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

doi:10.3390/ph14050422

Design, Synthesis, and Molecular Docking Study of New Tyrosyl-DNA Phosphodiesterase 1 (TDP1) Inhibitors Combining Resin Acids and Adamantane Moieties

Pharmaceuticals (Basel). 2021 May 1;14(5):422. doi: 10.3390/ph14050422.

Authors

Kseniya Kovaleva¹, Olga Yarovaya^{1

2}, Konstantin Ponomarev¹, Sergey Cheresiz², Amirhossein Azimirad², Irina Chernyshova², Alexandra Zakharenko³, Vasily Konev⁴, Tatiana Khlebnikova⁴, Evgenii Mozhaytsev¹, Evgenii Suslov¹, Dmitry Nilov⁵, Vytas Švedas^{5

6}, Andrey Pokrovsky², Olga Lavrik^{2

3}, Nariman Salakhutdinov¹

Affiliations

¹ N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, Lavrentiev Ave. 9, 630090 Novosibirsk, Russia.
² V. Zelman Institute for the Medicine and Psychology, Novosibirsk State University, Pirogova St. 1, 630090 Novosibirsk, Russia.
³ Novosibirsk Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Lavrentiev Ave. 8, 630090 Novosibirsk, Russia.
⁴ Boreskov Institute of Catalysis, Siberian Branch of the Russian Academy of Sciences, Lavrentiev Ave. 5, 630090 Novosibirsk, Russia.
⁵ Belozersky Institute of Physicochemical Biology, Lomonosov Moscow State University, Lenin Hills 1, Bldg. 40, 119991 Moscow, Russia.
⁶ Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Lenin Hills 1, Bldg. 73, 119991 Moscow, Russia.

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 inhibitory 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 cytotoxicity 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.

Keywords: TDP1; adamantane; resin acid; tyrosil-DNA-phosphodiesterase 1.

Grants and funding

19-73-00051/Russian Science Support Foundation