Structural optimizations and bioevaluation of N-substituted acridone derivatives as strong topoisomerase II inhibitors.

[Display omitted] • Structural optimizations of acridone derivatives based on E17 and E24. • Structure-activity outcome was enriched. • The most potent compound 6h is a strong topo IIa/b poison. • 6h can cause obvious DNA damage and DSBS breaks. • 6h can induce apoptosis. Previously, an array of N -substituted acridone derivatives have been reported as potent topoisomerase II (topo II) inhibitors, and preliminary structure–activity relationship (SAR) outcomes revealed that the linker between 1-NH and N -methyl piperazine motif of the tricyclic acridone scaffold significantly affected their anti-proliferative potencies. To further explore the SARs of acridone-derived topo II inhibitors, a wider range of novel acridone derivatives were herein synthesized via two rounds of structural optimizations on two validated hits, E17 and E24. Initially, the linker length was optimized, and then influences of N -methyl piperazinyl moiety and disposition of three N atoms on the bioactivity were investigated. As a result, a newly developed topo II inhibitor 6 h was found to be more potent than E17 and E24 , thereby serving as a tool compound for the follow-up mechanistic study. Compound 6 h functioned as a strong topo IIα/β inhibitor, caused obvious DNA damage, and induced apoptosis by triggering the loss of mitochondrial membrane potential (Δψ m). Further molecular docking and MD study illustrated the favorable interactions of 6 h with both topo IIα and topo IIβ subtypes. [ABSTRACT FROM AUTHOR]