New amphiphilic silicon(IV) phthalocyanines as efficient photosensitizers for photodynamic therapy: synthesis, photophysical properties, and in vitro photodynamic activities

A novel series of silicon(IV) phthalocyanines substituted axially with one or two 1,3-bis(dimethylamino)-2-propoxy group(s) have been prepared by ligand substitution and alkoxy exchange reactions. Two dicationic and tetracationic phthalocyanines have also been prepared by methylation of two of these compounds. The nonionic phthalocyanines are essentially nonaggregated in common organic solvents and show a weak fluorescence emission, while the methylated derivatives are also nonaggregated, even in aqueous media, and exhibit a strong fluorescence emission. These new phthalocyanines, in particular the unsymmetrical and amphiphilic analogues, are highly potent against HepG2 human hepatocarcinoma cells and J774 mouse macrophage cells with IC50 values down to 0.02 microM. The photodynamic activities are related to the cellular uptake and the efficiency to generate singlet oxygen. A higher positive charge at the phthalocyanine hinders the uptake, reflected by the lower intracellular fluorescence intensity. Fluorescence microscopic studies have also revealed that the unsymmetrical phthalocyanine SiPc[C3H5(NMe2)2O](OMe) (4) has a high and selective affinity to the mitochondria of HepG2 cells.     

Synthesis,Supramolecular Behavior,and In Vitro Photodynamic Activities of Novel Zinc(II) Phthalocyanines “Side‐strapped” with Crown Ether Bridges

Two new tetra‐ or di‐α‐substituted zinc(II) phthalocyanines 5 and 6 have been prepared through a “side‐strapped” method. In the molecules, the adjacent benzene rings of the phthalocyanine core are linked at α‐position through a triethylene glycol bridge to form a hybrid aza‐/oxa‐crown ether. The tetra‐α‐substituted phthalocyanine 5 shows an eclipsed self‐assembly property in CH₂Cl₂ and the effect on the di‐α‐substituted analogue 6 is significantly weakened. Furthermore, the crown ethers of these compounds can selectively complex with Fe³⁺ or Cu²⁺ ion in DMF, leading to formation of J‐aggregated nano‐assemblies, which can be disaggregated in the presence of some organic or inorganic ligands, such as triethylamine, tetramethylethylenediamine, CH₃COO^?, or OH^?. In addition, both compounds are efficient singlet oxygen generators with the singlet oxygen quantum yields (Φ_Δ) of 0.54‐0.74 in DMF relative to unsubstituted zinc(II) phthalocyanine (Φ_Δ=0.56). They exhibit photodynamic activities toward HepG2 human hepatocarcinoma cells, but the compound 6 , which has more than 40‐fold lower IC₅₀ value (0.08 μM ) compared to the analogue 5 (IC₅₀=3.31 μM ), shows remarkablely higher in vitro photocytotoxicity due to its significantly higher cellular uptake and singlet oxygen generation efficiency. The results suggest that these compounds can serve as promising multifunctional materials both in (opto)electronic field and photodynamic therapy.     

Synthesis and properties of axially-phenoxycyclotriphosphazenyl substituted silicon phthalocyanine

An hydroxyl substituted hexa(phenoxy)cyclotriphosphazene (3) is reacted with silicon phthalocyanine (4), SiPc(Cl)₂, to give an axially-disubstituted phenoxycyclotriphosphazenyl silicon phthalocyanine (5). In this study, an axially phosphazene substituted phthalocyanine complex synthesized at the first time. Newly synthesized silicon phthalocyanine complex has been fully characterized by elemental analysis, ESI mass spectrometry, FT-IR, ¹H, ¹³C and ³¹P NMR spectroscopy. Photophysical (fluorescence quantum yield and lifetime) and photochemical (singlet oxygen generation and photodegradation quantum yield) properties of complex 5 are reported in DMSO. The fluorescence quenching behaviour of this complex by 1,4-benzoquinone (BQ) is also reported in DMSO.     

Synthesis,photophysical and photochemical properties of tetra- and octa-substituted gallium and indium phthalocyanines

The synthesis, photophysical and photochemical properties of the tetra- and octa-[4-(benzyloxyphenoxy)] substituted gallium(III) and indium(III) phthalocyanines are reported for the first time. The new compounds have been characterized by elemental analysis, IR, ¹H NMR spectroscopy and electronic spectroscopy. General trends are described for quantum yields of photodegredation, fluorescence quantum yields and lifetimes, triplet lifetimes and triplet quantum yields as well as singlet oxygen quantum yields of these compounds in dimethylsulfoxide (DMSO). Substituted indium phthalocyanine complexes (7b–9b) showed much higher quantum yields of triplet state and shorter triplet lifetimes, compared to the substituted GaPc derivatives due to enhanced intersystem crossing (ISC) in the former. The gallium and indium phthalocyanine complexes showed phototransformation during laser irradiation due to ring reduction. The singlet oxygen quantum yields (Φ_Δ), which give an indication of the potential of the complexes as photosensitizers in applications where singlet oxygen is required (Type II mechanism) ranged from 0.51 to 0.94. Thus, these complexes show potential as photodynamic therapy of cancer.     

