Synthesis, DNA binding and cytotoxicity of 1-[[omega-(9-acridinyl)amino]alkyl]carbonyl -3-(chloromethyl)-6-hydroxyindolines, a new class of DNA-targeted alkylating agents.

We report the first synthesis of examples of the seco-CI DNA alkylating moiety 3-(chloromethyl)-6-hydroxyindoline linked to a 9-aminoacridine DNA-intercalating unit (compounds 1a-1c). The sequence-specificity of DNA alkylation by these compounds was studied by the gel electrophoresis cleavage assay. In contrast to the known trimethoxyindole-linked compound (1d), which alkylates exclusively at N3 of adenines in the minor groove, the acridine-linked analogues (1a-1c) alkylate predominantly at the N7 of guanines in the major groove (the first CI analogues reported to do so), although DNase I footprinting experiments show that the initial non-covalent binding of 1a-1c is not base sequence selective. DNA unwinding experiments show that the acridine moiety of 1a-1c remains intercalated after alkylation.