TY - JOUR

T1 - Dehydroabietylamine-based thiazolidin-4-ones and 2-thioxoimidazolidin-4-ones as novel tyrosyl-DNA phosphodiesterase 1 inhibitors

AU - Kovaleva, Kseniya

AU - Mamontova, Evgeniya

AU - Yarovaya, Olga

AU - Zakharova, Olga

AU - Zakharenko, Alexandra

AU - Lavrik, Olga

AU - Salakhutdinov, Nariman

N1 - Funding Information: This work was supported by Foundation by the Russian Foundation Research (N 18-33-00297). The authors would like to express their gratitude to the Collective Use Chemical Service Center of the Siberian Branch, Russian Academy of Sciences, for the obtained spectra and analytical data. Publisher Copyright: © 2020, Springer Nature Switzerland AG.

PY - 2021/11

Y1 - 2021/11

N2 - 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.

AB - 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.

KW - 2-thioxoimidazolidin-4-one

KW - Dehydroabietylamine

KW - SCAN1

KW - TDP1

KW - Thiazolidin-4-one

KW - Thiazolidin-4-thione

KW - Tyrosyl-DNA phosphodiesterase 1

KW - HUMAN-CELLS

KW - TOPOISOMERASE-I

KW - DAMAGE

KW - REPAIR

KW - ENZYME

KW - CAMPTOTHECIN

KW - 4-THIAZOLIDINONE

KW - DERIVATIVES

KW - ANTIMICROBIAL ACTIVITY

KW - Phosphoric Diester Hydrolases

UR - http://www.scopus.com/inward/record.url?scp=85089753124&partnerID=8YFLogxK

UR - https://www.mendeley.com/catalogue/9897a49f-7771-35ce-a654-7d67501721a3/

U2 - 10.1007/s11030-020-10132-z

DO - 10.1007/s11030-020-10132-z

M3 - Article

C2 - 32833106

AN - SCOPUS:85089753124

VL - 25

SP - 2389

EP - 2397

JO - Molecular Diversity

JF - Molecular Diversity

SN - 1381-1991

IS - 4

ER -