A novel lutetium(III) acetate phthalocyanine directly substituted with N,N’-dimethylaminophenyl groups via CC bonds and its water-soluble derivative for photodynamic therapy

In this study, the novel 4-(N,N′-dimethylamino)phenyl substituted lutetium(III) acetate phthalocyanine (2) and its quaternized derivative (3) were synthesized via a Suzuki-Miyaura coupling reaction between tetrakis(iodo) lutetium(III)acetate phthalocyanine (1) and 4-(N,N-dimethylamino)phenylboronic acid, and subsequent quaternization using dimethyl sulfate, respectively. The obtained phthalocyanine 3 exhibited excellent solubility in water which is important for photodynamic therapy applications. Photophysical properties such as fluorescence quantum yield and fluorescence lifetime, and photochemical properties such as singlet oxygen generation and photostability were investigated to determine their suitability for photodynamic therapy. The lutetium(III) phthalocyanines, especially quaternized derivative 3, showed promising properties as potential photosensitizers for the treatment of cancer, producing higher singlet oxygen (Φ_Δ = 0.59) than motexafin lutetium (Φ_Δ = 0.31) which is a clinically used lutetium texaphyrin photosensitizer.     

Synthesis,characterization, and determination of photophysicochemical properties of peripheral and nonperipheral tetra‐7‐oxy‐3,4‐dimethylcoumarin substituted zinc,indium phthalocyanines

The photochemical and photophysical properties of peripheral and nonperipheral zinc and indium phthalocyanines containing 7‐oxy‐3,4‐dimethylcoumarin synthesized were investigated in this study. 7‐Hydroxy‐3,4‐dimethylcoumarin ( 1 ) was synthesized via Pechmann condensation reaction and then the phthalonitrile derivatives [4‐(7‐oxy‐3,4‐dimethylcoumarino)phthalonitrile ( 2 ) and 3‐(7‐oxy‐3,4‐dimethylcoumarino)phthalonitrile ( 3 )] were synthesized by nucleophilic aromatic substitution. Phthalocyanine compounds containing coumarin units on peripheral ( 4 and 5 ) and nonperipheral ( 6 and 7 ) positions were prepared via cyclotetramerization of phthalonitrile compounds. All compounds' characterizations were performed by spectroscopic methods and elemental analysis. The phthalocyanine derivatives' ( 4–7 ) photochemical and photophysical properties were studied in DMF. The photophysical (fluorescence quantum yields and lifetimes) and photochemical (singlet oxygen and photodegradation quantum yields) properties of these novel phthalocyanines ( 4 – 7 ) were studied in DMF. They produced good singlet oxygen (e.g., Φ_Δ = 0.93 for 7 ) and showed appropriate photodegradation (in the order of 10^?5), which is very important for photodynamic therapy applications.     

Effect of Axial Ligands on the Molecular Configurations,Stability, Reactivity,and Photodynamic Activities of Silicon Phthalocyanines

To demonstrate the effect of axial ligands on the structure–activity relationship, a series of axially substituted silicon phthalocyanines (SiPcs) have been synthesized with changes to the axial ligands. The reactivity of the axial ligand upon shielding by the phthalocyanine ring current, along with their stability, photophysical, and photodynamic therapy (PDT) activities were compared and evaluated for the first time. As revealed by single‐crystal XRD analysis, rotation of the axial ? OMe ligands was observed in SiPc 3 , which resulted in two molecular configurations coexisting synchronously in both the solid and solution states and causing a split of the phthalocyanine α protons in the ¹H NMR spectra that is significantly different from all SiPcs reported so far. The remarkable photostability, good singlet oxygen quantum yield, and efficient in vitro photodynamic activity synergistically show that compound 3 is one of the most promising photosensitizers for PDT.     

