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

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

Журнал

Pharmaceuticals
ISSN: 1424-8247

Вых. Данные

Год: 2021, Том: 14, Номер: 5, Номер статьи : 422, Страниц : DOI: 10.3390/ph14050422

Ключевые слова

tyrosil-DNA-phosphodiesterase 1; adamantane; resin acid; TDP1

Авторы

Kovaleva Kseniya ¹ , Yarovaya Olga ^1,2 , Ponomarev Konstantin ¹ , Cheresiz Sergey ² , Azimirad Amirhossein ² , Chernyshova Irina ² , Zakharenko Alexandra ³ , Konev Vasily ⁴ , Khlebnikova Tatiana ⁴ , Mozhaytsev Evgenii ¹ , Suslov Evgenii ¹ , Nilov Dmitry ⁵ , Švedas Vytas ^5,6 , Pokrovsky Andrey ² , Lavrik Olga ^2,3 , Salakhutdinov Nariman ¹

Организации

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	Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Lenin Hills 1, Bldg. 73, 119991 Moscow, Russia
6	Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Lenin Hills 1, Bldg. 73, 119991 Moscow, Russia

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.

Kovaleva K. , Yarovaya O. , Ponomarev K. , Cheresiz S. , Azimirad A. , Chernyshova I. , Zakharenko A. , Konev V. , Khlebnikova T. , Mozhaytsev E. , Suslov E. , Nilov D. , Švedas V. , Pokrovsky A. , Lavrik O. , Salakhutdinov N.
Design, Synthesis, and Molecular Docking Study of New Tyrosyl-DNA Phosphodiesterase 1 (TDP1) Inhibitors Combining Resin Acids and Adamantane Moieties

Pharmaceuticals. 2021. V.14. N5. 422 . DOI: 10.3390/ph14050422 WOS Scopus РИНЦ

Полный текст от издателя

Опубликована online:

1 мая 2021 г.

Web of science	WOS:000654404200001
Scopus	2-s2.0-85105952939
РИНЦ	46067043
OpenAlex	W3158355266