DNA binding and growth inhibitory properties of a series of 2,7-di-alkyl-substituted derivatives of proflavine.
Proflavine (3,6-diaminoacridine) and its 2,7-dimethyl, 2,7-diethyl, 2,7-diisopropyl and 2,7 di-t-butyl derivatives have been compared with respect to their DNA binding and biological properties. The binding of the first three members of the series to covalently closed circular duplex DNA showed the unwinding properties expected of intercalators. The 2,7-diisopropyl showed intermediate properties and the 2,7-di-t-butyl derivative failed to unwind this DNA. Antibacterial toxicity, measured in cultures of Salmonella typhimurium, increased with increasing lipophilic character of the compounds. Mutagenicity in the TA1537 frameshift tester strain was restricted to the first two members of the series, although the mutagenicity of the more lipophilic members may have been masked by toxicity. In contrast, toxicity towards cultures of L1210 cells showed a possible transition between intercalating and non-intercalating derivatives. It is proposed that DNA intercalation provides the major component of the toxicity towards cultured leukaemia cells, whereas lipophilicity provides the major component towards bacteria.
D000166:Acridines / Q000494:pharmacology*; D004270:DNA, Circular / Q000378:metabolism*; D066298:In Vitro Techniques; D007364:Intercalating Agents; D009152:Mutagenicity Tests; D011370:Proflavine / Q000031:analogs & derivatives / Q000494:pharmacology*; D012486:Salmonella typhimurium / Q000187:drug effects
D000166:Acridines; D004270:DNA, Circular; D007364:Intercalating Agents; D011370:Proflavine