Dihydroimidazophenanthridinium (DIP)‐Based DNA Binding Agents with Tuneable Structures and Biological Activity

We have synthesised a library of dihydroimidazophenanthridinium cations (DIPs) with large structural diversity (1–29) using a “one-pot” approach. The DNA binding constants of DIPs range from 2 ' 10 4 to 1.3 ' 10 5 m � 1 , and the free energies for binding range from � 5.9 to � 6.40 kcal mol � 1 . Viscosity measurements demonstrated that the binding of the compounds caused DNA lengthening, thus signifying binding by intercalation. The cytotoxicities of the compounds were determined by tetrazolium dyebased microtitration assays and showed a large range of values (0.09–11.7 mm). Preliminary molecular modelling studies of the DNA–DIP interactions suggested that the DIP moieties can interact with DNA by intercalation, and some R groups might facilitate binding by minor-groove binding. The results provide insight into how to design biologically active DNA binding agents that can interact in these ways.