Synthesis and Anticancer Research ofN-(2-aminophenyl)benzamide Acridine Derivatives as Dual Topoisomerase I and Isoform-Selective HDAC Inhibitors

Topoisomerase (Topo) and histone deacetylase (HDAC) are considered to be effective targets for the treatment of cancer. In this study, 16 newN-(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 ademonstrated the highest anti-proliferative activity (IC50=0.12-0.35 mu M). Further studies showed that8 aand some analogues displayed Topo I inhibitory activity and exhibited selective inhibition for HDAC1 (class I HDAC). Additionally,8 acan significantly induce DNA damage and histone H3 acetylation in these tested cancer cells. Moreover,8 atriggered dose-dependent G0/G1 cell cycle arrest and induced cellular apoptosis. This study provides new perspectives for the further structural optimization ofN-(2-aminophenyl)benzamide acridine analogues for use in cancer research.