Amide-based derivatives of beta-alanine hydroxamic acid as histone deacetylase inhibitors: attenuation of potency through resonance effects.
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Liao V, Liu T, Codd R
Amide-based derivatives of beta-alanine hydroxamic acid as histone deacetylase inhibitors: attenuation of potency through resonance effects.
Bioorg Med Chem Lett. 2012 Oct 1;22(19):6200-4. doi: 10.1016/j.bmcl.2012.08.006. Epub 2012 Aug 9.
- PubMed ID
- 22932316 [ View in PubMed]
- Abstract
A library of amide-linked derivatives of beta-alanine hydroxamic acid were prepared (2-7) and the activity as inhibitors of Zn(II)-containing histone deacetylases (HDACs) determined in vitro against HDAC1 and the anti-proliferative activity determined in BE(2)-C neuroblastoma cells. The IC(50) values of the best-performing compounds (3-7) against HDAC1 ranged between 38 and 84muM. The least potent compound (2) inhibited a maximum of only 40% HDAC1 activity at 250muM. The anti-proliferative activity of 2-7 at 50muM against BE(2)-C neuroblastoma cells ranged between 57.0% and 88.6%. The structural similarity between the potent HDAC inhibitor trichostatin A (TSA, 1; HDAC1, IC(50) 12nM) and the present compounds (2-7) was high at the Zn(II) coordinating hydroxamic acid head group; and in selected compounds (2, 5), at the 4-(dimethylamino)phenyl tail. The significantly reduced potency of 2-7 relative to 1 underscores the rank importance of the linker region as part of the HDAC inhibitor pharmacophore. Molecular modeling of 1-7 using HDAC8 as the template suggested that the conformationally constrained 4'-methyl group of 1 may contribute to HDAC inhibitor potency through a sandwich-like interaction with a hydrophobic region containing F152 and F208; and that the absence of this group in 2-7 may reduce potency. The close proximity of the 5'-carbonyl oxygen atom in 2-7 to the sulfur atom of Met274 in HDAC8 or the corresponding isobutyl group of Leu274 in HDAC1 may attenuate potency through repulsive steric and dipole-dipole forces. In a unique resonance stabilized form of 2, this interaction could manifest as stronger ion-dipole repulsive forces, resulting in a further decrease in potency. This work suggests that resonance structures of HDAC inhibitors could modulate intermolecular interactions with HDAC targets, and potency.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) Vorinostat Histone deacetylase 1 IC 50 (nM) 110 N/A N/A Details