萘酞菁硅配合物的合成及激发态性质研究

本文合成了3种轴向配位的萘酞菁硅配合物(NcSiR₂，R=Cl、OH、OCH₃)，研究了3种萘酞菁配合物激发态性质，研究结果表明，随着轴向取代基推电子能力的逐渐增强，激发单线态寿命和激发三线态寿命逐渐缩短，产生单线态氧的能力逐渐下降。     

Highly photostable silicon(IV) phthalocyanines containing adamantane moieties: synthesis, structure, and properties

Two new axially disubstituted silicon(IV) phthalocyanines 1 and 2 have been synthesized by treating silicon phthalocyanine dichloride with 1-adamantanemethanol or 1-adamamtaneethanol, respectively. The crystal structure of compound 2 has been characterized by X-ray diffraction analysis. Both compounds are efficient singlet-oxygen generator with a quantum yield of 0.40-0.43. With two rigid bulky adamantane moieties at the axial positions, these phthalocyanines not only are essentially non-aggregated in common solvents, but also exhibit a high photostability. They are about 100 times more stable than zinc phthalocyanine under the same irradiation conditions. With the goal of enhancing the biocompatibilities, interactions and conjugations of these two compounds with bovine serum albumin have also been investigated.     

Photodynamic Mechanisms induced by a Combination of Hypericin and a Chlorin Based‐Photosensitizer in Head and Neck Squamous Cell Carcinoma Cells

The aim of this study was to elucidate photodynamic therapy (PDT) effects mediated by hypericin and a liposomal meso‐tetrahydroxyphenyl chlorin (mTHPC) derivative, with focus on their 1:1 mixture, on head and neck squamous cell carcinoma cell lines. Absorption, excitation and photobleaching were monitored using fluorescence spectrometry, showing the same spectral patterns for the mixture as measured for single photosensitizers. In the mixture mTHPC showed a prolonged photo‐stability. Singlet oxygen yield for light‐activated mTHPC was Φ_Δ = 0.66, for hypericin Φ_Δ = 0.25 and for the mixture Φ_Δ = ~0.4. A linear increase of singlet oxygen yield for mTHPC and the mixture was found, whereas hypericin achieved saturation after 35 min. Reactive oxygen species fluorescence was only visible after hypericin and mixture‐induced PDT. Cell viability was also more affected with these two treatment options under the selected conditions. Examination of death pathways showed that hypericin‐mediated cell death was apoptotic, with mTHPC necrotic and the 1:1 mixture showed features of both. Changes in gene expression after PDT indicated strong up‐regulation of selected heat‐shock proteins. The application of photosensitizer mixtures with the features of reduced dark toxicity and combined apoptotic and necrotic cell death may be beneficial in clinical PDT. This will be the focus of our future investigations.     

二-吡啶氧基-轴向取代-四-α-(3-戊氧基)锡(IV)酞菁的合成与表征

以3-硝基邻苯二甲腈为起始原料, 与正戊醇反应合成3-戊氧基邻苯二甲腈(1), 然后在高温溶剂1-氯萘中经缩聚反应合成二氯-轴向取代-四-α-(3-戊氧基)锡酞菁(2), 2进一步与2-羟基吡啶在N,N-二甲基甲酰胺中合成二-吡啶氧基-轴向取代-四-α-(3-戊氧基)锡酞菁配合物3, 同时对相关化合物分别进行了元素分析, IR, ¹H NMR, UV/Vis, 荧光和质谱表征.     

Synthesis, characterization and comparative studies on the photophysical and photochemical properties of metal-free and zinc(II) phthalocyanines with phenyloxyacetic acid functionalities

The synthesis and characterization of new peripherally and non-peripherally tetra-substituted metal-free and zinc(II) phthalocyanines with 2-, 3- and 4-phenyloxyacetic acid functionalities are described for the first time in this study. The new compounds have been characterized by elemental analysis, FT-IR, UV-Vis, MALDI-TOF and ¹H-NMR spectra. Photodegradation, singlet oxygen and fluorescence quantum yields, and fluorescence lifetimes of these compounds are studied in dimethylformamide (DMF). The influence of the substituent position on the phthalocyanine framework (non-peripherally or peripherally), central metal ion (metal-free or zinc) and the position of the COOH group (2-, 3- or 4-position on the phenyloxyacetic acid) on the spectroscopic, photophysical and photochemical properties have been investigated. Non-peripherally zinc(II) phthalocyanines (1b and 2b) and peripherally zinc(II) phthalocyanine (4b) gave good singlet oxygen quantum yields (Φ_Δ) (0.37, 0.39 and 0.38, respectively) which indicate the potential of the complexes as photosensitizers in applications of PDT.     

