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The Development of Tyrosyl-DNA Phosphodiesterase 1 Inhibitors. Combination of Monoterpene and Adamantine Moieties via Amide or Thioamide Bridges

1
Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of Russian Academy of Sciences, 8, Lavrentiev Ave., Novosibirsk 630090, Russia
2
N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of Russian Academy of Sciences, 9, Lavrentiev Ave., Novosibirsk 630090, Russia
3
Novosibirsk State University, 2, Pirogova Str., Novosibirsk 630090, Russia
4
School of Chemical Sciences, The University of Auckland, Private Bag 92019, Victoria Street West, Auckland 1142, New Zealand
5
School of Pharmacy, Keele University, Hornbeam Building, Staffordshire ST5 5BG, UK
6
Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Private Bag 92019, Victoria Street West, Auckland 1142, New Zealand
*
Author to whom correspondence should be addressed.
Appl. Sci. 2019, 9(13), 2767; https://doi.org/10.3390/app9132767
Received: 12 June 2019 / Revised: 2 July 2019 / Accepted: 3 July 2019 / Published: 9 July 2019
(This article belongs to the Section Chemistry)
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Abstract

Eleven amide and thioamide derivatives with monoterpene and adamantine substituents were synthesised. They were tested for their activity against the tyrosyl-DNA phosphodiesterase 1 DNA (Tdp1) repair enzyme with the most potent compound 47a, having an IC50 value of 0.64 µM. When tested in the A-549 lung adenocarcinoma cell line, no or very limited cytotoxic effect was observed for the ligands. However, in conjunction with topotecan, a well-established Topoisomerase 1 (Top1) poison in clinical use against cancer, derivative 46a was very cytotoxic at 5 µM concentration, displaying strong synergism. This effect was only seen for 46a (IC50—3.3 µM) albeit some other ligands had better IC50 values. Molecular modelling into the catalytic site of Tdp1 predicted plausible binding mode of 46a, effectively blocking access to the catalytic site. View Full-Text
Keywords: topotecan; A-549 lung adenocarcinoma cell line l; Topoisomerase 1; molecular modelling; chemical space; synergy; thermal shift assay; intrinsic tryptophan fluorescence binding assay; fluorescence biosensor assay topotecan; A-549 lung adenocarcinoma cell line l; Topoisomerase 1; molecular modelling; chemical space; synergy; thermal shift assay; intrinsic tryptophan fluorescence binding assay; fluorescence biosensor assay
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Chepanova, A.A.; Mozhaitsev, E.S.; Munkuev, A.A.; Suslov, E.V.; Korchagina, D.V.; Zakharova, O.D.; Zakharenko, A.L.; Patel, J.; Ayine-Tora, D.M.; Reynisson, J.; Leung, I.K.H.; Volcho, K.P.; Salakhutdinov, N.F.; Lavrik, O.I. The Development of Tyrosyl-DNA Phosphodiesterase 1 Inhibitors. Combination of Monoterpene and Adamantine Moieties via Amide or Thioamide Bridges. Appl. Sci. 2019, 9, 2767.

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