ANILINE MUSTARD ANALOGS OF THE DNA-INTERCALATING AGENT AMSACRINE - DNA INTERACTION AND BIOLOGICAL-ACTIVITY

Two series of analogues of the clinical antileukemic drug and DNA-inte rcalating ligand amsacrine have been prepared, containing aniline must ard sidechains of varying reactivity, linked either at the 4-position of the intercalating acridine chromophore (type A) or at the 1'-positi on of the 9-anilino group (type B). DNase I footprinting assays showed that compounds of type B had stronger reversible binding to DNA. than did compounds of type A. Compounds of each type showed similar patter ns of alkylation-induced cleavage of DNA, and alkylate at the N7 of gu anines in runs of guanines (similar to the pattern for untargeted must ards) as well as some adenines. Both classes of compounds crosslinked DNA, although those bearing relatively inactive mustards did so only a t high drug/base pair ratios. However, while the patterns of DNA alkyl ation were broadly similar, the compounds were considerably more cytot oxic than analogous untargeted mustards. Comparison of their cytotoxic ities in wild-type and DNA repair-deficient lines indicated this toxic ity was due to DNA crosslinks (except for the least reactive SO2-linke d mustards). The 4-linked analogues showed slightly higher in vivo ant ileukemic activity than the corresponding 1'-linked analogues.