Preferential DNA photocleavage potency of Zn(II) over Ni(II) derivatives of carboxymethyl tetracationic porphyrin: the role of the mode of binding to DNA

Abstract

The porphyrin-based photosensitizers capable of binding to DNA are perspective drug candidates. Here we report the interactions with calf thymus DNA of 5,10,15,20-tetrakis(N-carboxymethyl-4-pyridinium)porphyrin (P1) and its derivatives containing Zn(II) or Ni(II) in the coordination sphere. These interactions were studied with absorption and circular dichroism spectroscopy. NiP1 and ZnP1 formed different types of complexes with DNA. NiP1 intercalated into the double helix, whereas ZnP1 bound the DNA groove. Compound P1 displayed both binding modes. The ZnP1-DNA binding constant was approximately three times smaller than the respective values for P1-DNA and NiP1-DNA complexes. Light induced degradation of the reactive oxygen species (ROS) trap 1,3-diphenylisobenzofuran in the presence of P1 and its metal derivatives revealed that NiP1 was a weaker photooxidative agent, whereas P1 and ZnP1 generated ROS to similar extents. Nevertheless, the DNA photodamaging effect of ZnP1 was the most pronounced. Illumination of the supercoiled plasmid caused single-strand DNA photocleavage in the presence of P1 and ZnP1; double strand breaks were detectable with micromolar concentrations of ZnP1. The concentration of ZnP1 required for plasmid photonicking was two times smaller than that of P1 and ~20 times lower than that for NiP1. Thus, the modes of P1, NiP1 and ZnP1 binding to DNA determine the differential photodamaging potency of these porphyrins. A greater accessibility to the solvent of the groove binder ZnP1, compared to the shielded intercalator NiP1 and the intercalated P1 molecules, allows for an efficient local generation of ROS followed by DNA photocleavage.

Mechanisms of Phototoxic Effects of Cationic Porphyrins on Human Cells In Vitro

“…The P4 was TMPyP4 (Sigma Aldrich, Saint Louis, MO, USA). The compounds ZnP4, P1, and ZnP1 were obtained as described previously [ 8 , 21 , 22 ]. Stock solutions with a porphyrin concentration of 10 mM in DMSO (PanEko, Moscow, Russia) were used.…”

“…However, the introduction of zinc enhances the photochemical effect on DNA. It was previously shown that the introduction of zinc into tetracarboxymethyl-substituted pyridyl porphyrin leads to selective interaction and photooxidation of the telomeric sequence DNA [ 8 , 9 ].…”

Light-induced oxidation of the telomeric G4 DNA in complex with Zn(II) tetracarboxymethyl porphyrin

“…The concentration of each oligonucleotide was determined spectrophotometrically based on absorption at 260 nm in water at 90°С using the following molar extinction coefficients: ϵ(TQ23) = 269 000 М −1 ·cm −1 and ϵ(TQ23comp) = 233 000 М −1 ·cm −1 , ϵ(TQ22) = 261000 М −1 ·cm −1 , ϵ(nonG4) = 269000 М −1 ·cm −1 . Synthesis of ZnP1 was described previously (22). Stock solutions of ZnP1 (50 μМ or 5 mM) were prepared by dissolving the dry compound in water.…”

“…Tetracarboxymethyl porphyrins, including ZnP1 (Supplementary Figure S1), were synthesized (21,22) and their DNA binding properties were described by us earlier (22–24). Here, we focus on the mechanism of the interaction between the ZnP1 porphyrin and the telomeric sequence and its ability to light-induce oxidation of guanines within different G4 conformations.…”

Water‐Soluble Zinc Porphyrin Capable of Light‐Induced Photocleavage of DNA: Cell Localization Studies in Drosophila Melanogaster and Light Activated Treatment of Lung Cancer Cells

“…The core porphyrin used in these studies incorporates a pentafluorophenyl meso ‐substituent as a method of extending the excited state lifetime, as well as allowing for synthetic modulation at the fluoro position . A study of the effect of incorporating transition metals within the porphyrin core led to the observation that zinc(II) serves to enhance the photo‐induced reactivity toward biological systems . The role of the peripheral ruthenium(II) polyrpyridyl groups was utilized for their photoreactivity and biological activity associated with ruthenium complexes …”