The Search for Novel Cancer Therapies : Catalytic Inhibition of Topoisomerase II by Substituted 9-aminoacridine Derivatives

Fig.2The catalytic cycle of DNA topoisomerase II. Light blue – ATPase domain, dark blue – core domain, yellow – G-segment, green – T-segment. Free topoII binds to the G-segment of duplex DNA (1). ATP (red circle) binds to the ATPase domains promoting T-segment capture and ATPase dimerization (2). N-gate closure induces G-segment cleavage and hydrolysis of one ATP (3). The DNA-gate opens and the T-segment passes through the G-segment (4). Hydrolysis of the second ATP religates the G-segment, the C-gate opens, and the T-segment dissociates (5). Both ADPs dissociate from the ATPase domain, the N-gate opens, the Cgate closes, and topoII dissociates from DNA (6). Inhibitors and their inhibition points are shown. Red – topoII poisons, black – catalytic inhibitors, green – drugs under evaluation. 3-6