Design and synthesis of hydrazone-substituted BODIPY derivatives for photodynamic therapy

In this study, we substituted BODIPY dyes through hydrazone bonds at their 2- and 3-positions, formed new building blocks, and studied their efficacy in the pH-controlled release of photosensitizer units for targeted photodynamic therapy in cancer treatment. Two different singlet oxygen quenching mechanisms, C-N bond isomerization and Forster resonance energy transfer, were studied in two distinct structures, A and B. In one part of this work, the previously discovered direct C-N bond attachment/detachment effect on 1O2 production was studied using a longer wavelength-absorbing compound, A. The synthesis of styryl-substituted hydrazoneBODIPY compounds (e.g. compound A) is challenging, but this was successfully achieved for the first time in the current study. The design and synthesis of new hydrazone BODIPY derivatives and their activation capabilities at low pH for targeted photodynamic action were elucidated. With compounds A and B, it was demonstrated that singlet oxygen production could be successfully minimized using a C-N bond substitution strategy through both isomerization and FRET mechanisms in varying proportions. And the cleavage of the corresponding hydrazone bonds can convert the structures into cytotoxic 1O2-producing units for targeted cancer therapy. In the photocytotoxicity studies with low-pH-adjusted media, 1O2 production was unlocked effectively with compound A (250 nM, with MCF-7 cells) and B (500 nM, with HeLa cells) at pH 6.8.