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 Full article

Journal

Molecules
ISSN: 1420-3049

Output data

Year: 2024, Volume: 29, Number: 3, Article number : 581, Pages count : DOI: 10.3390/molecules29030581

Tags

deoxycholic acid; oxirane; thiols; TDP1 inhibitor; TDP2 inhibitor; cancer; tumor; molecular modeling

Authors

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

Affiliations

1	N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, SB RAS, 9, Lavrent’ev Ave., Novosibirsk 630090, Russia
2	Institute of Chemical Biology and Fundamental Medicine, SB RAS, 8, Lavrent’ev Ave., Novosibirsk 630090, Russia
3	School of Pharmacy and Bioengineering, Keele University, Hornbeam Building, Newcastle-under-Lyme, Staffordshire ST5 5BG, UK

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. , Salakhutdinov N.F. , 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 Scopus OpenAlex

Published print:

Jan 24, 2024

Web of science:	WOS:001160250100001
Scopus:	2-s2.0-85184687314
OpenAlex:	W4391175504

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