Zbynek Musil

Synthesis and comparison of photodynamic activity of alkylheteroatom substituted azaphthalocyanines

Abstract Optimal reaction conditions were developed for synthesis of octakis(butylamino), octakis(butylsulfanyl) and octakis(butoxy) azaphthalocyanines (AzaPc’s) with central metal Mg, Zn and metal-free. Their photodynamic activity was measured and compared as a dye-sensitised photooxidation of 1,3-diphenylisobenzofurane (DPBF). Compounds with alkylamino substituent are very poor producers of the singlet oxygen and therefore not suitable as sensitizers for photodynamic therapy (PDT). On the other hand, compounds with alkylsulfanyl and alkoxy substituents possess very good photodynamic activity and are suitable for PDT.

Synthesis and singlet oxygen production of azaphthalocyanines bearing functional derivatives of carboxylic acid

New metal-free, magnesium and zinc azaphthalocyanines (AzaPc) were prepared from 6-(3-tert-butylsulfany1-5,6-dicyanopyrazine-2-ylamino)hexanoic acid and its butylester and N,N-diethylamide. Their singlet oxygen production was measured by a dye-sensitized photooxidation of 1,3-diphenylisobenzofuran (DPBF) and ΦΔ values were calculated. It was found that the presence of carboxylic acid in the structure of AzaPc decreases their singlet oxygen production. Singlet oxygen activity of the newly prepared compounds (containing mixed alkylamino and alkylsulfanyl peripheral substituents) lies between purely alkylsulfanyl and alkylamino derivatives of AzaPc. This fact further supports previously proposed structure-activity relationships, where alkylsulfanyl derivatives belong to the best singlet oxygen producers while the presence of alkylamino substituents in the structure rapidly decreases their photodynamic properties.

Protonation and deprotonation of nitrogens in tetrapyrazino-porphyrazine macrocycles

Acid-base properties of zinc phthalocyanine (Pc) and zinc and metal-free tetrapyrazinoporphyrazine (TPPz) macrocycles with eight peripheral tert-butylsulfanyl or diethylamino substituents are investigated in this work by means of UV-vis spectroscopy. The Pc and TPPz are protonated on the azomethine nitrogens in acidic media. The monoprotonated form was found using trifluoroacetic acid and lower amounts of H2SO4. The higher concentrations of sulfuric acid lead to the appearance of the diprotonated form, and possibly also the triprotonated form in the case of Pc. It was found that the pyrazine nitrogens in the TPPz macrocycle undergo protonation at approx. 20-30% of sulfuric acid in THF solution. TPPz with diethylamino peripheral substituents are protonated preferably on these peripheral tertiary amines. Metal-free TPPz can readily lose the hydrogens on central nitrogens in strong basic media (e.g. tetrabutylammonium hydroxide) to directly form a dianion, with no presence of important or detectable amounts of the monoanion species. A different form of deprotonated macrocycle was observed in pyridine suggesting the formation of only a proton transfer complex, not a true ionic form. The acidity of the central nitrogens is dependent on the strength of the electron-donating effect of peripheral substituents. TPPz with tert-butylsulfanyl substituents is a stronger acid than the one with diethylamino substituents.

Influence of aggregation on interaction of lipophilic, water-insoluble azaphthalocyanines with DOPC vesicles.

Dioleoylphosphatidylcholine unilamellar vesicles made by extrusion technique (LUVETs) were studied as the delivery system for lipophilic water‐insoluble potential photosensitizers for photodynamic therapy (PDT). Two azaphthalocyanines (AzaPcs) with hydrophobic substituents only and two also possessing two charged amino groups were introduced into the study. All compounds are insoluble in water and form aggregates in PBS with tetrahydrofuran as cosolvent. The size of these aggregates depends on the concentration of AzaPc in solution. AzaPcs with tert‐butyl substituents were found to be incorporated into the lipid bilayer of vesicles in the monomeric form even at high concentrations. The stability of LUVETs with incorporated AzaPc was excellent for at least 4 weeks. Therefore, they are suitable for use as a delivery system for these water‐insoluble photosensitizers. Very low amount of AzaPc with n‐octyl substituents incorporated into LUVETs due to its stronger self‐aggregation. Values of binding constants determined for all AzaPcs showed inverse order than expected from their lipophilicities. However, the binding constants followed the order of the strength of aggregation forces. Aggregation of AzaPcs in water medium plays a very important role in the interaction of AzaPcs with LUVETs.