Chepanova, AA, Mozhaitsev, ES, Munkuev, AA, Suslov, EV, Korchagina, DV, Zakharova, OD, Zakharenko, AL, Patel, J, Ayine-Tora, DM, Reynisson, J and al, E (2019) The Development of Tyrosyl-DNA Phosphodiesterase 1 Inhibitors. Combination of Monoterpene and Adamantine Moieties via Amide or Thioamide Bridges. Applied Sciences, 9. 2767 -2767. ISSN 2076-3417

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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.

Item Type: Article
Additional Information: This is the final published version of the article (version of record). It first appeared online via MDPI at - please refer to any applicable terms of use of the publisher.
Uncontrolled 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
Subjects: R Medicine > RS Pharmacy and materia medica
Divisions: Faculty of Medicine and Health Sciences > School of Pharmacy
Depositing User: Symplectic
Date Deposited: 08 Aug 2019 15:11
Last Modified: 24 Mar 2021 12:52

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