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Tautomerism in some pyrimidine nucleoside analogues used in the treatment of cancer: an ab initio study

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Abstract

The tautomerism of pyrimidine \(2^\prime\)-deoxynucleoside, 2DN, has fundamental importance to understanding the mechanism of action in DNA replication and consequently to development of new drugs. In this work, the tautomerism of pyrimidine 2DN and some of its analogues with anticancer activity was analyzed along their potential energy surfaces by means of the MP2/cc-aug-pVDZ and QCISD/cc-aug-pVDZ theoretical methods of quantum chemistry. In gas phase and in solvent implicit (water), the energy barriers for hydrogen migration are above of 38.0 kcal/mol while tautomerization energies are between −4.9 and 10.2 kcal/mol. When hydrogen migration is catalyzed by one water molecule, the energy barriers for hydrogen migration are above of 14.2 kcal/mol, and tautomerization energies are found between 3.1 and 7.8 kcal/mol. This finding, supported by equilibrium constant and kinetic data, suggests that both tautomers, canonical and non-canonical, of each 2DN and analogues coexist in monohydrated medium forming mainly Watson–Crick pairs (WC) and some non-WC pairs. However, the calculated interaction energies of the pairs formed by guanine (G) and non-canonical pyrimidine (Pyr*) are higher than those WC pairs formed by G and Pyr, and therefore it is expected that the formation of these non-WC pairs plays an important role in the action of 2DN analogues in DNA replication.

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Acknowledgments

Guanajuato National Laboratory (CONACyT 123732) is acknowledged for supercomputing resources. The authors thank Igor I. Slowing and Marisol García-Reyes for helpful comments and suggestions. L. M-M (CVU 236809 ) thanks CONACyT for financial support.

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Authors and Affiliations

  1. División de Ciencias Naturales y Exactas, Departamento de Química, Universidad de Guanajuato, Noria Alta S/N, Col., 36050, Noria Alta, Guanajuato, Guanajuato, Mexico

    Luis Mejía-Mazariegos & Marco A. García-Revilla

  2. División de Ciencias Naturales y Exactas, Departamento de Farmacia, Universidad de Guanajuato, Noria Alta S/N, Col., 36050, Noria Alta, Guanajuato, Guanajuato, Mexico

    Juvencio Robles

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  1. Luis Mejía-Mazariegos
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  3. Marco A. García-Revilla
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Correspondence to Marco A. García-Revilla.

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Published as part of the special collection of articles “Festschrift in honour of A. Vela”.

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Mejía-Mazariegos, L., Robles, J. & García-Revilla, M.A. Tautomerism in some pyrimidine nucleoside analogues used in the treatment of cancer: an ab initio study. Theor Chem Acc 135, 233 (2016). https://doi.org/10.1007/s00214-016-1985-7

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