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New hybrid compounds combining fragments of usnic acid and thioether are inhibitors of human enzymes TDP1, TDP2 and PARP1. / Dyrkheeva, Nadezhda S.; Filimonov, Aleksandr S.; Luzina, Olga A. et al.

In: International Journal of Molecular Sciences, Vol. 22, No. 21, 11336, 01.11.2021.

Research output: Contribution to journal › Article › peer-review

Harvard

Dyrkheeva, NS, Filimonov, AS, Luzina, OA, Orlova, KA, Chernyshova, IA, Kornienko, TE, Malakhova, AA, Medvedev, SP, Zakharenko, AL, Ilina, ES, Anarbaev, RO, Naumenko, KN, Klabenkova, KV, Burakova, EA, Stetsenko, DA, Zakian, SM, Salakhutdinov, NF & Lavrik, OI 2021, 'New hybrid compounds combining fragments of usnic acid and thioether are inhibitors of human enzymes TDP1, TDP2 and PARP1', International Journal of Molecular Sciences, vol. 22, no. 21, 11336. https://doi.org/10.3390/ijms222111336

APA

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. (2021). New hybrid compounds combining fragments of usnic acid and thioether are inhibitors of human enzymes TDP1, TDP2 and PARP1. International Journal of Molecular Sciences, 22(21), [11336]. https://doi.org/10.3390/ijms222111336

Vancouver

Dyrkheeva NS, Filimonov AS, Luzina OA, Orlova KA, Chernyshova IA, Kornienko TE et al. 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 Nov 1;22(21):11336. doi: 10.3390/ijms222111336

Author

Dyrkheeva, Nadezhda S. ; Filimonov, Aleksandr S. ; Luzina, Olga A. et al. / New hybrid compounds combining fragments of usnic acid and thioether are inhibitors of human enzymes TDP1, TDP2 and PARP1. In: International Journal of Molecular Sciences. 2021 ; Vol. 22, No. 21.

BibTeX

@article{9e0a57780a3f49c9ba685c1273c08075,
title = "New hybrid compounds combining fragments of usnic acid and thioether are inhibitors of human enzymes TDP1, TDP2 and PARP1",
abstract = "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.",
keywords = "HEK293 knockout cell line, Inhibiting activity, PARP1, Synergy, TDP1 inhibitor, TDP2, Thioether, Topotecan, Tyrosyl‐DNA phosphodiesterase 1, Usnic acid",
author = "Dyrkheeva, {Nadezhda S.} and Filimonov, {Aleksandr S.} and Luzina, {Olga A.} and Orlova, {Kristina A.} and Chernyshova, {Irina A.} and Kornienko, {Tatyana E.} and Malakhova, {Anastasia A.} and Medvedev, {Sergey P.} and Zakharenko, {Alexandra L.} and Ilina, {Ekaterina S.} and Anarbaev, {Rashid O.} and Naumenko, {Konstantin N.} and Klabenkova, {Kristina V.} and Burakova, {Ekaterina A.} and Stetsenko, {Dmitry A.} and Zakian, {Suren M.} and Salakhutdinov, {Nariman F.} and Lavrik, {Olga I.}",
note = "Funding Information: This research was funded by a grant from the Ministry of Science and Higher Education Russian Federation (agreement no. 075?15?2020?773). Acknowledgments: The authors would like to acknowledge the Multi?Access Chemical Research Center SB RAS, Novosibirsk, Russia, for their assistance with the analytical and spectroscopic meas-urements. Cell lines were obtained from the Russian Cell Culture Collection (RCCC) Institute of Cytology RAS, St. Petersburg, Russia. Funding Information: Funding: This research was funded by a grant from the Ministry of Science and Higher Education Russian Federation (agreement no. 075‐15‐2020‐773). Publisher Copyright: {\textcopyright} 2021 by the author. Licensee MDPI, Basel, Switzerland.",
year = "2021",
month = nov,
day = "1",
doi = "10.3390/ijms222111336",
language = "English",
volume = "22",
journal = "International Journal of Molecular Sciences",
issn = "1661-6596",
publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",
number = "21",

}

RIS

TY - JOUR

T1 - New hybrid compounds combining fragments of usnic acid and thioether are inhibitors of human enzymes TDP1, TDP2 and PARP1

AU - Dyrkheeva, Nadezhda S.

AU - Filimonov, Aleksandr S.

AU - Luzina, Olga A.

AU - Orlova, Kristina A.

AU - Chernyshova, Irina A.

AU - Kornienko, Tatyana E.

AU - Malakhova, Anastasia A.

AU - Medvedev, Sergey P.

AU - Zakharenko, Alexandra L.

AU - Ilina, Ekaterina S.

AU - Anarbaev, Rashid O.

AU - Naumenko, Konstantin N.

AU - Klabenkova, Kristina V.

AU - Burakova, Ekaterina A.

AU - Stetsenko, Dmitry A.

AU - Zakian, Suren M.

AU - Salakhutdinov, Nariman F.

AU - Lavrik, Olga I.

N1 - Funding Information: This research was funded by a grant from the Ministry of Science and Higher Education Russian Federation (agreement no. 075?15?2020?773). Acknowledgments: The authors would like to acknowledge the Multi?Access Chemical Research Center SB RAS, Novosibirsk, Russia, for their assistance with the analytical and spectroscopic meas-urements. Cell lines were obtained from the Russian Cell Culture Collection (RCCC) Institute of Cytology RAS, St. Petersburg, Russia. Funding Information: Funding: This research was funded by a grant from the Ministry of Science and Higher Education Russian Federation (agreement no. 075‐15‐2020‐773). Publisher Copyright: © 2021 by the author. Licensee MDPI, Basel, Switzerland.

PY - 2021/11/1

Y1 - 2021/11/1

N2 - 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.

AB - 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.

KW - HEK293 knockout cell line

KW - Inhibiting activity

KW - PARP1

KW - Synergy

KW - TDP1 inhibitor

KW - TDP2

KW - Thioether

KW - Topotecan

KW - Tyrosyl‐DNA phosphodiesterase 1

KW - Usnic acid

UR - http://www.scopus.com/inward/record.url?scp=85117293493&partnerID=8YFLogxK

U2 - 10.3390/ijms222111336

DO - 10.3390/ijms222111336

M3 - Article

C2 - 34768766

AN - SCOPUS:85117293493

VL - 22

JO - International Journal of Molecular Sciences

JF - International Journal of Molecular Sciences

SN - 1661-6596

IS - 21

M1 - 11336

ER -

ID: 34464385