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
, E-ISSN: 1420-3049

Output data

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

Authors

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

Affiliations

1	N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry of Siberian Branch of Russian Academy of Sciences
2	Institute of Chemical Biology and Fundamental Medicine SB RAS
3	Keele University

Funding (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

Submitted:	Nov 9, 2023
Accepted:	Jan 22, 2024
Published print:	Jan 24, 2024
Published online:	Jan 24, 2024

Web of science	WOS:001160250100001
OpenAlex	W4391175504