Far-red-absorbing cationic phthalocyanine photosensitizers: synthesis and evaluation of the photodynamic anticancer activity and the mode of cell death induction.

Novel zinc, magnesium, and metal-free octasubstituted phthalocyanine photosensitizers bearing [(triethylammonio)ethyl]sulfanyl substituents in the peripheral or nonperipheral positions were synthesized and investigated for their photophysical properties (ΦΔ value up to 0.91, λmax up to 750 nm) and photodynamic anticancer activity. The photodynamic treatment of 3T3, HeLa, SK-MEL-28, and HCT 116 cancer cells revealed that the magnesium complexes were not active (IC50 > 100 μM), whereas the IC50 values of the zinc complexes typically reached values in the submicromolar range with low toxicity in the dark (TC50 ≈ 1500 μM). The subcellular changes upon photodynamic treatment of the HeLa cells indicated that the studied photosensitizers induced damage primarily to the lysosomes, which was followed by a relocalization and damage to other organelles. The time-lapse morphological changes along with the flow cytometry and caspase activity measurements indicated a predominant involvement of necrosis-like cell death.

[1]  J. Tomé,et al.  Amphiphilic phthalocyanine-cyclodextrin conjugates for cancer photodynamic therapy. , 2014, Chemical communications.

[2]  T. Nyokong,et al.  Synthesis, photophysical and photochemical studies of water soluble cationic zinc phthalocyanine derivatives , 2009 .

[3]  C. Chignell,et al.  Photosensitized oxidation of 2',7'-dichlorofluorescin: singlet oxygen does not contribute to the formation of fluorescent oxidation product 2',7'-dichlorofluorescein. , 2002, Free radical biology & medicine.

[4]  David Kessel,et al.  Photodynamic therapy of cancer: An update , 2011, CA: a cancer journal for clinicians.

[5]  T. Vanden Berghe,et al.  Major cell death pathways at a glance. , 2009, Microbes and infection.

[6]  Pui-Chi Lo,et al.  A glutathione-activated phthalocyanine-based photosensitizer for photodynamic therapy. , 2014, Chemistry.

[7]  Taniyuki Furuyama,et al.  Design, synthesis, and properties of phthalocyanine complexes with main-group elements showing main absorption and fluorescence beyond 1000 nm. , 2014, Journal of the American Chemical Society.

[8]  D. Ng,et al.  A dual activatable photosensitizer toward targeted photodynamic therapy. , 2014, Journal of medicinal chemistry.

[9]  Y. Tohyama,et al.  Caspase-3 activation by lysosomal enzymes in cytochrome c-independent apoptosis in myelodysplastic syndrome-derived cell line P39. , 2001, Cancer research.

[10]  V. Ahsen,et al.  Modulation of the electronic and spectroscopic properties of Zn(II) phthalocyanines by their substitution pattern. , 2014, Dalton transactions.

[11]  Lei Duan,et al.  Preparation and in vitro photodynamic activity of amphiphilic zinc(II) phthalocyanines substituted with 2-(dimethylamino)ethylthio moieties and their N-alkylated derivatives. , 2010, Bioorganic & medicinal chemistry.

[12]  K. Roberg.  Relocalization of Cathepsin D and Cytochrome c Early in Apoptosis Revealed by Immunoelectron Microscopy , 2001, Laboratory Investigation.

[13]  A. Rosa,et al.  Pyrazinoporphyrazines with externally appended pyridine rings. 13. Structure, UV-visible spectral features, and noncovalent interaction with DNA of a positively charged binuclear (Zn(II)/Pt(II)) macrocycle with multimodal anticancer potentialities. , 2013, Inorganic chemistry.

[14]  Jinguo Huang,et al.  Synthesis and evaluation of cationic phthalocyanine derivatives as potential inhibitors of telomerase. , 2008, Bioorganic & medicinal chemistry.

[15]  Petr Zimcik,et al.  Comparison of aggregation properties and photodynamic activity of phthalocyanines and azaphthalocyanines , 2006 .

[16]  K. Berg,et al.  Assessing autophagy in the context of photodynamic therapy , 2010, Autophagy.

[17]  S. Monti,et al.  A cationic Zn(II) porphyrazine induces a stable parallel G-quadruplex conformation in human telomeric DNA. , 2011, Organic & biomolecular chemistry.

[18]  Patrizia Agostinis,et al.  Molecular effectors of multiple cell death pathways initiated by photodynamic therapy. , 2007, Biochimica et biophysica acta.

[19]  D. Brault,et al.  Cationic azaphthalocyanines bearing aliphatic tertiary amino substituents—Synthesis, singlet oxygen production and spectroscopic studies , 2006 .

