Abstract
In discovery of HDAC inhibitors with improved activity and selectivity, fluorine substitution was performed on our previously derived lead compound. The synthesized molecules N-(2-amino-4-fluorophenyl)-4-[bis-(2-chloroethyl)-amino]-benzamide (FNA) exhibited class I (HDAC1, 2, and 3) selectivity in the in vitro enzymatic assay and especially potent against HDAC3 activity (IC50: 95.48 nM). The results of in vitro antiproliferative assay indicated that FNA exhibited solid tumor cell inhibitory activities with IC50 value of 1.30 μM against HepG2 cells compared with SAHA (17.25 μM). Moreover, the in vivo xenograft model study revealed that FNA could inhibit tumor growth with tumor growth inhibition (TGI) of 48.89% compared with SAHA (TGI of 48.13%). Further HepG2 cell–based apoptosis and cell cycle studies showed that promotion of apoptosis and G2/M phase arrest make contributions to the antitumor activity of FNA. In addition, drug combination results showed that 0.5 μM of FNA could improve the anticancer activity of taxol and camptothecin. The present studies revealed the potential of FNA utilized as a high potent lead compound for further discovery of isoform selective HDAC inhibitors.
Highlights
Histone deacetylases and histone acetylases are important enzymes participating in the regulation of gene expression by acetylating and deacetylating of histones [1, 2]
Benzamide HDAC inhibitors (HDACIs) exhibited the advantage of class I selectivity compared with HDACIs with hydroxamic acid as their zinc-binding group (ZBG)
None of the benzamide HDACIs have been approved by US Food and Drug Administration (FDA) yet
Summary
Histone deacetylases and histone acetylases are important enzymes participating in the regulation of gene expression by acetylating and deacetylating of histones [1, 2]. Class III HDACs are a group of NAD+-dependent enzymes ( known as sirtuins), whose activity does not require the presence of zinc iron [9,10,11,12,13]. It had been shown that overexpression of HDACs led to increased deacetylation of histones, which increases the gravitational pull between DNA and histones by Nitrogen Mustard HDAC Inhibitor restoring the positive charge of the histones, making the relaxed nucleosomes very tight and unfavorable for the expression of specific genes, including some tumor suppressor genes [22,23,24,25,26,27,28]
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