5,10,15,20-Tetra-(N-methyl-3-pyridyl)porphyrin destabilizes the antiparallel telomeric quadruplex d(TTAGGG)4

5,10,15,20-Tetra-(N-methyl-3-pyridyl)porphyrin (TMPyP3) is a DNA-binding derivative of porphyrins. A comparative study of the binding of this ligand to biologically significant DNA structures was performed. For this purpose, the interactions of TMPyP3 with the antiparallel telomeric G-quadruplex d(TTAGGG)₄, oligonucleotide dTTAGGGTTAGAG(TTAGGG)₂ (not forming a quadruplex structure), double-stranded d(AC)₈ · d(GT)₈, and single-stranded d(AC)₈ and d(GT)₈ DNA molecules have been studied. Analysis of absorption isotherms has demonstrated that the binding constants and the number of binding sites for the complexes TMPyP3: DNA increase in the following order: d(AC)₈ < d(GT)₈ < d(AC)₈ · d(GT)₈ = d(TTAGGG)₄ < dTTAGGGTTAGAG(TTAGGG)₂. It has been for the first time demonstrated that the constant for TMPyP3 binding to unfolded dTTAGGGTTAGAG(TTAGGG)₂ strand (1.3 × 10⁷ M⁻¹) is approximately threefold higher than for the G-quadruplex d(TTAGGG)₄ (4.7 × 10⁶ M⁻¹). Binding of two TMPyP3 molecules to d(TTAGGG)₄ decreases the thermostability of G-quadruplex (ΔT_m = −8°C). Circular dichroism spectra of the TMPyP3 complexes with d(TTAGGG)₄ suggest that the ligand partially unfolds the G-quadruplex structure. Structural destabilization of the telomeric G-quadruplex by TMPyP3 can explain the relatively low activity of this ligand as a telomerase inhibitor and a low cytotoxicity for cultured tumor cells.