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

A major challenge of photodynamic cancer therapy is to improve the selectivity of photosensitizers to the target pathological tissue. To overcome this issue, a series of chlorophyll derivatives containing thiadiazole sulfonamide moiety or 4-(2-aminoethyl)benzene sulfonamide moiety were designed and synthesized. These compounds showed intense absorption at 670 nm with high molar extinction coefficients, and strong fluorescence emission around 674 nm. Their singlet oxygen generation ability was also demonstrated to be excellent. They displayed obvious photo-cytotoxic effects to MDA-MB-231 cells in vitro and to tumor-bearing Balb/c nude mice in vivo. The fluorescence images exhibited that N-[2-((5-Sulfamoyl-1,3,4-thiadiazol-2-yl)amino)-2-oxoethyl]pyropheophorbide (AZ-Ppa-2) preferentially accumulated in MDA-MB-231 cell lines overexpressing CAIX (Carbonic anhydrase IX). Molecular Docking simulation revealed that AZ-Ppa-2 could closely bind to the active site residues of CAIX. Sub-organelle localization test indicated that AZ-Ppa-2 primarily localized in the lysosomes. These experiments suggested that AZ-Ppa-2, as a photosensitizer targeting CAIX, possessed an outstanding PDT anti-tumor effect with lasting regression of tumors, and deserved for further study.

Automated summary

This article reports a method to improve the selectivity of photosensitizers to target pathological tissue by designing and synthesizing chlorophyll derivatives. These compounds showed intense absorption and fluorescence emission characteristics, as well as excellent singlet oxygen generation ability. One of the compounds, AZ-Ppa-2, demonstrated the ability to preferentially accumulate in cells overexpressing CAIX and showed outstanding photodynamic therapy anti-tumor effects.