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A series of novel β-carboline-based hydroxamate derivatives ( 8a-n ) as HDAC inhibitors have been designed and synthesized. Most of these compounds displayed potent histone deacetylase inhibitory effects and good antiproliferative activity with IC 50 s in the low micromolar range. One of the most potent compounds ( 8k ) showed the strongest inhibition of the proliferation of human hepatocellular carcinoma (HCC) cells in vitro , with IC 50 values lower than that of the currently approved HDAC inhibitor SAHA. Compound 8k also increased acetylation of histone H3 and α-tubulin, consistent with its potent HDAC inhibition. Importantly, 8k induced hypochromism by electrostatic interactions with CT-DNA, suggesting potential induction of DNA damage. Finally, 8k significantly induced HepG2 cell apoptosis by regulating apoptotic relative proteins expression. Together, our findings suggest that these novel β-carboline-based hydroxamate derivatives may provide a new framework for the discovery of novel antitumor agents for the intervention of human carcinoma cells.

Development of novel β-carboline-based hydroxamate derivatives as HDAC inhibitors with DNA damage and apoptosis inducing abilities