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The first berberine-based inhibitors of tyrosyl-dna phosphodiesterase 1 (Tdp1), an important dna repair enzyme. / Gladkova, Elizaveta D.; Nechepurenko, Ivan V.; Bredikhin, Roman A. et al.

In: International Journal of Molecular Sciences, Vol. 21, No. 19, 7162, 01.10.2020, p. 1-16.

Research output: Contribution to journalArticlepeer-review

Harvard

Gladkova, ED, Nechepurenko, IV, Bredikhin, RA, Chepanova, AA, Zakharenko, AL, Luzina, OA, Ilina, ES, Dyrkheeva, NS, Mamontova, EM, Anarbaev, RO, Reynisson, J, Volcho, KP, Salakhutdinov, NF & Lavrik, OI 2020, 'The first berberine-based inhibitors of tyrosyl-dna phosphodiesterase 1 (Tdp1), an important dna repair enzyme', International Journal of Molecular Sciences, vol. 21, no. 19, 7162, pp. 1-16. https://doi.org/10.3390/ijms21197162

APA

Gladkova, E. D., Nechepurenko, I. V., Bredikhin, R. A., Chepanova, A. A., Zakharenko, A. L., Luzina, O. A., Ilina, E. S., Dyrkheeva, N. S., Mamontova, E. M., Anarbaev, R. O., Reynisson, J., Volcho, K. P., Salakhutdinov, N. F., & Lavrik, O. I. (2020). The first berberine-based inhibitors of tyrosyl-dna phosphodiesterase 1 (Tdp1), an important dna repair enzyme. International Journal of Molecular Sciences, 21(19), 1-16. [7162]. https://doi.org/10.3390/ijms21197162

Vancouver

Gladkova ED, Nechepurenko IV, Bredikhin RA, Chepanova AA, Zakharenko AL, Luzina OA et al. The first berberine-based inhibitors of tyrosyl-dna phosphodiesterase 1 (Tdp1), an important dna repair enzyme. International Journal of Molecular Sciences. 2020 Oct 1;21(19):1-16. 7162. doi: 10.3390/ijms21197162

Author

Gladkova, Elizaveta D. ; Nechepurenko, Ivan V. ; Bredikhin, Roman A. et al. / The first berberine-based inhibitors of tyrosyl-dna phosphodiesterase 1 (Tdp1), an important dna repair enzyme. In: International Journal of Molecular Sciences. 2020 ; Vol. 21, No. 19. pp. 1-16.

BibTeX

@article{4761867a678a4299b3a1e8088abd9a6b,
title = "The first berberine-based inhibitors of tyrosyl-dna phosphodiesterase 1 (Tdp1), an important dna repair enzyme",
abstract = "A series of berberine and tetrahydroberberine sulfonate derivatives were prepared and tested against the tyrosyl-DNA phosphodiesterase 1 (Tdp1) DNA-repair enzyme. The berberine derivatives inhibit the Tdp1 enzyme in the low micromolar range; this is the first reported berberine based Tdp1 inhibitor. A structure–activity relationship analysis revealed the importance of bromine substitution in the 12-position on the tetrahydroberberine scaffold. Furthermore, it was shown that the addition of a sulfonate group containing a polyfluoroaromatic moiety at position 9 leads to increased potency, while most of the derivatives containing an alkyl fragment at the same position were not active. According to the molecular modeling, the bromine atom in position 12 forms a hydrogen bond to histidine 493, a key catalytic residue. The cytotoxic effect of topotecan, a clinically important topoisomerase 1 inhibitor, was doubled in the cervical cancer HeLa cell line by derivatives 11g and 12g; both displayed low toxicity without topotecan. Derivatives 11g and 12g can therefore be used for further development to sensitize the action of clinically relevant Topo1 inhibitors.",
keywords = "Berberine, Cancer, DNA repair enzyme, Molecular modeling, SAR, Tdp1 inhibitor, Tetrahydroberberine",
author = "Gladkova, {Elizaveta D.} and Nechepurenko, {Ivan V.} and Bredikhin, {Roman A.} and Chepanova, {Arina A.} and Zakharenko, {Alexandra L.} and Luzina, {Olga A.} and Ilina, {Ekaterina S.} and Dyrkheeva, {Nadezhda S.} and Mamontova, {Evgeniya M.} and Anarbaev, {Rashid O.} and J{\'o}hannes Reynisson and Volcho, {Konstantin P.} and Salakhutdinov, {Nariman F.} and Lavrik, {Olga I.}",
note = "Publisher Copyright: {\textcopyright} 2020 by the authors. Licensee MDPI, Basel, Switzerland.",
year = "2020",
month = oct,
day = "1",
doi = "10.3390/ijms21197162",
language = "English",
volume = "21",
pages = "1--16",
journal = "International Journal of Molecular Sciences",
issn = "1661-6596",
publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",
number = "19",

