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Synthesis and biological evaluation of JAHAs: ferrocene-based histone deacetylase inhibitors
journal contribution
posted on 2023-06-09, 21:24 authored by John SpencerJohn Spencer, Jahangir Amin, Minghua Wang, Graham Packham, Sharifah S S Alwi, Graham J Tizzard, Simon J Coles, Ronald M Paranal, James E Bradner, Tom D HeightmanN1-Hydroxy-N8-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 (IC50 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. 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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Publication status
- Published
Journal
ACS Medicinal Chemistry LettersISSN
1948-5875Publisher
American Chemical SocietyExternal DOI
Issue
5Volume
2Page range
358-362Event location
United StatesDepartment affiliated with
- Chemistry Publications
Full text available
- No
Peer reviewed?
- Yes
Legacy Posted Date
2020-07-24Usage metrics
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