POTENTIAL ANTI-TUMOR AGENTS .28. DEOXYRIBONUCLEIC-ACID POLYINTERCALATING AGENTS

DNA monointercalating agents of the 4′-(9-acridinylamino) methanesulfonanilide series provide high, broad-spectrum experimental antitumor activity. Certain consequences of a DNA intercalation site of action have been explored. For a topologically constrained, negatively supercoiled, twin-helical DNA, drug association constants in relation to those for the corresponding linear, relaxed DNA should increase exponentially as the number of equivalent intercalating nuclei in a drug increases. As a preliminary to preparing DNA polyintercalating agents for antitumor evaluation the structural features necessary for bisintercalation have been investigated. Drug binding to nucleic acids was monitored by spectrofluorometric quantitation of the displacement of ethidium from DNA; results are provided as C50 values, those micromolar drug concentrations necessary to displace 50% of DNA-bound ethidium. Potential bisintercalators prepared differed in the structures employed to space the intercalating nuclei and the separation of the latter. Each homologous series of potential bisintercalators provided an individual pattern of progression of C50 values. Viscometric studies showed selected agents of low C50 values to unwind the supercoiling of PM2 bacteriophage DNA in a manner characteristic of intercalating agents. A symmetrical diacridine provided a high unwinding figure (41°, in relation to ethidium at 26°), twice that of the monomeric acridine precursor and, to this criterion, is a bisintercalating agent. Although considered supralipophilic many agents containing two spaced acridine nuclei, or one acridine and one quinoline nucleus, proved active against the P-388 and L1210 leukemias; more hydrophilic examples may display greater antitumor activity. There was no clear correspondence between PM2-DNA unwinding angles or C50 values and level of biologic activity. © 1978, American Chemical Society. All rights reserved.