EFFECTS OF BIFUNCTIONAL NETROPSIN-RELATED MINOR GROOVE-BINDING LIGANDS ON MAMMALIAN TYPE-I DNA TOPOISOMERASE

We investigated the effects of compounds with two covalently linked ne tropsin moieties (bis-netropsin) on the function of mammalian type I D NA topoisomerase (topo I) in vitro. We initiated these studies because earlier studies had shown that certain bis-netropsins possess a sever al-fold higher antitumor and antiviral activity than netropsin. We con firmed that the parent compound netropsin, but not its bifunctional de rivatives, induce supercoils in closed DNA. We determined that bis-net ropsins inhibit the binding of topo I to DNA more efficiently than net ropsin and that bis-netropsins but not netropsin induce specific DNA s trand cleavage in the presence of topo I. We discuss a model explainin g the different effects of netropsin and bis-netropsins on topo I. Cop yright (C) 1997 Elsevier Science Inc.