}

RIS

TY - JOUR

T1 - The first berberine-based inhibitors of tyrosyl-dna phosphodiesterase 1 (Tdp1), an important dna repair enzyme

AU - Gladkova, Elizaveta D.

AU - Nechepurenko, Ivan V.

AU - Bredikhin, Roman A.

AU - Chepanova, Arina A.

AU - Zakharenko, Alexandra L.

AU - Luzina, Olga A.

AU - Ilina, Ekaterina S.

AU - Dyrkheeva, Nadezhda S.

AU - Mamontova, Evgeniya M.

AU - Anarbaev, Rashid O.

AU - Reynisson, Jóhannes

AU - Volcho, Konstantin P.

AU - Salakhutdinov, Nariman F.

AU - Lavrik, Olga I.

N1 - Publisher Copyright: © 2020 by the authors. Licensee MDPI, Basel, Switzerland.

PY - 2020/10/1

Y1 - 2020/10/1

N2 - A series of berberine and tetrahydroberberine sulfonate derivatives were prepared and tested against the tyrosyl-DNA phosphodiesterase 1 (Tdp1) DNA-repair enzyme. The berberine derivatives inhibit the Tdp1 enzyme in the low micromolar range; this is the first reported berberine based Tdp1 inhibitor. A structure–activity relationship analysis revealed the importance of bromine substitution in the 12-position on the tetrahydroberberine scaffold. Furthermore, it was shown that the addition of a sulfonate group containing a polyfluoroaromatic moiety at position 9 leads to increased potency, while most of the derivatives containing an alkyl fragment at the same position were not active. According to the molecular modeling, the bromine atom in position 12 forms a hydrogen bond to histidine 493, a key catalytic residue. The cytotoxic effect of topotecan, a clinically important topoisomerase 1 inhibitor, was doubled in the cervical cancer HeLa cell line by derivatives 11g and 12g; both displayed low toxicity without topotecan. Derivatives 11g and 12g can therefore be used for further development to sensitize the action of clinically relevant Topo1 inhibitors.

AB - A series of berberine and tetrahydroberberine sulfonate derivatives were prepared and tested against the tyrosyl-DNA phosphodiesterase 1 (Tdp1) DNA-repair enzyme. The berberine derivatives inhibit the Tdp1 enzyme in the low micromolar range; this is the first reported berberine based Tdp1 inhibitor. A structure–activity relationship analysis revealed the importance of bromine substitution in the 12-position on the tetrahydroberberine scaffold. Furthermore, it was shown that the addition of a sulfonate group containing a polyfluoroaromatic moiety at position 9 leads to increased potency, while most of the derivatives containing an alkyl fragment at the same position were not active. According to the molecular modeling, the bromine atom in position 12 forms a hydrogen bond to histidine 493, a key catalytic residue. The cytotoxic effect of topotecan, a clinically important topoisomerase 1 inhibitor, was doubled in the cervical cancer HeLa cell line by derivatives 11g and 12g; both displayed low toxicity without topotecan. Derivatives 11g and 12g can therefore be used for further development to sensitize the action of clinically relevant Topo1 inhibitors.

KW - Berberine

KW - Cancer

KW - DNA repair enzyme

KW - Molecular modeling

KW - SAR

KW - Tdp1 inhibitor

KW - Tetrahydroberberine

UR - http://www.scopus.com/inward/record.url?scp=85091724433&partnerID=8YFLogxK

U2 - 10.3390/ijms21197162

DO - 10.3390/ijms21197162

M3 - Article

C2 - 32998385

AN - SCOPUS:85091724433

VL - 21

SP - 1

EP - 16

JO - International Journal of Molecular Sciences

JF - International Journal of Molecular Sciences

SN - 1661-6596

IS - 19

M1 - 7162

ER -

ID: 25676495