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Dehydroabietylamine-based thiazolidin-4-ones and 2-thioxoimidazolidin-4-ones as novel tyrosyl-DNA phosphodiesterase 1 inhibitors

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Abstract

Tyrosyl-DNA phosphodiesterase 1 (TDP1) is a DNA repair enzyme that plays a key role in repairing damage caused by various antitumor drugs. It is a promising target in medicinal chemistry for the creation of cancer adjuvant therapy. Inhibition of this enzyme together with the use of anticancer chemotherapy enhances the effect of the latter. The natural mutant of TDP1, TDP1(H493R), causes severe neurodegenerative disease spinocerebellar ataxia syndrome with axonal neuropathy (SCAN1). Inhibition of TDP1(H493R) appears to be useful in containment the progression of the disease. A library of compounds was synthesized starting from dehydroabietylamine including heterocyclic pharmacophore groups in the core. To obtain the desired products, the starting dehydroabietylamine was introduced sequentially in reaction with isothiocyanate and ethyl bromoacetate. Different classes of heterocyclic derivatives—2-iminothiazolidin-4-ons and 2-thioxoimidazolidin-4-ones—were obtained depending on the addition order of reagents. 2-Iminothiazolidin-4-thiones were obtained from 2-iminothiazolidin-4-ones under the action of the Lawesson’s reagent. Effective TDP1 inhibitors were found among the obtained compounds that work in submicromolar concentrations. The inhibitor of TDP1(H493R) was also detected.

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Acknowledgement

This work was supported by Foundation by the Russian Foundation Research (N 18-33-00297). The authors would like to express their gratitude to the Collective Use Chemical Service Center of the Siberian Branch, Russian Academy of Sciences, for the obtained spectra and analytical data.

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Authors and Affiliations

  1. N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russian Federation, 630090

    Kseniya Kovaleva, Olga Yarovaya & Nariman Salakhutdinov

  2. Novosibirsk State University, Novosibirsk, Russian Federation, 630090

    Kseniya Kovaleva, Olga Yarovaya, Alexandra Zakharenko, Olga Lavrik & Nariman Salakhutdinov

  3. Novosibirsk Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russian Federation, 630090

    Evgeniya Mamontova, Olga Zakharova, Alexandra Zakharenko & Olga Lavrik

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  1. Kseniya Kovaleva
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Kovaleva, K., Mamontova, E., Yarovaya, O. et al. Dehydroabietylamine-based thiazolidin-4-ones and 2-thioxoimidazolidin-4-ones as novel tyrosyl-DNA phosphodiesterase 1 inhibitors. Mol Divers 25, 2389–2397 (2021). https://doi.org/10.1007/s11030-020-10132-z

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