Novel pyropheophorbide a dimers: Synthesis and photobiological evaluation as potent photosensitizers for photodynamic therapy

In this paper, the dimer of pyropheophorbide a via 3 1-ether bond linkage as novel chlorin photosensitiz-ers (PSs) for tumor photodynamic therapy (PDT) was designed and synthesized. We have separated it into two stereoisomers 5a (less polar) and 5b (more polar) by flash column chromatography and investigated their photophysical properties, PDT antitumor efficacy and mechanism. The results demonstrated that they should be a pair of epimers. Both dimers 5a and 5b showed stronger phototoxicity and higher dark -toxicity / phototoxicity ratio (> 350) against A549, HeLa and B16-F10 cells than their precursor 1 and Talaporfin. Moreover, photocytotoxicity and dark-cytotoxicity of 5b were both significantly higher than those of 5a , which seemed to be the first report that a couple of chlorin-based dimers stereoisomers via 3 1-ether linkage exhibited significant differences in vitro PDT antitumor efficacy. They could enhance intracellular ROS production to a greater extent than Talaporfin under light irradiation and also should have better in vivo PDT antitumor efficacy on C57BL/6 mice bearing B16 -F10 tumor than Talaporfin at the same dosage. As a result, dimers 5a and 5b are promising photosensitizer for PDT applications be-cause of its strong absorption in the phototherapeutic window (lambda max = 666 nm), relatively high ROS yield and dark toxicity/phototoxicity ratio, and excellent PDT antitumor efficacy. (c) 2022 Published by Elsevier B.V.

Automated summary

In this study, a novel chlorin-based photosensitizer was designed and synthesized for tumor photodynamic therapy. The photosensitizer showed high phototoxicity, high dark toxicity/phototoxicity ratio, and excellent PDT antitumor efficacy in vitro and in vivo.