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The role of carboxymethyl substituents in the interaction of tetracationic porphyrins with DNA

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Abstract

Cationic porphyrin-based compounds capable of interacting with DNA are currently under extensive investigation as prospective anticancer and anti-infective drugs. One of the approaches to enhancing the DNA-binding affinity of these ligands is chemical modification of functional groups of the porphyrin macrocycle. We analyzed the interaction with DNA of novel derivatives containing carboxymethyl and ethoxycarbonylmethyl substituents at quaternary nitrogen atoms of pyridinium groups at the periphery of the porphyrin macrocycle. The parameters of binding of 5,10,15,20-tetrakis(N-carboxymethyl-4-pyridinium)porphyrin (P1) and 5,10,15,20-tetrakis(N-ethoxycarbonylmethyl-4-pyridinium)porphyrin (P2) to double-stranded DNA sequences of different nucleotide content were determined using optical spectroscopy. The association constant of P1 interaction with calf thymus DNA (K = 3.4 × 106 M−1) was greater than that of P2 (K = 2.8 × 105 M−1). Preferential binding of P1 to GC- rather than AT-rich oligonucleotides was detected. In contrast, P2 showed no preference for particular nucleotide content. Modes of binding of P1 and P2 to GC and AT duplexes were verified using the induced circular dichroism spectra. Molecular modeling confirmed an intercalative mode of interaction of P1 and P2 with CpG islands. The carboxyl groups of the peripheral substituent in P1 determine the specific interactions with GC-rich DNA regions, whereas ethoxycarbonylmethyl substituents disfavor binding to DNA. This study contributes to the understanding of the impact of peripheral substituents on the DNA-binding affinity of cationic porphyrins, which is important for the design of DNA-targeting drugs.

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Acknowledgments

The authors thank O. Mamaeva for assistance in CD measurements. This study was supported by the Russian Foundation for Basic Research (grant 12-04-00929-a).

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Authors and Affiliations

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

    Oxana A. Kovaleva, Anna K. Shchyolkina, Olga F. Borisova & Dmitry N. Kaluzhny

  2. Moscow Institute of Physics and Technology, State University, Dolgoprudny, 141700, Russia

    Oxana A. Kovaleva

  3. Orekhovich Institute of Biomedical Chemistry, Russian Academy of Medical Sciences, Moscow, 119121, Russia

    Vladimir B. Tsvetkov

  4. Topchiev Institute of Petrochemical Synthesis, Russian Academy of Sciences, Moscow, 119991, Russia

    Vladimir B. Tsvetkov

  5. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, Moscow, 119991, Russia

    Valentina A. Ol’shevskaya & Anton V. Makarenkov

  6. Ivanovo State University of Chemistry and Technology, Ivanovo, 153000, Russia

    Alexander S. Semeikin

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

    Alexander A. Shtil

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  1. Oxana A. Kovaleva
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  2. Vladimir B. Tsvetkov
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  3. Anna K. Shchyolkina
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  4. Olga F. Borisova
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  8. Alexander A. Shtil
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  9. Dmitry N. Kaluzhny
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Correspondence to Dmitry N. Kaluzhny.

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Kovaleva, O.A., Tsvetkov, V.B., Shchyolkina, A.K. et al. The role of carboxymethyl substituents in the interaction of tetracationic porphyrins with DNA. Eur Biophys J 41, 723–732 (2012). https://doi.org/10.1007/s00249-012-0848-y

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  • DOI: https://doi.org/10.1007/s00249-012-0848-y

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