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

Результат исследования: Научные публикации в периодических изданияхстатьярецензирование

Аннотация

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.

Язык оригиналаанглийский
Номер статьи422
ЖурналPharmaceuticals
Том14
Номер выпуска5
DOI
СостояниеОпубликовано - мая 2021

Предметные области OECD FOS+WOS

  • 3.01.TU ФАРМАКОЛОГИЯ И ФАРМАЦИЯ

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