Electrophilic aromatic halogenation of perylenequinones: a strategy to improve photodynamic properties

Halogen substitution is a widely used strategy in medicinal chemistry to modulate the physicochemical and biological properties of drug candidates. Here, we report the electrophilic aromatic halogenation of two fungal perylenequinones, ent-shiraiachrome A (1) and hypocrellin B (2), using N-halosuccinimides, where the reaction conditions were optimized to obtain three products per reaction (i.e., 8-halo, 5-halo, and di-halogenated derivatives), resulting in a total of 18 analogues (i.e., 3-20). Iodinated, brominated, and chlorinated derivatives were synthesized and fully characterized by NMR, HRMS, ECD, and UV-vis analyses. Additionally, X-ray crystallography was used to further confirm the location of the halogens within three of the monosubstituted analogues (i.e., 6, 15, and 16). Compounds 1-20 were assessed for cytotoxicity toward cancer cells with and without light exposure, using different illumination wavelengths to measure photodynamic activity. Photophysical and bioactivity evaluations indicated that most analogues exhibited enhanced activity upon light irradiation while demonstrating reduced dark toxicity. Furthermore, the halogenated analogues displayed a bathochromic shift, indicating improved absorption in the red-light region.