Development of <i>N</i>‑Hydroxycinnamamide-Based Histone Deacetylase Inhibitors with an Indole-Containing Cap Group

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

(C&D) Coronal CT examinations.

<p>it showed their relationship. (FR: foramen rotundum; PSC: Palatosphenoidal Canal (Palatovaginal Canal); VC: vidian nerve).</p

The anatomy step of Meckel Cave.

<p><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0091444#pone-0091444-g004" target="_blank">Figure 4</a>.4: the position of the front door of vidian canal and vidian nerve; <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0091444#pone-0091444-g004" target="_blank">Figure 4</a>.5: after removal anterior and lateral part of the bone of Meckel cave, Meckel cave which was covered by the dura mater was exposed, the interior and inferior margin of which is the internal carotid artery, lateral side is V2 and V3 branches; <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0091444#pone-0091444-g004" target="_blank">Figure 4</a>.6: Dura mater was resected, Meckel cave was opened. (C: clivis; ICA: internal carotid artery; M: meckel cave; QS: quadrilateral space; SS: sphenoid sinus; V: trigeminal nerve; V2: maxillary branch of the trigeminal nerve; V3: mandibular branch of the trigeminal nerve; VI: abducent nerve; VN: vidian nerve).</p

(A&B) Axial CT examinations.

<p>It showed relationship of foramen rotundum, vidian canal and palatosphenoidal canal (palatovaginal canal). (PPF: pterygomandibular fossa; PC: vidian canal; PSC: Palatosphenoidal Canal (Palatovaginal Canal); VC: vidian nerve).</p