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Mechanisms of the Cytotoxic Action of Novel Cyclic Hydroxamic Acids

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Abstract—

Cyclic hydroxamic acids (CHAs) based on quinazoline-4(3H)-one and dihydroquinazoline-4(1H)-one have been synthesized. The antioxidant and iron-chelating properties of these compounds, their effect on the activity of the histone deacetylase enzyme, and their cytotoxic effect on cells of various tumor lines have been investigated. Among the synthesized CHAs two compounds-hits exhibiting the multipharmacological type of the antineoplastic activity have been identified. Their cytotoxic effect on cells of human lung carcinoma A549 and breast adenocarcinoma MCF-7 is obviously associated with their ability to modulate the level of reactive oxygen species (ROS) and to chelate Fe(II) ions, as well as to inhibit the metalloenzymes, histone deacetylases (HDACs), involved in the epigenetic regulation of tumor genesis. Thus, the synthesized CHAs may be considered as a promising basis for creating potential oncolytics.

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ACKNOWLEDGMENTS

The authors are grateful to the Center for the Collective Use (IPAC RAS) for providing the opportunity to conduct experiments using laboratory animals.

Funding

The work supported by the Russian Foundation for Basic Research (project no. 18-33-01185 mol_a), the chemical part of the work was carried out within the framework of State Assignment 0090-2019-0006.

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Authors and Affiliations

  1. Institute of Physiologically Active Compounds of the Russian Academy of Sciences (IPAC RAS), Severnii pr. 1, 142432, Chernogolovka, Moscow region, Russia

    M. E. Neganova, Yu. R. Aleksandrova, S. A. Pukhov & S. G. Klochkov

  2. N.N. Blokhin National Medical Research Center of Oncology (Blokhin NMRC of Oncology), Kashirskoe sh. 23, 115478, Moscow, Russia

    V. N. Osipov

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  1. M. E. Neganova
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  2. Yu. R. Aleksandrova
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  3. S. A. Pukhov
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  4. S. G. Klochkov
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  5. V. N. Osipov
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Correspondence to M. E. Neganova.

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All manipulations requiring the use of animals were approved by the Bioethics Commission (IPAC RAS).

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The authors declare that they have no conflicts of in-terest.

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Translated by A. Medvedev

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Neganova, M.E., Aleksandrova, Y.R., Pukhov, S.A. et al. Mechanisms of the Cytotoxic Action of Novel Cyclic Hydroxamic Acids. Biochem. Moscow Suppl. Ser. B 14, 340–346 (2020). https://doi.org/10.1134/S1990750820040095

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  • DOI: https://doi.org/10.1134/S1990750820040095

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