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Planta Med 2019; 85(02): 103-111
DOI: 10.1055/a-0681-7069
Biological and Pharmacological Activity
Original Papers
Georg Thieme Verlag KG Stuttgart · New York

Inhibitory Effect of New Semisynthetic Usnic Acid Derivatives on Human Tyrosyl-DNA Phosphodiesterase 1

Nadezhda Dyrkheeva
1   Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russian Federation
,
Olga Luzina
2   N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russian Federation
,
Aleksandr Filimonov
2   N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russian Federation
3   Novosibirsk State University, Novosibirsk, Russian Federation
,
Olga Zakharova
1   Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russian Federation
,
Ekaterina Ilina
1   Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russian Federation
,
Alexandra Zakharenko
1   Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russian Federation
,
Maxim Kuprushkin
1   Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russian Federation
,
Dmitry Nilov
4   Lomonosov Moscow State University, Belozersky Institute of Physicochemical Biology, Moscow, Russian Federation
,
Irina Gushchina
5   Lomonosov Moscow State University, Faculty of Bioengineering and Bioinformatics, Moscow, Russian Federation
,
Vytas Švedas
4   Lomonosov Moscow State University, Belozersky Institute of Physicochemical Biology, Moscow, Russian Federation
5   Lomonosov Moscow State University, Faculty of Bioengineering and Bioinformatics, Moscow, Russian Federation
,
Nariman Salakhutdinov
2   N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russian Federation
3   Novosibirsk State University, Novosibirsk, Russian Federation
,
Olga Lavrik
1   Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russian Federation
3   Novosibirsk State University, Novosibirsk, Russian Federation
› Author Affiliations
Further Information

Publication History

received 13 March 2018
revised 04 July 2018

accepted 08 August 2018

Publication Date:
24 August 2018 (online)

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Abstract

Usnic acid, a lichen secondary metabolite produced by a whole number of lichens, has attracted the interest of researchers owing to its broad range of biological activity, including antiviral, antibiotic, anticancer properties, and it possessing a certain toxicity. The synthesis of new usnic acid derivatives and the investigation of their biological activity may lead to the discovery of compounds with better pharmacological and toxicity profiles. In this context, a series of new usnic acid derivatives comprising a terpenoid moiety were synthesized, and their ability to inhibit the catalytic activity of the human DNA repair enzyme tyrosyl-DNA phosphodiesterase 1 was investigated. The most potent compounds (15a, 15b, 15g, and 16a, 16b, 16g) had IC50 values in the range of 0.33 – 2.7 µM. The inhibitory properties were mainly dependent on the flexibility and length of the terpenoid moiety, but not strongly dependent on the configuration of the asymmetric centers. The synthesized derivatives showed low cytotoxicity against human cell lines in an MTT assay. They could be used as a basis for the development of more effective anticancer therapies when combined with topoisomerase 1 inhibitors.

Key words

Usneaceae - Usnea barbata - usnic acid - terpenophenols - tyrosyl-DNA phosphodiesterase 1 - Tdp1 inhibitor

Supporting Information

    NMR spectra of the compounds 15a – g/16a – g (measured in CDCl3), optical rotation, HRMS data, and the dose-response curves of the dependence of Tdp1 residual activity as a function of the concentration of usnic acid derivatives are presented as Supporting Information.

  • Supporting Information
 

  • References

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