The relationship between frameshift mutagenicity and DNA-binding affinity in a series of acridine-substituted derivatives of the experimental antitumour drug 4′-(9-acridinylamino)methanesulphonanilide (AMSA)

Abstract

The mutagenicity and DNA-binding affinity of members of a series of acridine-substituted derivatives of 4′-(9-acridinylamino)methanesulphonanilide (AMSA) have been compared. The series includes compounds ranging from highly active to inactive in the L1210 murine leukaemia. Binding to DNA was measured by an ethidium displacement technique, with a correction being made for acridine-induced quenching of ethidium. Mutagenicity was assessed by measuring the reversion frequencies of the frameshift tester strain Salmonella typhimurium TA1537 in liquid culture. The results indicate that maximum mutagenicity is found in a “window” of DNA-binding affinities between 10 6 and 5 × 10 6 M −1 (determined at 0.01 ionic strength). Compounds with binding affinities below 10 6 M −1 generally lacked both antitumour and mutagenic activity, whereas those with affinities above 5 × 10 6 M −1 were active against L1210 leukaemia but virtually inactive in inducing frameshift mutations.