Affiliation:
1. Pharmaceutical Research Center and School of Chemistry and Chemical Engineering Southeast University Nanjing 211189 China
2. Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research Southeast University Nanjing 211189 China
3. School of Pharmacy Jilin Medical University Jilin City 132013 Jilin Province China
Abstract
AbstractMulti‐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.
Funder
National Natural Science Foundation of China
Subject
Organic Chemistry,General Pharmacology, Toxicology and Pharmaceutics,Molecular Medicine,Drug Discovery,Biochemistry,Pharmacology