Inhibition of Tyrosyl-DNA Phosphodiesterase 1 by Lipophilic Pyrimidine Nucleosides

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.

Small molecule microarray identifies inhibitors of tyrosyl-DNA phosphodiesterase 1 that simultaneously access the catalytic pocket and two substrate binding sites

“…A number of TDP1 inhibitors have previously been reported with some exerting synergy with TOP1 inhibitors. 10,12,14,16,18,19 However, the precise manner in which these ligands bind to the TDP1 protein are unknown, which limits further development using structure-based approaches. Our current work represents a qualitative departure from previous efforts in the way that it rst interrogates the ability of ligands to bind to TDP1 using a microarray including more than 20 000 ligands.…”

“…5,6 Accordingly, such agents may represent a promising new class of therapeutics with potential use for the treatment of cancer in synergistic combination with current TOP1 inhibitors. 4,[7][8][9][10][11][12][13][14][15][16][17][18][19] While signicant effort has been devoted to developing TDP1 inhibitors and a variety of inhibitors have been reported, the structural basis for how these inhibitors interact with TDP1 is generally unknown, which may limit the derivation of new analogues through structure-based approaches. 6,20 In addition, many TDP1 inhibitors exhibit physiochemical properties, which could potentially endow them with promiscuous mechanisms of inhibition that would make them of questionable value for further development.…”

A Dual-Sensor-Based Screening System for In Vitro Selection of TDP1 Inhibitors

“…However, most compounds have not been tested in vivo and are only tested in vitro for inhibition of TDP1 (not inhibition of TOP1) [ 10 , 12 , 17 , 20 , 72 , 73 , 74 ]. When comparing data for other TDP1 inhibitors tested in vivo in cell cultures [ 18 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 ] to data in this study, it is noticeable that our TDP1 inhibitors have a good effect on reducing cell survival even at low concentrations of both TDP1 inhibitor and TOP1 poison. In conclusion, the TDP1 inhibitors, namely NAF-15, PSTHQ-2, and PSTHQ-13, identified in this study show promising perspectives for further testing of clinical utility.…”

Design, Synthesis, and Molecular Docking Study of New Tyrosyl-DNA Phosphodiesterase 1 (TDP1) Inhibitors Combining Resin Acids and Adamantane Moieties

“…The search for inhibitors of key DNA repair enzymes is a promising area of medical chemistry, as it represents one of the ways to design effective therapies for cancer, as well as cardiovascular and neurodegenerative diseases. Recently, a number of TDP1 inhibitor structural classes have been studied, including pyrimidine nucleosides [ 11 ], furamidine [ 12 ], compounds with benzopentathiepine moiety [ 13 ], indenoisoquinolines [ 14 ], and 5-arylidenethioxothiazolidinones [ 15 ] ( Figure 1 ).…”