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

Nadezhda Dyrkheeva; Olga Luzina; Aleksandr Filimonov; Olga Zakharova; Ekaterina Ilina; Alexandra Zakharenko; Maxim Kuprushkin; Dmitry Nilov; Irina Gushchina; Vytas Švedas; Nariman Salakhutdinov; Olga Lavrik

doi:10.1055/a-0681-7069

Planta Medica, Table of Contents

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

¹Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russian Federation

,

Olga Luzina

²N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russian Federation

,

Aleksandr Filimonov

²N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russian Federation

³Novosibirsk State University, Novosibirsk, Russian Federation

,

Olga Zakharova

¹Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russian Federation

,

Ekaterina Ilina

¹Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russian Federation

,

Alexandra Zakharenko

¹Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russian Federation

,

Maxim Kuprushkin

¹Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russian Federation

,

Dmitry Nilov

⁴Lomonosov Moscow State University, Belozersky Institute of Physicochemical Biology, Moscow, Russian Federation

,

Irina Gushchina

⁵Lomonosov Moscow State University, Faculty of Bioengineering and Bioinformatics, Moscow, Russian Federation

,

Vytas Švedas

⁴Lomonosov Moscow State University, Belozersky Institute of Physicochemical Biology, Moscow, Russian Federation

⁵Lomonosov Moscow State University, Faculty of Bioengineering and Bioinformatics, Moscow, Russian Federation

,

Nariman Salakhutdinov

²N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russian Federation

³Novosibirsk State University, Novosibirsk, Russian Federation

,

Olga Lavrik

¹Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russian Federation

³Novosibirsk State University, Novosibirsk, Russian Federation

› Author Affiliations

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

Full Text

References

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