b) suggested that the ferrocenyl moiety in <b>7</b> can overlap with the aryl cap of SAHA and should display similar HDAC inhibition, which was borne out in an in vitro assay (IC<sub>50</sub> values against HDAC8 (μM, SD in parentheses): SAHA, 1.41 (0.15); <b>7</b>, 1.36 (0.16). Thereafter, a small library of related JAHA analogues has been synthesized, and preliminary SAR studies are presented. IC<sub>50</sub> values as low as 90 pM toward HDAC6 (class IIb) have been determined, highlighting the excellent potential of JAHAs as bioinorganic probes
