Synthesis and Anticancer Research of <i>N</i> ‐(2‐aminophenyl)benzamide Acridine Derivatives as Dual Topoisomerase I and Isoform‐Selective HDAC Inhibitors
Bin Zhang, Qiting Zhang, Zedong Liu, Ning Wang, Haixiao Jin, Feng Liu, Cunlong Zhang, Shan He
Abstract
Abstract Topoisomerase (Topo) and histone deacetylase (HDAC) are considered to be effective targets for the treatment of cancer. In this study, 16 new N ‐(2‐aminophenyl)benzamide acridine analogues ( 8 a‐8 p ) were designed and synthesized as Topo I and subtype‐selective HDAC inhibitors. Most of the compounds displayed good antiproliferative activity against CCRF‐CEM, K562 and U937 cells. Among them, 8 a demonstrated the highest anti‐proliferative activity (IC 50 =0.12‐0.35 μM). Further studies showed that 8 a and some analogues displayed Topo I inhibitory activity and exhibited selective inhibition for HDAC1 (class I HDAC). Additionally, 8 a can significantly induce DNA damage and histone H3 acetylation in these tested cancer cells. Moreover, 8 a triggered dose‐dependent G0/G1 cell cycle arrest and induced cellular apoptosis. This study provides new perspectives for the further structural optimization of N ‐(2‐aminophenyl)benzamide acridine analogues for use in cancer research.