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- Title
Inhibition of Tyrosyl-DNA Phosphodiesterase 1 by Lipophilic Pyrimidine Nucleosides.
- Authors
Zakharenko, Alexandra L.; Drenichev, Mikhail S.; Dyrkheeva, Nadezhda S.; Ivanov, Georgy A.; Oslovsky, Vladimir E.; Ilina, Ekaterina S.; Chernyshova, Irina A.; Lavrik, Olga I.; Mikhailov, Sergey N.; Seley-Radtke, Katherine; Agrofoglio, Luigi A.
- 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.
- Subjects
PYRIMIDINE nucleosides; URACIL derivatives; POLY ADP ribose; DNA ligases; NUCLEOSIDE derivatives; MOIETIES (Chemistry); BENZOIC acid
- Publication
Molecules, 2020, Vol 25, Issue 16, p3694
- ISSN
1420-3049
- Publication type
Article
- DOI
10.3390/molecules25163694