STRUCTURE-ACTIVITY-RELATIONSHIPS FOR DNA PHOTOCLEAVAGE BY CATIONIC PORPHYRINS

The influence of molecular structure and DNA binding mode on the abili ty of cationic porphyrins to photosensitize DNA strand break formation has been studied for a series of meso-substituted pyridinium porphyri ns using electrophoretic and DNA sequencing techniques. Porphyrins sub stituted with pyridyl groups in which the heterocyclic nitrogen is in the para or meta position vis-a-vis the substitution point are capable of intercalative binding and are considerably more efficient DNA phot osensitizers than the corresponding non-intercalating ortho compounds. Within each group of porphyrins the photosensitizer efficiency increa ses with the number of positive charges. Using DNA sequencing experime nts, we have demonstrated that photomodification occurs primarily at t he guanine and thymine bases, and that alkali-labile sites produced by photo-oxidation are as important as direct cleavage events. The kinet ics of strand degradation in aerated and degassed solution suggest tha t type II reactions (probably mediated by singlet oxygen) occur with s ignificantly higher yield than type I reactions and are responsible fo r the formation of alkali-labile sites in aerated systems. These obser vations seem to confirm the hypothesis that those structural features which influence the strength and mode of binding also serve to establi sh favourable porphyrin-DNA interactions for photosensitization.