DNA adducts of 9-anilinoacridine mustards: Characterization by NMR

Two types of 9-anilinoacridine-linked mustards, containing aniline mustard side chains linked either at the 4-position of the intercalating acridine chromophore (type A) or at the 1'-position of the 9-anilino group (type B), were reacted with calf thymus DNA. Adducts were isolated by preparative TLC, and their structures were determined by a variety of one-dimensional and two-dimensional NMR experiments. The only isolated product from the reaction of the 4-linked mustard (type A) was a guanine N7 adduct (55% yield), arising from alkylation in the major groove. In contrast, the major product (57% yield) from reaction of the 1'-linked mustard (type B) was an adenine N3 adduct from alkylation in the minor groove, with a smaller proportion (20%) of guanine N7 adduct. Computer modeling studies of drug-DNA alkylation complexes resulted in minimum-energy structures and averaged molecular dynamics structures that agreed with the adduct studies. The models suggest the aniline ring of the carrier is located in the DNA minor groove, with the acridine ring intercalated between two base pairs with the 4-position pointing into the major groove.