Role of Secondary Structure and Time‐Dependent Binding on Disruption of Phthalocyanine Aggregates by Guanine‐Rich Nucleic Acids

Phthalocyanines are versatile photodynamic therapy agents whose biological activity depends on their aggregation state, which is expected to be influenced by binding to biomolecules. Here, guanine-rich nucleic acid binding of a water-soluble cationic, regiopure C_4h zinc phthalocyanine bearing four triethylene glycol methyl ether and four N-methyl-4-pyridinium substituents (1) is reported. In contrast to double-stranded DNA, guanine systems GpG, (GG)₁₀, poly(G) and quadruplex DNA are shown to effectively disrupt phthalocyanine aggregates in buffered solution. This process is accompanied by evolution of the Q-band absorbance and enhanced emission. Increasing the sequence length from GpG to (GG)₁₀ increases the binding and confirms the importance of multiple binding interactions. Enhanced binding in the presence of KCl suggests the importance of nucleobase hydrogen-bonded mosaics in phthalocyanine binding. Notably, the (GT)₁₀ sequence is even more effective than quadruplex and pure guanine systems at disrupting the aggregates of 1. Significant time-dependent binding of 1 with poly(G) reveals biexponential binding over minutes and hours, which is linked to local conformations of poly(G) that accommodate monomers of 1 over time. The study highlights the ability of biomacromolecules to disrupt phthalocyanines aggregates over time, which is an important consideration when rationalizing photoactivity of photosensitizers in-vivo.