[20]  Shanyong Zhou,et al.  An effective zinc phthalocyanine derivative for photodynamic antimicrobial chemotherapy , 2014 .

[21]  G. Gores,et al.  Lysosomes in cell death , 2004, Oncogene.

[22]  Z. Bayır.  Synthesis and characterization of novel soluble octa-cationic phthalocyanines , 2005 .

[23]  D. Kessel,et al.  Localization and Photodynamic Efficacy of Two Cationic Porphyrins Varying in Charge Distribution¶ , 2003 .

[24]  T. Nyokong,et al.  Synthesis and electrochemical characterisation of new tantalum (V) alkythio phthalocyanines , 2010 .

[25]  J. Castro,et al.  Apoptotic and necrotic blebs in epithelial cells display similar neck diameters but different kinase dependency , 2003, Cell Death and Differentiation.

[26]  D. Wöhrle,et al.  Un symmetrica My Substituted Benzonaphthoporphyrazines: A New Class of Cationic Photosensitizers for the Photodynamic Therapy of Cancer * , 1996 .

[27]  J. Lenčo,et al.  Structural factors influencing the intramolecular charge transfer and photoinduced electron transfer in tetrapyrazinoporphyrazines. , 2014, Physical chemistry chemical physics : PCCP.

[28]  Tebello Nyokong,et al.  Synthetic pathways to water-soluble phthalocyanines and close analogs , 2010 .

[29]  H. Perlman,et al.  Aspartic protease and caspase 3/7 activation are central for macrophage apoptosis following infection with Escherichia coli , 2007, Journal of leukocyte biology.

[30]  W. Bursch.  The autophagosomal–lysosomal compartment in programmed cell death , 2001, Cell Death and Differentiation.

[31]  M. Vicente,et al.  Syntheses and properties of a series of cationic water-soluble phthalocyanines. , 2008, Journal of medicinal chemistry.

[32]  D. Klionsky,et al.  Regulation mechanisms and signaling pathways of autophagy. , 2009, Annual review of genetics.

[33]  Min Wei,et al.  A Supermolecular Photosensitizer with Excellent Anticancer Performance in Photodynamic Therapy , 2014 .

[34]  Jun Li,et al.  Synthesis and in vitro photodynamic activity of oligomeric ethylene glycol-quinoline substituted zinc(II) phthalocyanine derivatives. , 2013, Journal of medicinal chemistry.

[35]  Elena Ranyuk,et al.  Phthalocyanine-peptide conjugates: receptor-targeting bifunctional agents for imaging and photodynamic therapy. , 2013, Journal of medicinal chemistry.

[36]  Ayşe Gül Gürek,et al.  Towards near-infrared photosensitisation: a photosensitising hydrophilic non-peripherally octasulfanyl-substituted Zn phthalocyanine , 2012 .

[37]  W. Fong,et al.  Phthalocyanine-polyamine conjugates as highly efficient photosensitizers for photodynamic therapy. , 2011, Journal of medicinal chemistry.

[38]  E. Rudolf,et al.  Water-soluble non-aggregating zinc phthalocyanine and in vitro studies for photodynamic therapy. , 2013, Chemical communications.

[39]  N. Katunuma,et al.  Participation of a cathepsin L-type protease in the activation of caspase-3. , 1999, Cell structure and function.

[40]  E. Rudolf,et al.  Synthesis, Properties and In Vitro Photodynamic Activity of Water‐soluble Azaphthalocyanines and Azanaphthalocyanines , 2010, Photochemistry and photobiology.

[41]  C Haanen,et al.  A novel assay for apoptosis. Flow cytometric detection of phosphatidylserine expression on early apoptotic cells using fluorescein labelled Annexin V. , 1995, Journal of immunological methods.

[42]  A. Růžička,et al.  Role of steric hindrance in the Newman-Kwart rearrangement and in the synthesis and photophysical properties of arylsulfanyl tetrapyrazinoporphyrazines. , 2014, The Journal of organic chemistry.

[43]  Wei Li,et al.  Induction of cell death by the lysosomotropic detergent MSDH , 2000, FEBS letters.

[44]  H. Ogata,et al.  Effect of peripheral substitution on the electronic absorption and fluorescence spectra of metal-free and zinc phthalocyanines. , 2003, Chemistry.

[45]  Y. Hagiya,et al.  Current states and future views in photodynamic therapy , 2011 .

[46]  S. Makhseed,et al.  Heavy metal effects on physicochemical properties of non-aggregated azaphthalocyanine derivatives , 2012 .

[47]  K. Lang,et al.  Magnesium azaphthalocyanines: an emerging family of excellent red-emitting fluorophores. , 2012, Inorganic chemistry.