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

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 M. 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 M concentration, displaying strong synergism. This effect was only seen for 46a (IC50—3.3 M) 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.

Promising New Inhibitors of Tyrosyl-DNA Phosphodiesterase I (Tdp 1) Combining 4-Arylcoumarin and Monoterpenoid Moieties as Components of Complex Antitumor Therapy

“…In addition to the activity assay that we reported above, we wanted to confirm the interactions between compound 3ba and Tdp1 before progressing to in vivo studies. Using an intrinsic tryptophan fluorescence quenching assay that we previously applied to study the binding interactions of Tdp1 and its inhibitors [43,45,48,49,52], we evaluated the binding of compound 3ba to recombinant Tdp1. Clear quenching of the Tdp1 intrinsic fluorescence was observed upon the addition of 3ba (Supplementary Figure S1).…”

“…To date, many Tdp1 inhibitors have been identified. A major class of Tdp1 inhibitors comprises those based on natural products including usnic acid derivatives [41][42][43][44][45], coumarins [46], adamantanes [47][48][49], nucleoside analogs [50], dehydroabietylamine derivatives [51], chromenes [52], bile acids derivatives [53], and fungal products [54][55][56]. There are also early reports of Tdp1 inhibition based on diamidines [57], antibiotics [58,59], steroids [60], and other compounds [61].…”

Design, Synthesis, and Biological Investigation of Novel Classes of 3-Carene-Derived Potent Inhibitors of TDP1

“…Some of these derivatives exhibit analgesic, antiviral, neuroprotective, and antitumor properties [ 14 ]. Moreover, new classes of TDP1 inhibitors with submicromolar half maximal inhibitory concentration (IC 50 ) values have been developed that contain monoterpene moieties; for example, coumarin [ 16 ], 4-arylcoumarin [ 17 ], and adamantane [ 18 , 19 , 20 , 21 ] derivatives as well as octahydro-2 H -chromenes 3 (see Figure 1 ) synthesized from p -menthane monoterpenoid (-)-isopulegol [ 22 ]. Their ability to enhance the Tpc cytotoxic potential was demonstrated for several of these derivatives.…”

“…For example, 7-hydroxycoumarin derivative 4 ( Figure 1 ) with a pinene-type fragment reduced the CC 50 (median cytotoxic concentration causing 50% cell death) of camptothecin eight-fold for the human breast adenocarcinoma cell line MCF-7 [ 16 ] while the hybrid molecule 5 , comprising of (4-fluorophenyl)-coumarin and geraniol moieties, showed a significant increase in the antitumor effect of Tpc on Krebs-2 ascites in an in vivo tumor model [ 17 ]. Among the adamantane derivatives, strong synergism was found for 6 and 7 ( Figure 1 ), both containing the acyclic monoterpene substituents, when lung adenocarcinoma cells A549 were treated in combination with Tpc [ 18 , 20 ].…”

New Hydrazinothiazole Derivatives of Usnic Acid as Potent Tdp1 Inhibitors

“…In addition, Tdp1 inhibitors have also been found from natural sources. It has been reported that natural products that are isolated from anamorphic fungus (e.g., compound 5 , Figure 2) [12], triptamine derivatives of bile acids 6 [13], and monoterpenoid derivatives such as 7 and 8 that are attached to 7-hydroxycoumarin [14] or adamantane fragments [15,16,17] all show inhibitory activity against Tdp1 in the micromolar and submicromolar concentration ranges.…”