Abstract
Inhibition of DNA repair enzymes tyrosyl-DNA phosphodiesterase 1 and poly(ADP-ribose)polymerases 1 and 2 in the presence of pyrimidine nucleoside derivatives was studied here. New effective Tdp1 inhibitors were found in a series of nucleoside derivatives possessing 2′,3′,5′-tri-O-benzoyl-d-ribofuranose and 5-substituted uracil moieties and have half-maximal inhibitory concentrations (IC50) in the lower micromolar and submicromolar range. 2′,3′,5′-Tri-O-benzoyl-5-iodouridine manifested the strongest inhibitory effect on Tdp1 (IC50 = 0.6 μM). A decrease in the number of benzoic acid residues led to a marked decline in the inhibitory activity, and pyrimidine nucleosides lacking lipophilic groups (uridine, 5-fluorouridine, 5-chlorouridine, 5-bromouridine, 5-iodouridine, and ribothymidine) did not cause noticeable inhibition of Tdp1 (IC50 > 50 μM). No PARP1/2 inhibitors were found among the studied compounds (residual activity in the presence of 1 mM substances was 50–100%). Several O-benzoylated uridine and cytidine derivatives strengthened the action of topotecan on HeLa cervical cancer cells.
Highlights
DNA repair systems are resistant to the action of chemotherapeutic drugs and ionizing radiation, and the beneficial effect of antitumor therapy depends on the effectiveness of DNA repair systems in tumor cells
On HeLa cells, we studied the effect of the synthesized tyrosyl-DNA phosphodiesterase 1 (Tdp1) inhibitors in combination with topotecan, which is the topoisomerase 1 (Top1) poison used in clinical practice
We studied the inhibition of DNA repair enzymes (PARP1, PARP2, and Tdp1) by lipophilic pyrimidine nucleosides
Summary
DNA repair systems are resistant to the action of chemotherapeutic drugs and ionizing radiation, and the beneficial effect of antitumor therapy depends on the effectiveness of DNA repair systems in tumor cells. Targeted inhibition of DNA repair enzymes can increase the effectiveness of chemotherapeutic drugs used in clinical practice and may enable reducing their dose, which in turn can decrease the overall toxicity of treatment [1,2,3,4,5,6,7,8]. Poly(ADP-ribose)polymerase 1 (PARP1, EC 2.4.2.30)—a key regulator of DNA repair mechanisms—is the most studied pharmacological target for the creation of targeted drugs [16]. Four PARP1 inhibitors (olaparib, rucaparib, niraparib, and talazoparib) are used in clinical practice for the treatment of ovarian cancer. Among promising targets is the enzyme tyrosyl-DNA phosphodiesterase 1 (Tdp1), which is considered an important target for the antitumor therapy based on topoisomerase 1 (Top1) inhibitors [17]
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