Abstract
A new series of 2-, 3-, and 4-acylaminocinnamyl-N-hydroxyamides 1-3 have been prepared, and their anti- HDAC (against maize HD2, HD1-B, and HD1-A enzymes) activities have been assessed. Cinnamyl-hydroxyamides bearing acylamino substituents at the C2 position of the benzene ring (compounds 1a-g) showed very low HDAC inhibiting activities, with IC50 values in the high micromolar range. By shifting the same acylamino groups from C2 to C3 (compounds 2a-g) as well as C4 (compounds 3a-f) position of the benzene ring, a number of highly potent HDAC inhibitors have been obtained. In the anti-HD2 assay 3c (IC50 = 11 nM) was the most potent compound, being > 11600-, 4.5-, and 10-fold more potent than sodium valproate, SAHA, and HC-toxin, respectively, and showing the same activity as trapoxin. HD1-B and HD1-A assays have been performed to screen the inhibitory action of 1-3 against mammalian class I (HD1-B) and class II (HD1- A) HDAC homologous enzymes. From the corresponding IC50 data, a selectivity ratio has been calculated. In general, compounds 1-3 showed no or little selectivity towards the class II homologue HD1-A, the most selective being 2a with class II selectivity ratio = 4.3. About the inhibitory potency, the 4-(2-naphthoylamino)cinnamyl-N-hydroxyamide 3f showed the highest inhibiting effect against the two enzymes (IC50-HD1-B = 36 nM; IC50-HD1-A = 42 nM). Selected 2 and 3 compounds will be evaluated to determine their antiproliferative and cyto differentiating activities on HL-60 cells.
Keywords: hydroxamic acid, histone deacetylase, chromatin remodelling, cinnamyl-hydroxyamide
Medicinal Chemistry
Title: Synthesis and Biological Evaluation of 2-, 3-, and 4-Acylaminocinnamyl-Nhydroxyamides as Novel Synthetic HDAC Inhibitors
Volume: 1 Issue: 3
Author(s): A. Mai, S. Massa, R. Pezzi, S. Valente, P. Loidl and G. Brosch
Affiliation:
Keywords: hydroxamic acid, histone deacetylase, chromatin remodelling, cinnamyl-hydroxyamide
Abstract: A new series of 2-, 3-, and 4-acylaminocinnamyl-N-hydroxyamides 1-3 have been prepared, and their anti- HDAC (against maize HD2, HD1-B, and HD1-A enzymes) activities have been assessed. Cinnamyl-hydroxyamides bearing acylamino substituents at the C2 position of the benzene ring (compounds 1a-g) showed very low HDAC inhibiting activities, with IC50 values in the high micromolar range. By shifting the same acylamino groups from C2 to C3 (compounds 2a-g) as well as C4 (compounds 3a-f) position of the benzene ring, a number of highly potent HDAC inhibitors have been obtained. In the anti-HD2 assay 3c (IC50 = 11 nM) was the most potent compound, being > 11600-, 4.5-, and 10-fold more potent than sodium valproate, SAHA, and HC-toxin, respectively, and showing the same activity as trapoxin. HD1-B and HD1-A assays have been performed to screen the inhibitory action of 1-3 against mammalian class I (HD1-B) and class II (HD1- A) HDAC homologous enzymes. From the corresponding IC50 data, a selectivity ratio has been calculated. In general, compounds 1-3 showed no or little selectivity towards the class II homologue HD1-A, the most selective being 2a with class II selectivity ratio = 4.3. About the inhibitory potency, the 4-(2-naphthoylamino)cinnamyl-N-hydroxyamide 3f showed the highest inhibiting effect against the two enzymes (IC50-HD1-B = 36 nM; IC50-HD1-A = 42 nM). Selected 2 and 3 compounds will be evaluated to determine their antiproliferative and cyto differentiating activities on HL-60 cells.
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Mai A., Massa S., Pezzi R., Valente S., Loidl P. and Brosch G., Synthesis and Biological Evaluation of 2-, 3-, and 4-Acylaminocinnamyl-Nhydroxyamides as Novel Synthetic HDAC Inhibitors, Medicinal Chemistry 2005; 1 (3) . https://dx.doi.org/10.2174/1573406053765431
DOI https://dx.doi.org/10.2174/1573406053765431 |
Print ISSN 1573-4064 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-6638 |
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