Novel β‑Carboline/Hydroxamic Acid Hybrids Targeting Both Histone Deacetylase and DNA Display High Anticancer Activity via Regulation of the p53 Signaling Pathway

A novel series of hybrids from β-carboline and hydroxamic acid were designed and synthesized. Several compounds (<b>5m</b>, <b>11b</b>–<b>d</b>, and <b>11h</b>) not only exerted significant antiproliferation activity against four human colorectal cancer (CRC) cell lines but also showed histone deacetylase inhibitory effects in vitro. The most potent compound, <b>11c</b>, exhibited anticancer potency sevenfold higher than that of SAHA. <b>11c</b> triggered more significant cancer cell apoptosis than did SAHA by cleavage of both PARP and caspase 3 in a dose-dependent manner. Furthermore, <b>11c</b> simultaneously increased the acetylation of histone H3 and α-tubulin, enhanced expression of DNA damage markers histone H2AX phosphorylation and p-p53 (Ser15), and activated p53 signaling pathway in HCT116 cells. Finally, <b>11c</b> showed low acute toxicity in mice and inhibited the growth of implanted human CRC in mice more potently than did SAHA. Together, <b>11c</b> possessed potent antitumor activity and may be a promising candidate for the potential treatment of human CRC