Synthesis and evaluation of aryliden- and hetarylidenfuranone derivatives of usnic acid as highly potent Tdp1 inhibitors

Olga Zakharova, Olga Luzina, Alexandra Zakharenko, Dmitry Sokolov, Alexandr Filimonov, Nadezhda Dyrkheeva, Arina Chepanova, Ekaterina Ilina, Anna Ilyina, Kristina Klabenkova, Boris Chelobanov, Dmitry Stetsenko, Ayesha Zafar, Chatchakorn Eurtivong, Jóhannes Reynisson, Konstantin Volcho, Nariman Salakhutdinov, Olga Lavrik

Research output: Contribution to journalArticlepeer-review

18 Citations (Scopus)

Abstract

Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is a repair enzyme for stalled DNA-topoisomerase 1 (Top 1) cleavage complexes and other 3′-end DNA lesions. Tdp1 is a promising target for anticancer therapy, since it can repair DNA lesions caused by Top1 inhibitors leading to drug resistance. Hence, Tdp1 inhibition should result in synergistic effect with Top1 inhibitors. Twenty nine derivatives of (+)-usnic acid were tested for in vitro Tdp1 inhibitory activity using a fluorescent-based assay. Excellent activity was obtained, with derivative 6m demonstrating the lowest IC50 value of 25 nM. The established efficacy was verified using a gel-based assay, which gave close results to that of the fluorescent assay. In addition, molecular modeling in the Tdp1 substrate binding pocket suggested plausible binding modes for the active analogues. The synergistic effect of the Tdp1 inhibitors with topotecan, a Top1 poison in clinical use, was tested in two human cell lines, A-549 and HEK-293. Compounds 6k and 6x gave very promising results. In particular, 6x has a low cytotoxicity and an IC50 value of 63 nM, making it a valuable lead compound for the development of potent Tdp1 inhibitors for clinical use.

Original languageEnglish
Pages (from-to)4470-4480
Number of pages11
JournalBioorganic and Medicinal Chemistry
Volume26
Issue number15
DOIs
Publication statusPublished - 15 Aug 2018

Keywords

  • TYROSYL-DNA PHOSPHODIESTERASE
  • EMPIRICAL SCORING FUNCTIONS
  • PHASE PEPTIDE-SYNTHESIS
  • PROTEIN-LIGAND DOCKING
  • BIOLOGICAL EVALUATION
  • NATURAL-PRODUCTS
  • DATA-BANK
  • I TDP1
  • ANTICANCER
  • ALCOHOL
  • Allosteric Regulation
  • Humans
  • Substrate Specificity
  • Structure-Activity Relationship
  • Cell Survival/drug effects
  • HEK293 Cells
  • Binding Sites
  • Furans/chemistry
  • Protein Structure, Tertiary
  • Recombinant Proteins/biosynthesis
  • Benzofurans/chemical synthesis
  • Phosphodiesterase Inhibitors/chemical synthesis
  • Antineoplastic Agents/chemical synthesis
  • DNA/chemistry
  • Phosphoric Diester Hydrolases/chemistry
  • Molecular Docking Simulation

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