Facile synthesis and biological evaluation of [a]-benzannulated BODIPY derivatives as novel heavy-atom-free photosensitizers for photodynamic anticancer therapy.

Boron dipyrromethenes (BODIPYs) have garnered significant attention for their broad applications in photodynamic anticancer therapy. However, the development of these materials remains a challenging task, partially due to their low singlet oxygen (1O2) quantum yield usually require incorporating heavy atoms and high laser power density to produce thermal energy and synergistically enhance photodynamic therapy (PDT). Concerns about potential dark toxicity of heavy atoms and the strong photothermal radiation causing acute pain significantly reduces patient compliance, hinders the broader clinical application of PDT. Here, we report a straightforward method for synthesizing structurally diverse substituted benzo dipyrromethene derivatives via a Pd-catalyzed one-step cascade cyclization reaction. This approach enables the rapid assembly of a library of heavy-atom-free [a]-benzannulated BODIPYs, facilitating their use in investigating biological activities. In vitro antitumor studies identified compound 4j as a standout endoplasmic reticulum (ER)-targeted photosensitizer (PS), exhibiting superior phototoxicity against MCF-7 cell line, with an IC50 value of 3.28 μM, and phototherapeutic index (PI) of 41.4. Remarkably, in vivo antitumor efficacy studies demonstrated that even under an ultralow laser dose of 30 J/cm2 (50 mW/cm2, 10 min) and single irradiation, 4j effectively completed MCF-7 tumor eradication and outperformed the clinically approved photosensitizer Ce6 in PDT activity. These findings highlight the potential of 4j as a promising heavy-atom-free and ER-targeted photosensitizer, providing a compelling strategy for advancing PDT with reduced dark toxicity and enhanced therapeutic efficacy.