Novel Semisynthetic Derivatives of Bile Acids as Effective Tyrosyl-DNA Phosphodiesterase 1 Inhibitors

Novel Semisynthetic Derivatives of Bile Acids as Effective Tyrosyl-DNA Phosphodiesterase 1 Inhibitors Научная публикация

Журнал

Molecules
, E-ISSN: 1420-3049

Вых. Данные

Год: 2018, Том: 23, Номер: 3, Номер статьи : 679, Страниц : DOI: 10.3390/molecules23030679

Ключевые слова

deoxycholic acid; chenodeoxycholic acid; ursodeoxycholic acid; amide; Tdp1 inhibitor; cancer; tumor; virtual screening; molecular modelling

Авторы

Salomatina Oksana V. ¹ , Popadyuk Irina I. ¹ , Zakharenko Alexandra L. ² , Zakharova Olga D. ² , Fadeev Dmitriy S. ¹ , Komarova Nina I. ¹ , Reynisson Johannes ³ , Arabshahi H.John ³ , Chand Raina ³ , Volcho Konstantin P. ^1,4 , Salakhutdinov Nariman F. ^1,4 , Lavrik Olga I. ^2,4

Организации

1	(Данные Web of science) SB RAS, NN Vorozhtsov Novosibirsk Inst Organ Chem, Acad Lavrentjev Ave 9, Novosibirsk 630090, Russia
2	(Данные Web of science) SB RAS, Novosibirsk Inst Chem Biol & Fundamental Med, Novosibirsk 630090, Russia
3	(Данные Web of science) Univ Auckland, Sch Chem Sci, Auckland 1142, New Zealand
4	(Данные Web of science) Novosibirsk State Univ, Pirogova Str 2, Novosibirsk 630090, Russia

An Important task in the treatment of oncological and neurodegenerative diseases is the search for new inhibitors of DNA repair system enzymes. Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is one of the DNA repair system enzymes involved in the removal of DNA damages caused by topoisomerase I inhibitors. Thus, reducing the activity of Tdp1 can increase the effectiveness of currently used anticancer drugs. We describe here a new class of semisynthetic small molecule Tdp1 inhibitors based on the bile acid scaffold that were originally identified by virtual screening. The influence of functional groups of bile acids (hydroxy and acetoxy groups in the steroid framework and amide fragment in the side chain) on inhibitory activity was investigated. In vitro studies demonstrate the ability of the semisynthetic derivatives to effectively inhibit Tdp1 with IC50 up to 0.29 mu M. Furthermore, an excellent fit is realized for the ligands when docked into the active site of the Tdpl enzyme.

Salomatina O.V. , Popadyuk I.I. , Zakharenko A.L. , Zakharova O.D. , Fadeev D.S. , Komarova N.I. , Reynisson J. , Arabshahi H.J. , Chand R. , Volcho K.P. , Salakhutdinov N.F. , Lavrik O.I.
Novel Semisynthetic Derivatives of Bile Acids as Effective Tyrosyl-DNA Phosphodiesterase 1 Inhibitors

Molecules. 2018. V.23. N3. 679 . DOI: 10.3390/molecules23030679 WOS Scopus РИНЦ

Полный текст от издателя

Опубликована online:

17 мар. 2018 г.

Web of science	WOS:000428514100170
Scopus	2-s2.0-85044436142
РИНЦ	35515080
OpenAlex	W2794010685