New hybrid compounds combining fragments of usnic acid and thioether are inhibitors of human enzymes TDP1, TDP2 and PARP1

New hybrid compounds combining fragments of usnic acid and thioether are inhibitors of human enzymes TDP1, TDP2 and PARP1 Full article

Journal

International Journal of Molecular Sciences
ISSN: 1661-6596

Output data

Year: 2021, Volume: 22, Number: 21, Article number : 11336, Pages count : DOI: 10.3390/ijms222111336

Tags

HEK293 knockout cell line; Inhibiting activity; PARP1; Synergy; TDP1 inhibitor; TDP2; Thioether; Topotecan; Tyrosyl‐DNA phosphodiesterase 1; Usnic acid

Authors

Dyrkheeva Nadezhda S. ¹ , Filimonov Aleksandr S. ² , Luzina Olga A. ² , Orlova Kristina A. ³ , Chernyshova Irina A. ¹ , Kornienko Tatyana E. ¹ , Malakhova Anastasia A. ^1,4 , Medvedev Sergey P. ^1,4 , Zakharenko Alexandra L. ^1,5 , Ilina Ekaterina S. ¹ , Anarbaev Rashid O. ¹ , Naumenko Konstantin N. ¹ , Klabenkova Kristina V. ^3,4 , Burakova Ekaterina A. ^3,4 , Stetsenko Dmitry A. ^3,4 , Zakian Suren M. ^1,4 , Salakhutdinov Nariman F. ² , Lavrik Olga I. ^1,3,5

Affiliations

1	Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, 630090, Russian Federation
2	N.N. Vorozhtsov, Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, 630090, Russian Federation
3	Department of Natural Sciences, Novosibirsk State University, Novosibirsk, 630090, Russian Federation
4	Federal Research Centre Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, 630090, Russian Federation
5	Department of Physical and Chemical Biology and Biotechnology, Altai State University, Barnaul, 656049, Russian Federation

Tyrosyl‐DNA phosphodiesterase 1 (TDP1) catalyzes the cleavage of the phosphodiester bond between the tyrosine residue of topoisomerase 1 (TOP1) and the 3′ phosphate of DNA in the single‐strand break generated by TOP1. TDP1 promotes the cleavage of the stable DNA–TOP1 complexes with the TOP1 inhibitor topotecan, which is a clinically used anticancer drug. This article reports the synthesis and study of usnic acid thioether and sulfoxide derivatives that efficiently suppress TDP1 activity, with IC50 values in the 1.4–25.2 μM range. The structure of the heterocyclic substituent introduced into the dibenzofuran core affects the TDP1 inhibitory efficiency of the com-pounds. A five‐membered heterocyclic fragment was shown to be most pharmacophoric among the others. Sulfoxide derivatives were less cytotoxic than their thioester analogs. We observed an un-competitive type of inhibition for the four most effective inhibitors of TDP1. The anticancer effect of TOP1 inhibitors can be enhanced by the simultaneous inhibition of PARP1, TDP1, and TDP2. Some of the compounds inhibited not only TDP1 but also TDP2 and/or PARP1, but at significantly higher concentration ranges than TDP1. Leader compound 10a showed promising synergy on HeLa cells in conjunction with the TOP1 inhibitor topotecan. © 2021 by the author. Licensee MDPI, Basel, Switzerland.

Dyrkheeva N.S. , Filimonov A.S. , Luzina O.A. , Orlova K.A. , Chernyshova I.A. , Kornienko T.E. , Malakhova A.A. , Medvedev S.P. , Zakharenko A.L. , Ilina E.S. , Anarbaev R.O. , Naumenko K.N. , Klabenkova K.V. , Burakova E.A. , Stetsenko D.A. , Zakian S.M. , Salakhutdinov N.F. , Lavrik O.I.
New hybrid compounds combining fragments of usnic acid and thioether are inhibitors of human enzymes TDP1, TDP2 and PARP1
International Journal of Molecular Sciences. 2021. V.22. N21. 11336 . DOI: 10.3390/ijms222111336 WOS Scopus РИНЦ

Submitted:	Sep 30, 2021
Accepted:	Oct 17, 2021
Published online:	Oct 20, 2021

Web of science	WOS:000719582900001
Scopus	2-s2.0-85117293493
Elibrary	47515032
OpenAlex	W3207456008