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

  • Structural-Functional Analysis of Biopolymers and Their Complexes
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Abstract

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 (ΔTm = −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.

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Abbreviations

CD:

circular dichroism

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Authors and Affiliations

  1. Blokhin Cancer Research Center, Russian Academy of Medical Sciences, Moscow, 115478, Russia

    Yu. V. Dutikova & A. A. Shtil

  2. Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, 119991, Russia

    O. F. Borisova, A. K. Shchyolkina & D. N. Kaluzhny

  3. National Yang-Ming University, Taipei, Taiwan (Republic of China)

    J. Lin

  4. National Defense Medical Center, Taipei, Taiwan (Republic of China)

    S. Huang

Authors
  1. Yu. V. Dutikova
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  2. O. F. Borisova
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  3. A. K. Shchyolkina
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  4. J. Lin
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  5. S. Huang
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  6. A. A. Shtil
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  7. D. N. Kaluzhny
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Correspondence to O. F. Borisova.

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Original Russian Text © Yu.V. Dutikova, O.F. Borisova, A.K. Shchyolkina, J. Lin, S. Huang, A.A. Shtil, D.N. Kaluzhny, 2010, published in Molekulyarnaya Biologiya, 2010, Vol. 44, No. 5, pp. 929–937.

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Dutikova, Y.V., Borisova, O.F., Shchyolkina, A.K. et al. 5,10,15,20-Tetra-(N-methyl-3-pyridyl)porphyrin destabilizes the antiparallel telomeric quadruplex d(TTAGGG)4 . Mol Biol 44, 823–831 (2010). https://doi.org/10.1134/S0026893310050201

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