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

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)

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 IC 50 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.

Original languageEnglish
Pages (from-to)103-111
Number of pages9
JournalPlanta Medica
Volume85
Issue number2
DOIs
Publication statusPublished - 1 Jan 2019

Keywords

  • Tdp1 inhibitor
  • terpenophenols
  • tyrosyl-DNA phosphodiesterase 1
  • Usnea barbata
  • Usneaceae
  • usnic acid
  • Phosphoric Diester Hydrolases/drug effects
  • Escherichia coli
  • Humans
  • MCF-7 Cells/drug effects
  • HEK293 Cells/drug effects
  • Benzofurans/chemical synthesis
  • Cell Line, Tumor/drug effects
  • Microorganisms, Genetically-Modified
  • Phosphodiesterase Inhibitors/chemistry
  • Molecular Docking Simulation
  • REPAIR
  • BIOLOGICAL EVALUATION
  • ASSAY
  • CRYSTAL-STRUCTURE
  • VANADATE
  • I INHIBITORS
  • ANTICANCER
  • GENE
  • TDP1
  • BINDING

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