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, CN bond isomerization and Förster resonance energy transfer, were studied in two distinct structures, A and B. In one part of this work, the previously discovered direct CN bond attachment/detachment effect on ¹O₂ production was studied using a longer wavelength-absorbing compound, A. The synthesis of styryl-substituted hydrazone-BODIPY 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 CN 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.