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

Featured Application: Inhibition of Tdp1 has the potential to increase the potency of the anticancer drugs topotecan and irinotecan, topoisomerase 1 poisons. Furthermore, Tdp1 inhibitors can facilitate the therapeutic use of these drugs in other cancer types. 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. [ABSTRACT FROM AUTHOR]