New Dual Inhibitors of Tyrosyl-DNA Phosphodiesterase 1 and 2 Based on Deoxycholic Acid: Design, Synthesis, Cytotoxicity, and Molecular Modeling

New Dual Inhibitors of Tyrosyl-DNA Phosphodiesterase 1 and 2 Based on Deoxycholic Acid: Design, Synthesis, Cytotoxicity, and Molecular Modeling Научная публикация

Журнал

Molecules
, E-ISSN: 1420-3049

Вых. Данные

Год: 2024, Том: 29, Номер: 3, Номер статьи : 581, Страниц : DOI: 10.3390/molecules29030581

Авторы

Salomatina Oksana V. ¹ , Kornienko Tatyana E. ² , Zakharenko Alexandra L. ² , Komarova Nina I. ¹ , Achara Chigozie ³ , Reynisson Jóhannes ³ , Nariman F. Salakhutdinov ¹ , Lavrik Olga I. ² , Volcho Konstantin P. ¹

Организации

1	Новосибирский институт органической химии им. Н.Н. Ворожцова СО РАН
2	Федеральное государственное бюджетное учреждение науки Институт химической биологии и фундаментальной медицины Сибирского отделения Российской академии наук
3	Keele University

Информация о финансировании (1)

Российский Научный Фонд

19-13-00040

Deoxycholic acid derivatives containing various heterocyclic functional groups at C-3 on the steroid scaffold were designed and synthesized as promising dual tyrosyl-DNA phosphodiesterase 1 and 2 (TDP1 and TDP2) inhibitors, which are potential targets to potentiate topoisomerase poison antitumor therapy. The methyl esters of DCA derivatives with benzothiazole or benzimidazole moieties at C-3 demonstrated promising inhibitory activity in vitro against TDP1 with IC50 values in the submicromolar range. Furthermore, methyl esters 4d–e, as well as their acid counterparts 3d–e, inhibited the phosphodiesterase activity of both TDP1 and TDP2. The combinations of compounds 3d–e and 4d–e with low-toxic concentrations of antitumor drugs topotecan and etoposide showed significantly greater cytotoxicity than the compounds alone. The docking of the derivatives into the binding sites of TDP1 and TDP2 predicted plausible binding modes of the DCA derivatives.

Salomatina O.V. , Kornienko T.E. , Zakharenko A.L. , Komarova N.I. , Achara C. , Reynisson J. , Nariman F. Salakhutdinov , Lavrik O.I. , Volcho K.P.
New Dual Inhibitors of Tyrosyl-DNA Phosphodiesterase 1 and 2 Based on Deoxycholic Acid: Design, Synthesis, Cytotoxicity, and Molecular Modeling
Molecules. 2024. V.29. N3. 581 . DOI: 10.3390/molecules29030581 WOS

Поступила в редакцию:	9 нояб. 2023 г.
Принята к публикации:	22 янв. 2024 г.
Опубликована в печати:	24 янв. 2024 г.
Опубликована online:	24 янв. 2024 г.

Web of science	WOS:001160250100001
OpenAlex	W4391175504