Design, Synthesis, and Biological Evaluation of Histone Deacetylase Inhibitors Derived from Erianin and Its Derivatives

Multi-target histone deacetylase (HDAC) inhibitors can be designed by introducing dominant structures of Natural Products to enhance activity and efficacy while avoiding the toxicity from other targets. In this study, we reported a series of novel HDAC inhibitors based on erianin and amino erianin upon pharmacophore fusion strategy. Two representative compounds, N-hydroxy-2-(2-methoxy-5- (3,4,5-trimethoxyphenethyl)phenoxy)acetamide and N-Hydroxy-8-((2-methoxy-5- (3,4,5-trimethoxyphenethyl)phenyl)amino)octanamide, possessed good inhibitory effect against five Cancer cells tested (IC₅₀ =0.30-1.29 μΜ, 0.29-1.70 μΜ) with strong HDAC inhibition, and low toxicity toward L02 cells, which were selected for subsequent biological studies in PANC-1 cells. They were also found to promote the intracellular generation of Reactive Oxygen Species, cause DNA damage, block the cell cycle at G2/M phase, and activate the mitochondria-related apoptotic pathway to induce cell Apoptosis, which are significant for the discovery of new HDAC inhibitors.

Amino erianin; Apoptosis; Erianin; HDAC inhibitors; Toxicity.