Effects of the number and position of the substituents on the in vitro photodynamic activities of glucosylated zinc(ii) phthalocyanines

A series of mono-β-, di-α- and di-β-substituted phthalonitriles which contain one or two tetraethylene-glycol-linked 1,2:5,6-di-O-isopropylidene-α-d-glucofuranose unit(s) were prepared by typical substitution reactions. These precursors underwent self-cyclisation or mixed-cyclisation with an excess of unsubstituted phthalonitrile in the presence of Zn(OAc)₂·2H₂O and DBU to give the corresponding zinc(ii) phthalocyanines with 1, 2 or 4 glucosylated substituent(s). For the di-α- and tetra-β-glucosylated analogues, removal of the isopropylidene groups was also performed by the treatment with trifluoroacetic acid and water to give the corresponding water-soluble deprotected glucosylated derivatives. All of these glucoconjugated phthalocyanines were fully characterised with various spectroscopic methods and studied for their photophysical properties and in vitro photodynamic activities against HT29 human colon adenocarcinoma and HepG2 human hepatocarcinoma cells. The tetra-β-glucosylated phthalocyanines ZnPc(β-PGlu)₄ (4) and ZnPc(β-Glu)₄ (5) were found to be essentially non-cytotoxic. By contrast, the mono- and di-glucosylated analogues ZnPc(β-PGlu) (7), ZnPc(α-PGlu)₂ (11), ZnPc(α-Glu)₂ (12) and ZnPc(β-PGlu)₂ (20) exhibited substantial photocytotoxicity. The isopropylidene-protected di-α-substituted derivative 11 was particularly potent, having IC₅₀ values as low as 0.03 μM. The different photodynamic activities of these compounds can be attributed to their different extent of cellular uptake and aggregation tendency in the biological media, which greatly affect their singlet oxygen generation efficiency. © 2009 The Royal Society of Chemistry.