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