Design, synthesis, and molecular docking study of new tyrosyl-dna phosphodiesterase 1 (Tdp1) inhibitors combining resin acids and adamantane moieties

Kseniya Kovaleva, Olga Yarovaya, Konstantin Ponomarev, Sergey Cheresiz, Amirhossein Azimirad, Irina Chernyshova, Alexandra Zakharenko, Vasily Konev, Tatiana Khlebnikova, Evgenii Mozhaytsev, Evgenii Suslov, Dmitry Nilov, Vytas Švedas, Andrey Pokrovsky, Olga Lavrik, Nariman Salakhutdinov

Research output: Contribution to journalArticlepeer-review

Abstract

In this paper, a series of novel abietyl and dehydroabietyl ureas, thioureas, amides, and thioamides bearing adamantane moieties were designed, synthesized, and evaluated for their in-hibitory activities against tyrosil-DNA-phosphodiesterase 1 (TDP1). The synthesized compounds were able to inhibit TDP1 at micromolar concentrations (0.19–2.3 µM) and demonstrated low cytotox-icity in the T98G glioma cell line. The effect of the terpene fragment, the linker structure, and the adamantane residue on the biological properties of the new compounds was investigated. Based on molecular docking results, we suppose that adamantane derivatives of resin acids bind to the TDP1 covalent intermediate, forming a hydrogen bond with Ser463 and hydrophobic contacts with the Phe259 and Trp590 residues and the oligonucleotide fragment of the substrate.

Original languageEnglish
Article number422
JournalPharmaceuticals
Volume14
Issue number5
DOIs
Publication statusPublished - 1 May 2021

Keywords

  • Adamantane
  • Resin acid
  • TDP1
  • Tyrosil-DNA-phosphodiesterase 1

OECD FOS+WOS

  • 3.01.TU PHARMACOLOGY & PHARMACY

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