Potential antitumor agents. 18. Bisquaternary ammonium heterocycles

Abstract

It was earlier proposed that a close approach to overall planarity was a structural prerequisite for mouse antileukemic activity (L1210) in bisquaternary ammonium heterocycles. The preparation of L1210 active 3,3''-[bicyclo[2.2.2]octane-1,4-dicarbonylbis(imino-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 is 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.