Cain B F, Atwell G J
J Med Chem. 1976 Dec;19(12):1417-9. doi: 10.1021/jm00234a013.
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.
早些时候有人提出，对于双季铵杂环化合物的抗白血病活性（L1210）而言，接近整体平面性是一个结构前提条件。制备含非平面桥环体系的具有L1210活性的3,3'-[双环[2.2.2]辛烷-1,4-二甲酰基双（氨基对苯二甲酰亚氨基）双（1-烷基吡啶鎓）盐否定了这一观点。一个替代的提议是，需要一个相对刚性的分子框架来维持季铵官能团的间距和定位，从而确保正确的位点选择。用双环[2.2.2]辛烷-1,4-二甲酰基残基取代对苯二甲酰基药物成分会降低DNA结合。对苯二甲酰基单元赋予必要的分子刚性、更强的DNA结合能力和更高的L1210活性。
