Physiologically Relevant Concentrations of NaCl and KCl Increase DNA Photocleavage by an N-Substituted 9-Aminomethylanthracene Dye

Abstract

This paper describes the synthesis of a new 9-aminomethylanthracene dye N-substituted with a pyridinylpolyamine side chain (4). The effects of NaCl and KCl on anthracene/DNA interactions were then studied, with the goal of simulating the conditions of high ionic strength that a DNA photosensitizer might encounter in the cell nucleus (~150 mM of NaCl and 260 mM of KCl). As exemplified by methylene blue (5), the expected effect of increasing ionic strength is to decrease DNA binding and photocleavage yields. In contrast, the addition of 150 mM of NaCl in combination with 260 mM of KCl to photocleavage reactions containing micromolar concentrations of 4 triggers the conversion of supercoiled, nicked, and linear forms of pUC19 plasmid into a highly degraded band of DNA fragments (350 nm hν, pH 7.0). Circular dichroism spectra point to a correlation between salt-induced unwinding of the DNA helix and the increase in DNA photocleavage yields. The results of circular dichroism, UV-vis absorption, fluorescence emission, thermal denaturation, and photocleavage inhibition experiments suggest that the combination of salts causes a change in the DNA binding mode of 4 from intercalation to an external interaction. This in turn leads to an increase in the anthracene-sensitized production of DNA-damaging reactive oxygen species.

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“…This result is very similar with the previous reports [44,45]. These results of pH and ionic strength stability further highlight that the PQDs may be completely tolerant to intracellular and in vivo environments, where the ionic concentration is known to be less than 150 mM [46]. …”

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“…The time dependent stability of the composites to conditions of ionic strength (100 to 500 mM NaCl) was monitored by UVvisible spectroscopy. The 4.5 nm and 15 nm composites were found to be stable up to 350 mM NaCl, which is almost twice the highest physiological NaCl concentration, 17 with no evidence for aggregation observed over 24 h and 80 % retained at 500 mM, see Fig. 4a and Fig.…”

Aminomethylanthracene Dyes as High‐Ionic‐Strength DNA‐Photocleaving Agents: Two Rings are Better than One

“…The use of excitation wavelengths that extend into the near‐infrared range is particularly important due to the greater tissue penetration depth afforded by low light absorption in this region by biogenic chromophores . Towards these ends, our group has been exploring the effects of elevated NaCl and KCl concentrations on the photodynamic action of various ultra‐violet, visible, and long‐wavelength absorbing DNA photosensitizing agents ,. As expected, the addition of salts inhibited DNA photocleavage in the case of most of the chromophores that we studied.…”

“…If the photosensitizer is positively charged, it can be displaced by a mass action effect in which the cations effectively compete for negatively charged binding sites on the DNA duplex . As exemplified by many DNA photosensitizers including those based on meso substituted porphyrins, cyanine dyes, 9,10‐bis(aminomethyl)anthracene, bis‐proflavine, and methylene blue, salt‐induced reductions in ligand binding affinity decrease levels of photosensitizer‐induced DNA damage.…”