Novel Inhibitors of DNA Repair Enzyme TDP1 Combining Monoterpenoid and Adamantane Fragments

Abstract

Background and Objective: The DNA repair enzyme tyrosyl-DNA-phosphodiesterase 1 (TDP1) is a current inhibition target to improve the efficacy of cancer chemotherapy. Previous studies showed that compounds combining adamantane and monoterpenoid fragments are active against TDP1 enzyme. This investigation is focused on the synthesis of monoterpenoid derived esters of 1-adamantane carboxylic acid as TDP1 inhibitors. Methods: New esters were synthesized by the interaction between 1-adamantane carboxylic acid chloride and monoterpenoid alcohols. The esters were tested against TDP1 and its binding to the enzyme was modeling. Results: 13 Novel ester-based TDP1 inhibitors were synthesized with yields of 21–94%; of these, nine esters had not been previously described. A number of the esters were found to inhibit TDP1, with IC50 values ranging from 0.86–4.08 µM. Molecular modelling against the TDP1 crystal structure showed a good fit of the active esters in the catalytic pocket, explaining their potency. A non-toxic dose of ester, containing a 3,7- dimethyloctanol fragment, was found to enhance the cytotoxic effect of topotecan, a clinically used anti-cancer drug, against the human lung adenocarcinoma cell line A549. Conclusion: The esters synthesized were found to be active against TDP1 in the lower micromolar concentration range, with these findings being corroborated by molecular modeling. Simultaneous action of the ester synthesized from 3,7-dimethyloctanol-1 and topotecan revealed a synergistic effect.

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

“…The compounds synthesized can be divided in to two groups: (1) amides and thioamides of 1-and 2-adamantane carboxylic acids (44a,b; 45a,b; 46a; 47a); (2) derivatives of citronellic acid (50a,b; 51). Comparing inhibitory activity of the first group (Table 1) and compounds synthesized previously [49] it can be concluded that amides 44-47 are less active than their ester counterparts are. For example, in the cases of derivatives 29 (ester), 44 (amide), 48 (thioamide), which are structural analogues, the following IC 50 values were obtained: 0.92, >75 and 3.3 µM, respectively.…”

“…Intrinsic protein fluorescence assay were conducted according to the protocol as described in references [35,45,49]. The concentrations of recombinant Tdp1 and ligand were 10 µM and 1 mM, respectively.…”

“…The binding and inhibition potency of the compounds were tested against purified recombinant Tdp1. Binding experiments were conducted using thermal shift assay [71] and an intrinsic fluorescence binding assay that we previously developed [35,45,49]. Thermal shift assay measures the stability of proteins against thermal degradation.…”

“…The adamantane derivatives were used in the nontoxic concentration of 5 µM. Most compounds had a In general, based on the results shown in Table 1 and previously published results [49], the following conclusions can be made: (1) Thioamides are more active than the esters and they have better activity than their amide counterparts; (2) 2-adamanatne substituted derivatives (45a, 45b, 47a, 50b and 51) are more active compared to 1-adamantane substituted isomers (44a, 44b, 46a and 50a).…”

The effect of 3,7-diazabicyclo[3.3.1]nonanescontaining monoterpenoid moieties on the physical activity of mice.

“…been developed based on adamantane [4][5][6][7][8]. The mechanism of action of adamantane derivatives that belong to the class of actoprotectors (bromantane, chlodantan) is related to the increased synthesis of dopamine and inhibition of the process of lipid peroxidation [9][10][11].…”