Potential antitumor agents. 44. Synthesis and antitumor activity of new classes of diacridines: importance of linker chain rigidity for DNA binding kinetics and biological activity.

Abstract

Four classes of diacridines, joined at the 9-position by linker chains of varying length, rigidity, and polarity, were evaluated for DNA-binding properties and antitumor activity. Diacridines linked by flexible chains of varying polarity show relatively fast chromophore exchange kinetics among DNA binding sites but slower dissociation rates, suggesting the potential for considerable "creeping" of the drug along the helix, and are inactive in vivo. The exchange kinetics can be slowed dramatically by inclusion of positive charges in the side chain, but the resulting polycationic drugs are inactive in vivo, possibly due to poor distribution. Diacridines linked by a rigid, polar but neutral dicarbamoylpyrazole chain retain slow exchange kinetics, have a greatly reduced potential "creep rate", and possess good in vitro potency and significant in vivo antileukemic activity.