Indolo[2,3-b]-Quinolizinium Bromide: An Efficient Intercalator with DNA-Photodamaging Properties

The associative interactions of indolo[2,3‐b]‐quinolizinium bromide with DNA and its DNA photocleavage properties were studied in detail. Absorption and emission spectroscopy, linear dichroism, and energy‐transfer measurements indicate that the indoloquinolizinium binds to DNA primarily by intercalation, with a preference for GC base pairs. In agreement with this data, the results of primer extension analysis indicate that photocleavage occurrs prevalently at the GC nucleotides. Molecular modeling studies confirm that intercalative stacking between adjacent base pairs is energetically favorable. However, it is also observed that the location of the dye in the minor groove of the DNA is energetically even more favorable. Upon UVA irradiation, the indoloquinolizinium causes single‐strand cleavage with an efficiency that varies with the dye–DNA ratio. This observation is rationalized in terms of more efficient photocleavage by the externally bound dye compared with the intercalated one. The kinetics of strand degradation under aerobic and anaerobic conditions suggest that a Type I reaction occurs, that is, radical‐mediated DNA damage. GC‐rich DNA regions are the preferred target for indolo[2,3‐b]‐quinolizinium bromide. This DNA‐damaging compound forms interlacation complexes with DNA helices and nucleotides such as poly[d(G‐C)]2, for which the minimum energy complex structure was determined by molecular modeling (see figure). A detailed binding analysis revealed a strong interaction which involved almost exclusively intercalation of indolo[2,3‐b]‐quinolizinium bromide.