Novel 4-Oxoquinazoline-Based<i>N</i>-Hydroxypropenamides as Histone Deacetylase Inhibitors: Design, Synthesis, and Biological Evaluation

Abstract

Two series of novel 4-oxoquinazoline-based <i>N</i>-hydroxypropenamides (<b>9a</b>-<b>m</b> and <b>10a</b>-<b>m</b>) were designed, synthesized, and evaluated for their inhibitory and cytotoxicity activities against histone deacetylase (HDAC). The compounds showed good to potent HDAC inhibitory activity and cytotoxicity against three human cancer cell lines (SW620, colon; PC-3, prostate; NCI-H23, lung cancer). In this series, compounds with the <i>N</i>-hydroxypropenamide functionality impeded at position 7 on the 4-oxoquinazoline skeleton (<b>10a</b>-<b>m</b>) were generally more potent than compounds with the <i>N</i>-hydroxypropenamide moiety at position 6 (<b>9a</b>-<b>m</b>). Also, the <i>N</i> ³-benzyl-substituted derivatives (<b>9h</b>-<b>m</b>, <b>10h</b>-<b>m</b>) exhibited stronger bioactivity than the <i>N</i> ³-alkyl-substituted ones (<b>9a</b>-<b>e</b>, <b>10a</b>-<b>e</b>). Two compounds <b>10l</b> and <b>10m</b> were the most potent ones. Their HDAC inhibitory activity (IC₅₀ values, 0.041-0.044 μM) and cytotoxicity (IC₅₀ values, 0.671-1.211 μM) were approximately 2- to 3-fold more potent than suberoylanilide hydroxamic acid (SAHA). Some compounds showed up to 10-fold more potent HDAC6 inhibition compared to their inhibitory activity in total HDAC extract assay. Analysis of selected compounds <b>10l</b> and <b>10m</b> revealed that these compounds strongly induced both early and late apoptosis and arrested SW620 cells at the G2/M phase. Docking studies were carried out on the HDAC6 isoform for series <b>10a</b>-<b>m</b> and revealed some important features contributing to the inhibitory activity of synthesized compounds.