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The First Berberine-Based Inhibitors of Tyrosyl-DNA Phosphodiesterase 1 (Tdp1), an Important DNA Repair Enzyme

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....

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Autores principales: Gladkova, Elizaveta D., Nechepurenko, Ivan V., Bredikhin, Roman A., Chepanova, Arina A., Zakharenko, Alexandra L., Luzina, Olga A., Ilina, Ekaterina S., Dyrkheeva, Nadezhda S., Mamontova, Evgeniya M., Anarbaev, Rashid O., Reynisson, Jóhannes, Volcho, Konstantin P., Salakhutdinov, Nariman F., Lavrik, Olga I.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7582571/
https://www.ncbi.nlm.nih.gov/pubmed/32998385
http://dx.doi.org/10.3390/ijms21197162
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author Gladkova, Elizaveta D.
Nechepurenko, Ivan V.
Bredikhin, Roman A.
Chepanova, Arina A.
Zakharenko, Alexandra L.
Luzina, Olga A.
Ilina, Ekaterina S.
Dyrkheeva, Nadezhda S.
Mamontova, Evgeniya M.
Anarbaev, Rashid O.
Reynisson, Jóhannes
Volcho, Konstantin P.
Salakhutdinov, Nariman F.
Lavrik, Olga I.
author_facet Gladkova, Elizaveta D.
Nechepurenko, Ivan V.
Bredikhin, Roman A.
Chepanova, Arina A.
Zakharenko, Alexandra L.
Luzina, Olga A.
Ilina, Ekaterina S.
Dyrkheeva, Nadezhda S.
Mamontova, Evgeniya M.
Anarbaev, Rashid O.
Reynisson, Jóhannes
Volcho, Konstantin P.
Salakhutdinov, Nariman F.
Lavrik, Olga I.
author_sort Gladkova, Elizaveta D.
collection PubMed
description 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.
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spelling pubmed-75825712020-10-28 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. Chepanova, Arina A. Zakharenko, Alexandra L. Luzina, Olga A. Ilina, Ekaterina S. Dyrkheeva, Nadezhda S. Mamontova, Evgeniya M. Anarbaev, Rashid O. Reynisson, Jóhannes Volcho, Konstantin P. Salakhutdinov, Nariman F. Lavrik, Olga I. Int J Mol Sci Article 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. MDPI 2020-09-28 /pmc/articles/PMC7582571/ /pubmed/32998385 http://dx.doi.org/10.3390/ijms21197162 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Gladkova, Elizaveta D.
Nechepurenko, Ivan V.
Bredikhin, Roman A.
Chepanova, Arina A.
Zakharenko, Alexandra L.
Luzina, Olga A.
Ilina, Ekaterina S.
Dyrkheeva, Nadezhda S.
Mamontova, Evgeniya M.
Anarbaev, Rashid O.
Reynisson, Jóhannes
Volcho, Konstantin P.
Salakhutdinov, Nariman F.
Lavrik, Olga I.
The First Berberine-Based Inhibitors of Tyrosyl-DNA Phosphodiesterase 1 (Tdp1), an Important DNA Repair Enzyme
title The First Berberine-Based Inhibitors of Tyrosyl-DNA Phosphodiesterase 1 (Tdp1), an Important DNA Repair Enzyme
title_full The First Berberine-Based Inhibitors of Tyrosyl-DNA Phosphodiesterase 1 (Tdp1), an Important DNA Repair Enzyme
title_fullStr The First Berberine-Based Inhibitors of Tyrosyl-DNA Phosphodiesterase 1 (Tdp1), an Important DNA Repair Enzyme
title_full_unstemmed The First Berberine-Based Inhibitors of Tyrosyl-DNA Phosphodiesterase 1 (Tdp1), an Important DNA Repair Enzyme
title_short The First Berberine-Based Inhibitors of Tyrosyl-DNA Phosphodiesterase 1 (Tdp1), an Important DNA Repair Enzyme
title_sort first berberine-based inhibitors of tyrosyl-dna phosphodiesterase 1 (tdp1), an important dna repair enzyme
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7582571/
https://www.ncbi.nlm.nih.gov/pubmed/32998385
http://dx.doi.org/10.3390/ijms21197162
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