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Open AccessArticle

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

1
N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, 9, Akademika Lavrentieva Ave., Novosibirsk 630090, Russia
2
Novosibirsk State University, Pirogova str. 1, Novosibirsk 630090, Russia
3
Novosibirsk Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 8, Akademika Lavrentieva Ave., Novosibirsk 630090, Russia
4
School of Pharmacy and Bioengineering, Keele University, Hornbeam Building, Staffordshire ST5 5BG, UK
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(19), 7162; https://doi.org/10.3390/ijms21197162
Received: 31 August 2020 / Revised: 22 September 2020 / Accepted: 26 September 2020 / Published: 28 September 2020
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. View Full-Text
Keywords: berberine; tetrahydroberberine; Tdp1 inhibitor; cancer; molecular modeling; DNA repair enzyme; SAR berberine; tetrahydroberberine; Tdp1 inhibitor; cancer; molecular modeling; DNA repair enzyme; SAR
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MDPI and ACS Style

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. The First Berberine-Based Inhibitors of Tyrosyl-DNA Phosphodiesterase 1 (Tdp1), an Important DNA Repair Enzyme. Int. J. Mol. Sci. 2020, 21, 7162. https://doi.org/10.3390/ijms21197162

AMA Style

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. The First Berberine-Based Inhibitors of Tyrosyl-DNA Phosphodiesterase 1 (Tdp1), an Important DNA Repair Enzyme. International Journal of Molecular Sciences. 2020; 21(19):7162. https://doi.org/10.3390/ijms21197162

Chicago/Turabian Style

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. 2020. "The First Berberine-Based Inhibitors of Tyrosyl-DNA Phosphodiesterase 1 (Tdp1), an Important DNA Repair Enzyme" Int. J. Mol. Sci. 21, no. 19: 7162. https://doi.org/10.3390/ijms21197162

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