Enhancing the photosensitizing activity of natural flavins: Tuning the heavy-atom effect in the isoalloxazine series.

Structure-photosensitizing activity relationships for a series of flavin analogues were investigated with the final goal of identifying the most potent photosensitizer in these series. The main structural modifications involved the introduction of various halogen atoms in C- and/or C-positions on the isoalloxazine ring. These compounds were synthesized by reacting judiciously-functionalized anilines with alloxan. The SAR trends showed that the photosensitizing activity increased with the size of the halogen atoms, confirming the importance of the heavy-atom effect on the photosensitizer's activity. The halogens in C were more active than the di-substituted halogens, which in turn were more active than the C-substituted equivalents. However, even if the photosensitizing activity is slightly less important for the 7- compared to the 8-substituted derivatives, the 7-haloisoalloxazines are promising photosensitizers, as they present a better cellular toxicity profile than the 8-substituted analoges. The photosensitizing activity perfectly correlated with the determined fluorescence for the same compounds. Except for the dihalogeno derivatives, all the compounds were not toxic up to a 50 μM range.