Synthesis and photophysical properties of silicon phthalocyanines with axial siloxy ligands bearing alkylamine termini

Eleven silicon phthalocyanines which can be grouped into two homologous series [SiPc[OSi(CH3)2(CH2)(n)N(CH3)2]2, n = 1-6 (series 1), and SiPc[OSi(CH3)2(CH2)3N((CH2)(n)H)2]2, n = 1-6 (series 2)] as well as an analogous phthalocyanine, SiPc[OSi(CH3)2(CH2)3NH2]2, were synthesized. The ground state absorption spectra, the triplet state dynamics, and singlet oxygen quantum yields of 10 of these phthalocyanines were measured. All compounds displayed similar ground state absorption spectral properties in dimethylformamide solution with single Q band maxima at 668 +/- 2 nm and B band maxima at 352 +/- 1 nm. Photoexcitation of all compounds in the B bands generated the optical absorptions of the triplet states which decayed with lifetimes in the hundreds of microseconds region. Oxygen quenching bimolecular rate constants near 2 x 10(9) M(-1) s(-1) were measured, indicating that energy transfer to oxygen was exergonic. Singlet oxygen quantum yields, phi(delta), were measured, and those phthalocyanines in which the axial ligands are terminated by dimethylamine residues at the end of alkyl chains having four or more methylene links exhibited yields near > or = 0.35. Others gave singlet oxygen quantum yields near 0.2, and still others showed singlet oxygen yields of <0.1. The reduced singlet oxygen yields are probably caused by a charge transfer quenching of the 1pi,pi* state of the phthalocyanine by interaction with the lone pair electrons on the nitrogen atoms of the amine termini. In some cases, these can approach and interact with the electronically excited pi-framework, owing to diffusive motions of the flexible oligo-methylene tether.     

Enhancement of singlet oxygen generation based on incorporation of oxoporphyrinogen (OxP) into microporous solids

Singlet oxygen, ¹O₂, generating compounds are highly useful for photodynamic therapy or organic oxidative transformations. In this work, the synthesis and photochemical performances for singlet oxygen generation of a range of oxoporphyrinogen-containing porous coordination polymers (OxP-PCPs) are reported. Oxoporphyrinogens, a previously unreported class of singlet oxygen generators derived from the oxidation of the antioxidant-substituted porphyrin tetrakis(3,5-di-tert-butyl-4-hydroxyphenyl)porphyrin, were converted to molecular tectons by the introduction of oligophenylene-carboxylate linkers and incorporated into porous coordination polymers using well-known oxo-Zr(IV)₆ cluster chemistry. Their structures and textural properties were analyzed revealing substantial surface areas up to 650 m² g^?1 for the optimum linker length (biphenylyl). The oxoporphyrinogen precursors exhibit good quantum yields of singlet oxygen generation (up to Φ = 0.37), and a high level of activity is maintained in the resulting coordination polymers, which appear to be superior for singlet oxygen generation to the precursors and to a reported reference material. These OxP-PCP materials were applied for the selective oxidation of sulfides to sulfoxides. This work demonstrates that the excellent singlet oxygen generator oxoporphyrinogens can be successfully incorporated as porous solids and conveniently applied in heterogeneous oxidative transformations.     

Phthalocyanines and related macrocycles for multi-electron transfer in catalysis,photochemistry and photoelectrochemistry

At different phthalocyanines and related macrocycles it is shown that one-step, multi-electron transfer and one-step, multi-change of oxidation states occur. At first, the catalytic oxidations of thiols and sulfide in the presence of different Co(II)phthalocyanines are discussed. Thiolates are oxidized to disulfides via a two-electron transfer whereas the reduction of O₂ occurs via a two- or four-electron transfer to H₂O₂ or H₂O. Zn(II) and Al(III)phthalocyanines are efficient sensitizers for the conversion of triplet to singlet dioxygen under illumination with visible light. In the presence of thiolates or sulfides an efficient photo-oxidation to sulfonic acids or sulfate is observed. The oxidation state of sulfur changes from ?2 to +4 or +6, respectively. This process of singlet oxygen reactions finds application in the photodynamic therapy of cancer. The unsubstituted zinc(II)-phthalocyanine as p-type molecular semiconductor can efficienfly reduce O₂ in photoelectrochemical experiments whereas zinc(II)phthalocyanines with electronwithdrawing groups as n-type conductors are active in the photoelectrochemical oxidation of thiols. All processes include multi-electron transfer. The electrocatalytic reduction of CO₂ is investigated at electrodes modified with Co(II)phthalocyanine. In particular, the phthalocyanine in a polyvinylpyridine membrane is active, so the CO₂ is reduced to CO by multi-electron transfer. In addition, two photon excitations of a Mg(II)phthalocyanine are presented and some examples are reviewed.     

