Synthesis and evaluation of new fluorinated pyropheophorbide-a derivatives for photodynamic therapy

The discovery of new photosensitizers with excellent photodynamic anti-tumor effects remains a challenge for photodynamic therapy and diagnosis. Here a series of chlorophyll derivatives containing fluorine-substituted alkyl side chain were designed and synthesized. These compounds exhibited strong absorption at 660–665 nm with excellent molar extinction coefficients. Their singlet oxygen generation ability was also proved to be excellent. Upon excitation with a 411 nm laser, strong fluorescence emission around 660–670 nm was observed. They also showed obvious photodynamic antitumor activity to A549 cell in vitro and to tumor-bearing mice in vivo. Their photodynamic anti-proliferative abilities were confirmed in vivo with histotomy. Flow cytometry test showed that new compounds could induce late period cell apoptosis or necrosis. Sub-organelle localization test indicated that they primarily localized in the endoplasmic reticulum. Among them, compound F-C4-Ppa possesses the most outstanding anti-tumor effect and therefore, it is a promising anti-tumor drug candidate in photodynamic therapy and photo-imaging diagnosis.