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

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 IC₅₀s 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 IC₅₀ 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.