Novel tdp1 inhibitors based on adamantane connected with monoterpene moieties via heterocyclic fragments

Novel tdp1 inhibitors based on adamantane connected with monoterpene moieties via heterocyclic fragments Full article

Journal

Molecules
, E-ISSN: 1420-3049

Output data

Year: 2021, Volume: 26, Number: 11, Article number : 3128, Pages count : DOI: 10.3390/molecules26113128

Tags

Cancer; Chemical space; DNA repair enzyme; Molecular modeling; Monoterpenoid; SAR; Topoisomerase 1

Authors

Munkuev A.A. ¹ , Mozhaitsev E.S. ¹ , Chepanova A.A. ² , Suslov E.V. ¹ , Korchagina D.V. ¹ , Zakharova O.D. ² , Ilina E.S. ² , Dyrkheeva N.S. ² , Zakharenko A.L. ² , Reynisson J. ³ , Volcho K.P. ¹ , Salakhutdinov N.F. ¹ , Lavrik O.I. ²

Affiliations

1	N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, 9, Akademika Lavrentieva Ave., Novosibirsk, 630090, Russian Federation
2	Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of Russian Academy of Sciences, 8, Lavrentiev Ave., Novosibirsk, 630090, Russian Federation
3	School of Pharmacy and Bioengineering, Keele University, Hornbeam Building, Staffordshire, ST5 5BG, United Kingdom

Funding (1)

Российский Научный Фонд

19-13-00040

Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is a promising target for anticancer therapy due to its ability to counter the effects topoisomerase 1 (Top1) poison, such as topotecan, thus, decreasing their efficacy. Compounds containing adamantane and monoterpenoid residues connected via 1,2,4-triazole or 1,3,4-thiadiazole linkers were synthesized and tested against Tdp1. All the derivatives exhibited inhibition at low micromolar or nanomolar concentrations with the most potent inhibitors having IC50 values in the 0.35–0.57 µM range. The cytotoxicity was determined in the HeLa, HCT-116 and SW837 cancer cell lines; moderate CC50 (µM) values were seen from the mid-teens to no effect at 100 µM. Furthermore, citral derivative 20c, α-pinene-derived compounds 20f, 20g and 25c, and the citronellic acid derivative 25b were found to have a sensitizing effect in conjunction with topotecan in the HeLa cervical cancer and colon adenocarcinoma HCT-116 cell lines. The ligands are predicted to bind in the catalytic pocket of Tdp1 and have favorable physicochemical properties for further development as a potential adjunct therapy with Top1 poisons. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Munkuev A.A. , Mozhaitsev E.S. , Chepanova A.A. , Suslov E.V. , Korchagina D.V. , Zakharova O.D. , Ilina E.S. , Dyrkheeva N.S. , Zakharenko A.L. , Reynisson J. , Volcho K.P. , Salakhutdinov N.F. , Lavrik O.I.
Novel tdp1 inhibitors based on adamantane connected with monoterpene moieties via heterocyclic fragments

Molecules. 2021. V.26. N11. 3128 . DOI: 10.3390/molecules26113128 WOS Scopus РИНЦ

Full text from publisher

Published online:

May 24, 2021

Web of science	WOS:000660468600001
Scopus	2-s2.0-85107398873
Elibrary	46833799
OpenAlex	W3165643857