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 (<b>1-29</b>) using a one-pot approach. The DNA binding constants of DIPs range from 2×10<sup>4</sup> to 1.3×10<sup>5</sup> M-1, and the free energies for binding range from -5.9 to -6.40 kcal mol<sup>-1</sup>. 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 dye-based microtitration assays and showed a large range of values (0.09-11.7 M). 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