13 July 2009 Synthesis, characterization, and subcellular localization studies of amino acid-substituted porphyrinic pigments
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Proceedings Volume 7380, Photodynamic Therapy: Back to the Future; 73805Q (2009) https://doi.org/10.1117/12.822910
Event: 12th World Congress of the International Photodynamic Association, 2009, Seattle, Washington, United States
Stopping cancer in its path occurs when photosensitizers (PSs) induce apoptotic cell death after their exposure to light and the subsequent formation of reactive oxygen species. In pursuit of our hypothesis that mitochondrial localizing PSs will enhance the efficacy of the photosensitizing process in photodynamic therapy, since they provoke cell death by inducing apoptosis, we synthesized and characterized tetraphenylporphyrins (TPPs) that are substituted at the paraphenyl positions by two amino acids and two fluoro or hydroxyl groups, respectively. They were prepared according to the Lindsey-modified Adler-Longo methodology using trifluoromethanesulfonylchloride (CF3SO2Cl) as a catalyst instead of trifluoroacetic acid. The use of CF3SO2Cl yielded cleaner products in significantly higher yields. During the synthesis, not only the yields and work-up procedure of the TPPs were improved by using CF3SO2Cl as a catalyst, but also a better means of synthesizing the precursor dipyrromethanes was tested by using indium(III) chloride. Column chromatography, HPLC, and NMR spectroscopy were used to separate and characterize the di-amino acid-dihydroxy, or difluoro-substituted porphyrins and to ascertain their purity before subcellular localization studies were carried out. Studies using androgen-sensitive human prostate adenocarcinoma cells LNCaP revealed that certain amino acid substituted porphyrins that are positively charged in the slightly acidic medium of cancer cells are very useful in shedding light on the targets of TPPs in subcellular organelles of cancer cells. Although some of these compounds have properties of promising photosensitizers by revealing increased water solubility, acidic properties, and innate ability to provoke cell death by apoptosis, the cell killing efficacy of these TPPs is low. This correlates with their subcellular localization. The di-amino acid, di-hydroxy substituted TPPs localize mainly to the lysosomes, whereas the di-fluoro-substituted TPPs are trapped in the plasma membrane. Only a pheophorbide derivative recently synthesized in our laboratory localized to the mitochondria of LNCaP cells, which are at the center of cell death as is reflected in their key role during apoptosis, thus reassuring our attempts toward rational drug design.
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Lisa van Diggelen, Lisa van Diggelen, Hnin Khin, Hnin Khin, Kip Conner, Kip Conner, Jenny Shao, Jenny Shao, Margaretta Sweezy, Margaretta Sweezy, Anna Hyewon Jung, Anna Hyewon Jung, Meden Isaac, Meden Isaac, Ursula Simonis, Ursula Simonis, } "Synthesis, characterization, and subcellular localization studies of amino acid-substituted porphyrinic pigments", Proc. SPIE 7380, Photodynamic Therapy: Back to the Future, 73805Q (13 July 2009); doi: 10.1117/12.822910; https://doi.org/10.1117/12.822910

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