Design, synthesis and evaluation of core and substituent modified porphyrins as novel second generation photodynamic therapy sensitizers.

摘要

Photodynamic therapy (PDT) is a new area of treatment for cancer, which utilizes light, oxygen, and a sensitizer to generate a cytotoxic event such as the generation of singlet oxygen. One advantage of this type of therapy is that it targets only the tumor, through the localization of the sensitizer and the ability to apply light directly. PhotofrinxRTM, a PDT sensitizer approved by the FDA, is a mixture of oligomers of hematoporphyrin and has been successfully used with light for the treatment of bladder, neck, lung, and skin cancers.; PDT generates cytotoxic agents via two processes: (1) the excited sensitizer transfers an electron to yield a radical species that is cytotoxic and (2) the excited sensitzer reacts with oxygen to yield superoxide radical anion or singlet oxygen. Both of which are cytotoxic.; This research designed and prepared new porphyrin sensitizers. The first design element was the insertion of ethyne-linked phenyl substituents at the 5, 10, 15 and 20 position of the porphyrin. Ethyne linkers have been used as a donor-acceptor linker, molecular conjugator, molecular wires and also in the synthesis of porphyrin based PDT sensitizers. The results from the study showed that the linker did not affect the photophysical properties such as absorbance and molar absorptivity as well as excitation lifetimes and rates.; The second design element was the preparation of core-modified porphyrins in which pyrrole nitrogens have been replaced by one or two chalcogen atoms. This replacement, in the porphyrin, which was predicted to give a greater singlet oxygen yield and increase the wavelength of absorption relative to PhotofrinRTM, generating promising new photosensitizers for photodynamic therapy. The core-modified porphyrins gave longer wavelength absorption maxima (690 nm), high quantum singlet oxygen generation (>0.50), and were phototoxic to Colo-26 cells in culture (LD50 50 mug/ml) with minimal dark toxicity.