Potential antitumor agents. 45. Synthesis, DNA-binding interaction, and biological activity of triacridine...

A series of amide-linked triacridines of varying interchromophore separation were synthesized as potential DNA trisintercalating agents. The corresponding diamide diacridines (lacking the central chromophore) were also prepared, and the DNA-binding and biological activities of both series of compounds were evaluated. Although one of the triacridines shows evidence of a trisintercalative binding mode, most of the triacridines (and all the diacridines) bound by bisintercalation. The diacridines showed great cytotoxicity and higher DNA association constants than the corresponding 9-[[3-(dimethylamino)propyl]amino]acridine monomer, but addition of a third chromophore did not provide corresponding increases in either DNA affinity, inhibition of RNA synthesis, or cytotoxicity. Some members of both series show minimal in vivo antileukemic activity. The results suggest that further development of trimeric molecules as potential antitumor agents should focus on smaller chromophores with lower capacity for nonspecific binding and/or the employment of rigid linker chains to provide true molecular "staples" for DNA.