Design, synthesis and biological evaluation of novel 7-alkylamino substituted benzo[a]phenazin derivatives as dual topoisomerase I/II inhibitors

• 26 new benzo[a]phenazin derivatives were design and synthesized as Topo inhibitors.
• Some of compounds exhibited significant Topo I and Topo II inhibitory activity.
• Compounds showed excellent antiproliferative activity against HL-60 cells.
• The compounds acted as Topo I poisons and Topo II catalytic inhibitors.

A novel series of benzo[a]phenazin derivatives bearing alkylamino side chains were designed, synthesized and evaluated for their topoisomerases inhibitory activity as well as cytotoxicity against four human cancer cell lines (HL-60, K-562, HeLa, and A549). These compounds were found to be dual inhibitors of topoisomerase (Topo) I and Topo II, and exhibited excellent antiproliferative activity, in particular against HL-60 cells with submicromolar IC50 values. Further mechanistic studies showed that this class of compounds acted as Topo I poisons by stabilizing the Topo I-DNA cleavage complexes and Topo II catalytic inhibitors by inhibiting the ATPase activity of hTopo II. Molecular docking studies revealed the binding modes of these compounds for Topo I and Topo II.

A series of benzo[a]phenazin derivatives were synthesized and evaluated for their topoisomerases inhibition and cytotoxicity. Their mechanistic studies showed that the compounds were Topo I poisons and Topo II catalytic inhibitors.Figure optionsDownload as PowerPoint slide