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 (5m, 11b–d, and 11h) 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, 11c, exhibited anticancer potency sevenfold higher than that of SAHA. 11c triggered more significant cancer cell apoptosis than
did SAHA by cleavage of both PARP and caspase 3 in a dose-dependent
manner. Furthermore, 11c 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, 11c showed low acute toxicity in mice and inhibited the growth
of implanted human CRC in mice more potently than did SAHA. Together, 11c possessed potent antitumor activity and may be a promising
candidate for the potential treatment of human CRC.