Potential antitumor agents. 18. Bisquaternary ammonium heterocycles

It was earlier proposed that a close approach to overall planarity was a structural prerequisite for antileukemic activity (L1210) in bisquaternary ammonium heterocycles. The preparation of L1210 active 3,3'-[bicyclo[2.2.2]octane-1,4-dicarbonylbis(mino-p-phenylenecarbonylimino)bis(1-alkylpyridinium) salts, containing a nonplanar bridged ring system, negates this view. A replacement proposal is that a relatively rigid molecular framework in necessary to maintain the spacing and positioning of the quaternary functions, thereby ensuring correct site selection. Replacement of a terephthaloyl drug component by a bicyclo[2.2.2]octane-1,4-dicarbonyl residue lowers DNA binding. A terephthaloyl unit confers necessary molecular rigidity, greater DNA binding, and higher L1210 activity.