Polymeric complex micelle loaded with axially substituted silicon(Ⅳ) phthalocyanine

A novel axially substituted silicon(Ⅳ)phthalocyanine,namely di-pyridyloxy axially substituted silicon(Ⅳ)phthalocyanine 2 was synthesized and characterized by UV/vis,IR,elemental analysis,MS as well as ~1H NMR spectroscopy.Hydrophobic 2 was encapsulated by amphiphilic triblock copolymer poly[N~ε-(benzyloxycarbonyl-lysine]-poly(ethylene glycol)-poly[N~ε-(benzyl oxycarbonyl) (PLL(Z)-b-PEG-b-PLL(Z))to form hydrophobic 2-loaded polymeric complex micelle(PIC)(2-loaded PIC).Atom force microscopy(AFM)image showe...     

Phthalocyanines prepared from 4-chloro-/4-hexylthio-5-(4-phenyloxyacetic acid)phthalonitriles and functionalization of the related phthalocyanines with hydroxymethylferrocene

The phthalonitrile derivative chosen for the synthesis of substituted phthalocyanines [M: 2H, Zn(II), Co(II)] with four chloro and four phenyloxyacetic acid substituents on the periphery is 4-chloro-5-(4-phenyloxyacetic acid)phthalonitrile. The sodium salt of carboxyl substituted zinc phthalocyanine is good soluble in water. Further reactions of zinc and cobalt phthalocyanines bearing phenyloxyacetic acid with thionylchloride gave the corresponding acylchlorides. This functional group reacted with hydroxymethylferrocene in dry DMF to obtain ferrocenyl substituted phthalocyanines. Also chloro substituent in new phthalonitrile was substituted with hexylsulfanyl substituent and its cyclotetramerization in the presence of Zn(AcO)₂·2H₂O and 2-(dimethylamino)ethanol resulted with zinc phthalocyanine. The compounds have been characterized by elemental analysis, MALDI-TOF mass, FT-IR, ¹H NMR, UV-Vis and fluorescence data. Aggregations properties of phthalocyanines were investigated at different concentrations in tetrahydrofuran, dimethylformamide, dimethylsulfoxide, water, and water/ethanol mixture. Also fluorescence spectral properties are reported.     

不同代硝基芳基苄醚树枝配体轴向取代硅(Ⅳ)酞菁光物理性质的比较

在二氯硅酞菁轴向位置引入硝基芳基苄醚树枝配体是一种减少酞菁配合物聚集体形成,提高其光动力活性的有效方法。本文采用UV/Vis、稳态和瞬态荧光光谱法比较了1-3代硝基芳基苄醚树枝配体轴向取代硅(Ⅳ)酞菁的光物理性质。研究结果表明,随着轴向树枝配体代数的增加,Q带最大吸收峰强度增大,酞菁核荧光强度增强,荧光量子产率降低,荧光寿命增长。研究结果将为开发轴向取代硅(Ⅳ)酞菁配合物作为新型光敏剂提供重要的理论依据。     

Axially phenoxy-derivative disubstituted phthalocyanine: synthesis,characterization and photophysical properties

Research on Chemical Intermediates - We report the highly soluble axially disubstituted 4-(methoxymethyl) phenol silicon (IV) (1) phthalocyanine which was synthesized by the reaction of silicon...     

Synthesis, photophysical and photochemical properties of substituted zinc phthalocyanines

The synthesis, photophysical and photochemical properties of the 4-({3,4,5-tris-[2-(2-ethoxyethoxy)ethyloxy]benzyl}oxy) and 4-({3,4,5-tris-[2-(2-ethoxyethoxy)ethyloxy]benzyl}thio) zinc(ii) phthalocyanines are reported for the first time. The new compounds have been characterized by elemental analysis, IR, (1)H and (13)C NMR spectroscopy, electronic spectroscopy and mass spectra. General trends are described for photodegradation, singlet oxygen, fluorescence and triplet excited state quantum yields, and triplet state and fluorescence lifetimes of these compounds in dimethylsulfoxide (DMSO). The fluorescence of the complexes was quenched by benzoquinone (BQ). The effects of the substitution on the photophysical and photochemical parameters of the zinc(II) phthalocyanines (6, 7 and 8) are also reported. Photophysical and photochemical properties of phthalocyanine complexes are very useful for PDT applications. The substituted Zn(II) phthalocyanines showed high triplet and singlet oxygen quantum yields. High singlet oxygen quantum yields are very important for Type II mechanism. Thus, these complexes show potential as Type II photosensitizers.