Synthesis and Biological Evaluation of JAHAs: Ferrocene-Based Histone Deacetylase Inhibitors.
John Spencer, Jahangir Amin, Minghua Wang, Graham Packham, SharifahSSyed Alwi, GrahamJ Tizzard, SimonJ Coles, RonaldM Paranal, JamesE Bradner, TomD Heightman
文献索引:ACS Med. Chem. Lett. 2(5) , 358-362, (2011)
全文:HTML全文
摘要
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 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 (IC(50) values against HDAC8 (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. IC(50) values as low as 90 pM toward HDAC6 (class IIb) have been determined, highlighting the excellent potential of JAHAs as bioinorganic probes.
相关化合物
相关文献:
2004-01-01
[Bioconjug. Chem. 15(1) , 121-7, (2004)]
2009-07-01
[Anal. Bioanal. Chem 394(6) , 1679-1685, (2009)]
Synthesis and properties of PI polyamide–SAHA conjugate. Ohtsuki et al.
[Tetrahedron Lett. 50(52) , 7288-7292, (2009)]
Synthesis of 1-Aminocyclopropyl-Pentanoic and-Heptanoic Acid Derivatives. Gensini et al.
[Lett. Org. Chem. 5(5) , 328-331, (2008)]
A cyclodextrin-capped histone deacetylase inhibitor. Amin et al.
[Biochem. Med. 23(11) , 3346-3348, (2013)]