High photodynamic activity was observed for hexadeca-cationic zinc, magnesium, and metal-free phthalocyanines (Pcs) and tetrapyrazinoporphyrazines with EC50 values as low as 5 nM (MCF-7 cells) for the best compound; this activity was several times better than that of clinically established photosensitizers verteporfin, temoporfin, S3AlOHPc, or protoporphyrin IX. This lead compound was characterized by low dark toxicity (TC50 = 369 μM), high efficiency against other cell lines (HCT 116 and HeLa), and possible activation by light above 680 nm. The excellent photodynamic activity resulted from the rigid spatial arrangement of the quaternized triazole moieties above and below the Pc core, as confirmed by X-ray crystallography. The triazole moieties thus formed two "cationic donuts" that protected the hydrophobic core against aggregation in water. The lysosomes were found to be the site of subcellular localization and were consequently the primary targets of photodynamic injury, resulting in predominantly necrotic cell death.

Department of Biochemical Sciences Faculty of Pharmacy in Hradec Kralove Charles University Heyrovskeho 1203 Hradec Kralove 500 05 Czech Republic

Department of Biophysics and Physical Chemistry Faculty of Pharmacy in Hradec Kralove Charles University Heyrovskeho 1203 Hradec Kralove 500 05 Czech Republic

Department of Chemistry Kuwait University P O Box 5969 Safat 13060 Kuwait

Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Faculty of Pharmacy in Hradec Kralove Charles University Heyrovskeho 1203 Hradec Kralove 500 05 Czech Republic

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Peripherally Crowded Cationic Phthalocyanines as Efficient Photosensitizers for Photodynamic Therapy