Dehydroabietylamine-based thiazolidin-4-ones and 2-thioxoimidazolidin-4-ones as novel tyrosyl-DNA phosphodiesterase 1 inhibitors

Dehydroabietylamine-based thiazolidin-4-ones and 2-thioxoimidazolidin-4-ones as novel tyrosyl-DNA phosphodiesterase 1 inhibitors Full article

Journal

Molecular Diversity
ISSN: 1381-1991 , E-ISSN: 1573-501X

Output data

Year: 2021, Volume: 25, Number: 4, Pages: 2389-2397 Pages count : 9 DOI: 10.1007/s11030-020-10132-z

Tags

2-thioxoimidazolidin-4-one; Dehydroabietylamine; SCAN1; TDP1; Thiazolidin-4-one; Thiazolidin-4-thione; Tyrosyl-DNA phosphodiesterase 1

Authors

Kovaleva K. ^1,2 , Mamontova E. ³ , Yarovaya O. ^1,2 , Zakharova O. ³ , Zakharenko A. ^2,3 , Lavrik O. ^2,3 , Salakhutdinov N. ^1,2

Affiliations

1	(Scopus) N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, 630090, Russian Federation
2	(Scopus) Novosibirsk State University, Novosibirsk, 630090, Russian Federation
3	(Scopus) Novosibirsk Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, 630090, Russian Federation

Abstract: Tyrosyl-DNA phosphodiesterase 1 (TDP1) is a DNA repair enzyme that plays a key role in repairing damage caused by various antitumor drugs. It is a promising target in medicinal chemistry for the creation of cancer adjuvant therapy. Inhibition of this enzyme together with the use of anticancer chemotherapy enhances the effect of the latter. The natural mutant of TDP1, TDP1(H493R), causes severe neurodegenerative disease spinocerebellar ataxia syndrome with axonal neuropathy (SCAN1). Inhibition of TDP1(H493R) appears to be useful in containment the progression of the disease. A library of compounds was synthesized starting from dehydroabietylamine including heterocyclic pharmacophore groups in the core. To obtain the desired products, the starting dehydroabietylamine was introduced sequentially in reaction with isothiocyanate and ethyl bromoacetate. Different classes of heterocyclic derivatives—2-iminothiazolidin-4-ons and 2-thioxoimidazolidin-4-ones—were obtained depending on the addition order of reagents. 2-Iminothiazolidin-4-thiones were obtained from 2-iminothiazolidin-4-ones under the action of the Lawesson’s reagent. Effective TDP1 inhibitors were found among the obtained compounds that work in submicromolar concentrations. The inhibitor of TDP1(H493R) was also detected. Graphic abstract: [Figure not available: see fulltext.]. © 2020, Springer Nature Switzerland AG.

Kovaleva K. , Mamontova E. , Yarovaya O. , Zakharova O. , Zakharenko A. , Lavrik O. , Salakhutdinov N.
Dehydroabietylamine-based thiazolidin-4-ones and 2-thioxoimidazolidin-4-ones as novel tyrosyl-DNA phosphodiesterase 1 inhibitors
Molecular Diversity. 2021. V.25. N4. P.2389-2397. DOI: 10.1007/s11030-020-10132-z WOS Scopus РИНЦ

Published online:

Aug 24, 2020

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