7 research outputs found
Synthesis and Biological Investigation of Oxazole Hydroxamates as Highly Selective Histone Deacetylase 6 (HDAC6) Inhibitors
Histone
deacetylase 6 (HDAC6) catalyzes the removal of an acetyl
group from lysine residues of several non-histone proteins. Here we
report the preparation of thiazole-, oxazole-, and oxadiazole-containing
biarylhydroxamic acids by a short synthetic procedure. We identified
them as selective HDAC6 inhibitors by investigating the inhibition
of recombinant HDAC enzymes and the protein acetylation in cells by
Western blotting (tubulin vs histone acetylation). The most active
compounds exhibited nanomolar potency and high selectivity for HDAC6.
For example, an oxazole hydroxamate inhibits HDAC6 with an IC<sub>50</sub> of 59 nM and has a selectivity index of >200 against
HDAC1
and HDAC8. This is the first report showing that the nature of a heterocycle
directly connected to a zinc binding group (ZBG) can be used to modulate
subtype selectivity and potency for HDAC6 inhibitors to such an extent.
We rationalize the high potency and selectivity of the oxazoles by
molecular modeling and docking
Synthesis and Biological Investigation of Oxazole Hydroxamates as Highly Selective Histone Deacetylase 6 (HDAC6) Inhibitors
Histone
deacetylase 6 (HDAC6) catalyzes the removal of an acetyl
group from lysine residues of several non-histone proteins. Here we
report the preparation of thiazole-, oxazole-, and oxadiazole-containing
biarylhydroxamic acids by a short synthetic procedure. We identified
them as selective HDAC6 inhibitors by investigating the inhibition
of recombinant HDAC enzymes and the protein acetylation in cells by
Western blotting (tubulin vs histone acetylation). The most active
compounds exhibited nanomolar potency and high selectivity for HDAC6.
For example, an oxazole hydroxamate inhibits HDAC6 with an IC<sub>50</sub> of 59 nM and has a selectivity index of >200 against
HDAC1
and HDAC8. This is the first report showing that the nature of a heterocycle
directly connected to a zinc binding group (ZBG) can be used to modulate
subtype selectivity and potency for HDAC6 inhibitors to such an extent.
We rationalize the high potency and selectivity of the oxazoles by
molecular modeling and docking
Supporting Information from Isoform-selective HDAC1/6/8 inhibitors with an imidazo-ketopiperazine cap containing stereochemical diversity
Experimental procedures for compound synthesis, biological assays and molecular dockin
Supporting Information from Isoform-selective HDAC1/6/8 inhibitors with an imidazo-ketopiperazine cap containing stereochemical diversity
Experimental procedures for compound synthesis, biological assays and molecular dockin
Supporting Information from Isoform-selective HDAC1/6/8 inhibitors with an imidazo-ketopiperazine cap containing stereochemical diversity
Experimental procedures for compound synthesis, biological assays and molecular dockin
Alkoxyurea-Based Histone Deacetylase Inhibitors Increase Cisplatin Potency in Chemoresistant Cancer Cell Lines
The
synthesis and biological evaluation of potent hydroxamate-based
dual HDAC1/6 inhibitors with modest HDAC6 preference and a novel alkoxyurea
connecting unit linker region are described. The biological studies
included the evaluation of antiproliferative effects and HDAC inhibitory
activity in the human ovarian cancer cell line A2780, the human squamous
carcinoma cell line Cal27, and their cisplatin resistant sublines
A2780CisR and Cal27CisR. The three most potent compounds <b>1g</b>–<b>i</b> showed IC<sub>50</sub> values in the low μM
and sub-μM range. <b>1g</b>–<b>i</b> revealed
low nM IC<sub>50</sub> values for HDAC6 with up to 15-fold preference
over HDAC1, >3500-fold selectivity over HDAC4, and >100-fold
selectivity
over HDAC8. Furthermore, their ability to enhance cisplatin sensitivity
was analyzed in Cal27 and Cal27CisR cells. Notably, a 48 h preincubation
of <b>1g</b>–<b>i</b> significantly enhanced the
antiproliferative effects of cisplatin in Cal27 and Cal27CisR. <b>1g</b>–<b>i</b> interacted synergistically with cisplatin.
These effects were more pronounced for the cisplatin resistant subline
Cal27CisR
Harnessing the Role of HDAC6 in Idiopathic Pulmonary Fibrosis: Design, Synthesis, Structural Analysis, and Biological Evaluation of Potent Inhibitors.
Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease characterized by a progressive-fibrosing phenotype. IPF has been associated with aberrant HDAC activities confirmed by our immunohistochemistry studies on HDAC6 overexpression in IPF lung tissues. We herein developed a series of novel hHDAC6 inhibitors, having low inhibitory potency over hHDAC1 and hHDAC8, as potential pharmacological tools for IPF treatment. Their inhibitory potency was combined with low in vitro and in vivo toxicity. Structural analysis of 6h and structure–activity relationship studies contributed to the optimization of the binding mode of the new molecules. The best-performing analogues were tested for their efficacy in inhibiting fibrotic sphere formation and cell viability, proving their capability in reverting the IPF phenotype. The efficacy of analogue 6h was also determined in a validated human lung model of TGF-β1-dependent fibrogenesis. The results highlighted in this manuscript may pave the way for the identification of first-in-class molecules for the treatment of IPF