Development of <i>N</i>‑Hydroxycinnamamide-Based
Histone Deacetylase Inhibitors with an Indole-Containing Cap Group
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Abstract
A novel series of histone deacetylase inhibitors combining <i>N</i>-hydroxycinnamamide bioactive fragment and indole bioactive
fragment was designed and synthesized. Several compounds (<b>17c</b>, <b>17g</b>, <b>17h</b>, <b>17j</b>, and <b>17k</b>) exhibited comparable, even superior, total HDACs inhibitory
activity and in vitro antiproliferative activities relative to the
approved drug SAHA. A representative compound <b>17a</b> with
moderate HDACs inhibition was progressed to isoform selectivity profile,
Western blot analysis, and in vivo antitumor assay. Although HDACs
isoform selectivity of <b>17a</b> was similar to that of SAHA,
our Western blot results indicated that intracellular effects of <b>17a</b> at 1 μM were class I selective. It was noteworthy
that the effect on histone H4 acetylation of SAHA decreased with time,
while the effect on histone H4 acetylation of <b>17a</b> was
maintained and even increased. Most importantly, compound <b>17a</b> exhibited promising in vivo antitumor activity in a U937 xenograft
model