Highly photocytotoxic 1,4-dipegylated zinc(ii) phthalocyanines. Effects of the chain length on the in vitro photodynamic activities

Abstract

A new series of 1,4-dipegylated zinc(II) phthalocyanines have been synthesised and spectroscopically characterised. The derivatives ZnPc[O(CH₂CH₂O)_nMe]₂ (n = 2, 4, ca. 12) have been prepared by mixed cyclisation of the corresponding disubstituted phthalonitriles with an excess of unsubstituted phthalonitrile in the presence of Zn(OAc)₂·2H₂O and 1,8-diazabicyclo[5.4.0]undec-7-ene. The other two analogues ZnPc[O(CH₂CH₂O)_nMe]₂ (n = 6, 8) have been prepared by chain elongation reaction of ZnPc[O(CH₂CH₂O)₄H]₂. These macrocycles are highly soluble and remain non-aggregated in DMF as shown by the sharp Q-band absorption. Compared with the unsubstituted zinc(II) phthalocyanine, these di-α-substituted analogues have a red-shifted Q band (at 689 vs. 670 nm) and exhibit a relatively weaker fluorescence emission and a higher efficiency at generating singlet oxygen. Upon illumination, these compounds are highly cytotoxic toward HT29 human colorectal carcinoma and HepG2 human hepatocarcinoma cells. The compounds with medium-length substituents are particularly potent, having IC₅₀ values as low as 0.02 µM. The high photodynamic activity of these compounds can be attributed to their high cellular uptake and low aggregation tendency in the biological media, which promote the generation of reactive oxygen species inside the cells. The effects of the chain length on the aggregation behaviour, photophysical properties, cellular uptake and in vitro photodynamic activities of this series of compounds have also been examined.