Deoxycholic acid as a molecular scaffold for tyrosyl-DNA phosphodiesterase 1 inhibition: A synthesis, structure–activity relationship and molecular modeling study

Deoxycholic acid as a molecular scaffold for tyrosyl-DNA phosphodiesterase 1 inhibition: A synthesis, structure–activity relationship and molecular modeling study Научная публикация

Журнал

Steroids
ISSN: 0039-128X , E-ISSN: 1878-5867

Вых. Данные

Год: 2021, Том: 165, Номер статьи : 108771, Страниц : DOI: 10.1016/j.steroids.2020.108771

Ключевые слова

Bile acid; Cancer; DNA repair enzyme; Molecular modelling; Tdp1 inhibitor; Tumor

Авторы

Salomatina Oksana V. ¹ , Popadyuk Irina I. ¹ , Zakharenko Alexandra L. ² , Zakharova Olga D. ² , Chepanova Arina A. ² , Dyrkheeva Nadezhda.S. ² , Komarova Nina I. ¹ , Reynisson Jóhannes ³ , Anarbaev Rashid O. ² , Salakhutdinov N.F. ¹ , Lavrik Olga I. ² , Volcho Konstantin P. ¹

Организации

1	N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, SB RAS, 9, Lavrent'ev Ave., Novosibirsk, 630090, Russian Federation
2	Institute of Chemical Biology and Fundamental Medicine, SB RAS, 8, Lavrent'ev Ave., Novosibirsk, 630090, Russian Federation
3	School of Pharmacy and Bioengineering, Keele University, Hornbeam Building, Staffordshire, ST5 5BG, United Kingdom

Информация о финансировании (1)

Российский Научный Фонд

19-13-00040

Para-Bromoanilides of deoxycholic acid with various functional groups on the steroid scaffold were designed as promising tyrosyl-DNA phosphodiesterase 1 (Tdp1) inhibitors. Tdp1 is a DNA repair enzyme, involved in removing DNA damage caused by topoisomerase I poisons; an important class of anticancer drugs. Thus, reducing the activity of Tdp1 can increase the efficacy of anticancer drugs in current use. Inhibitory activity in the low micromolar and submicromolar concentrations was observed with 3,12-dimethoxy para-bromoanilide 17 being the most active with an IC50 value of 0.27 μM. The activity of N-methyl para-bromoanilides was 3–4.8 times lower than of the corresponding para-bromoanilides. Increased potency of the ligands was seen with higher molecular weight and log P values. The ligands were evaluated for their cytotoxic potential in a panel of tumor cell lines; all were nontoxic to the A549 pulmonary adenocarcinoma cell line. However, derivatives containing a hydroxyl group at the 12th position were more toxic than their 12-hydroxyl group counterparts (acetoxy-, oxo- and methoxy- group) against HCT-116 human colon and HepG2 hepatocellular carcinomas. In addition, an N-methyl substitution led to an increase in toxicity for the HCT-116 and HepG2 cell lines. The excellent activity as well as low cytotoxicity, derivative 17 can be considered as a lead compound for further development. © 2020

Salomatina O.V. , Popadyuk I.I. , Zakharenko A.L. , Zakharova O.D. , Chepanova A.A. , Dyrkheeva N.S. , Komarova N.I. , Reynisson J. , Anarbaev R.O. , Salakhutdinov N.F. , Lavrik O.I. , Volcho K.P.
Deoxycholic acid as a molecular scaffold for tyrosyl-DNA phosphodiesterase 1 inhibition: A synthesis, structure–activity relationship and molecular modeling study
Steroids. 2021. V.165. 108771 . DOI: 10.1016/j.steroids.2020.108771 WOS Scopus РИНЦ

Опубликована в печати:

1 янв. 2021 г.

Web of science	WOS:000604788100006
Scopus	2-s2.0-85097165734
РИНЦ	45134768
OpenAlex	W3098485738