Synthesis and evaluation of aliphatic-chain hydroxamates capped with osthole derivatives as histone deacetylase inhibitors
Journal
European Journal of Medicinal Chemistry
Journal Volume
46
Journal Issue
9
Pages
4042-4049
Date Issued
2011
Author(s)
Huang W.-J.
Chao S.-W.
Yu C.-C.
Yang C.-Y.
Lin Y.-C.
Kuo C.-I.
Yang P.
Chang C.-I.
Abstract
Our previous studies have demonstrated that osthole, a Chinese herbal compound, could be incorporated into the hydroxycinnamide scaffold of LBH-589, a potent HDAC inhibitor, as an effective hydrophobic cap; the resulting compounds showed significant potency against several HDAC isoforms. Here, we presented a series of osthole derivatives fused with the aliphatic-hydroxamate core of suberoylanilide hydroxamic acid (SAHA), a clinically-approved HDAC inhibitor. Several compounds showed potent activity against nuclear HDACs. Further assays against individual HDAC isoforms revealed that some compounds showed not only SAHA-like activity towards HDAC1, -4 and -6, they inhibited HDAC8 by log difference than SAHA and thus exhibited a broader HDAC inhibition spectrum. Among them, compound 6g showed potent antiproliferative effect on several human cancer cell lines. ? 2011 Elsevier Masson SAS. All rights reserved.
SDGs
Other Subjects
antineoplastic agent; histone deacetylase 8; histone deacetylase inhibitor; n hydroxy 5 (3 hydroxy 4 (2 hydroxycarbamoylethyl) 2 isopentyl phenoxy) pentanamide; n hydroxy 5 (3,4 dihydro 8 isopentyl 2 oxo 2h chromen 7 yloxy)pentanamide; n hydroxy 5 (8 isopentyl 2 oxo 2h chromen 7 yloxy)pentanamide; n hydroxy 6 (3 hydroxy 4 (2 hydroxycarbamoylethyl) 2 isopentyl phenoxy) hexanamide; n hydroxy 6 (3,4 dihydro 8 isopentyl 2 oxo 2h chromen 7 yloxy)hexanamide; n hydroxy 6 (8 isopentyl 2 oxo 2h chromen 7 yloxy)hexanamide; n hydroxy 7 (3 hydroxy 4 (2 hydroxycarbamoylethyl) 2 isopentyl-phenoxy) heptanamide; n hydroxy 7 (3,4 dihydro 8 isopentyl 2 oxo 2h chromen 7 yloxy)heptanamide; n hydroxy 7 (8 isopentyl 2 oxo 2h chromen 7 yloxy)heptanamide; n hydroxy 8 (3 hydroxy 4 (2 hydroxycarbamoylethyl) 2 isopentyl phenoxy) octanamide; n hydroxy 8 (3,4 dihydro 8 isopentyl 2 oxo 2h chromen 7 yloxy)octanoate; n hydroxy 8 (8 isopentyl 2 oxo 2h chromen 7 yloxy)octanamide; osthole; unclassified drug; vorinostat; antineoplastic activity; article; cancer cell culture; drug activity; drug screening; drug synthesis; human; human cell; inhibition kinetics; neoplasm; Blotting, Western; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Hydroxamic Acids; Protein Conformation; Spectrometry, Mass, Electrospray Ionization
Type
journal article