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

Abstract

A series of novel β-carboline-based hydroxamate derivatives (<b>8a-n</b>) 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 (<b>8k</b>) showed the strongest inhibition of the proliferation of human hepatocellular carcinoma (HCC) cells <i>in vitro</i>, with IC₅₀ values lower than that of the currently approved HDAC inhibitor SAHA. Compound <b>8k</b> also increased acetylation of histone H3 and α-tubulin, consistent with its potent HDAC inhibition. Importantly, <b>8k</b> induced hypochromism by electrostatic interactions with CT-DNA, suggesting potential induction of DNA damage. Finally, <b>8k</b> 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.