A water-soluble cationic porphyrin showing pH-dependent G-quadruplex recognition specificity and DNA photocleavage activity

Abstract

G-quadruplex ligands lacking recognition specificity against duplex DNA are considered to be unsatisfactory due to non-specific cytotoxicity. However, a G-quadruplex ligand, which can interact with duplex DNA under acidic conditions but not under neutral conditions, may be highly desirable for cancer therapy because it can kill cancer cells with high efficiency, with very few side effects on healthy cells. Herein, a new water-soluble cationic porphyrin derivative 5,10,15,20-tetra-{4-[2-(1-methyl-1-piperidinyl)ethoxy]phenyl}porphyrin (i-TMPipEOPP) was synthesized and characterized, and its interactions with G-quadruplex and duplex DNA were compared using ultraviolet visible absorption, fluorescence, circular dichroism and gel electrophoresis assays. The results show that i-TMPipEOPP has pH-dependent G-quadruplex recognition specificity. That is, it can interact with both G-quadruplex and duplex DNA under acidic conditions, but can only interact with G-quadruplex under neutral conditions. Because of the synergy between π–π stacking and electrostatic interactions, i-TMPipEOPP interacts with G-quadruplex with higher binding affinity under acidic conditions than under neutral conditions in which only π–π stacking interactions occur. More interestingly, i-TMPipEOPP can mediate pH-dependent DNA photocleavage of duplex DNA and shows pH-dependent phototoxicity to cells. These findings suggest that i-TMPipEOPP may be developed as a promising photodynamic therapy drug showing higher cytotoxicity towards acidic tumor cells than neutral healthy cells.