Novel group of tyrosyl-DNA-phosphodiesterase 1 inhibitors based on disaccharide nucleosides as drug prototypes for anti-cancer therapy

Komarova, Anastasia O.; Drenichev, Mikhail S.; Dyrkheeva, Nadezhda S.; Kulikova, Irina V.; Oslovsky, Vladimir E.; Zakharova, Olga D.; Zakharenko, Alexandra L.; Mikhailov, Sergey N.; Lavrik, Olga I.

doi:10.1080/14756366.2018.1509210

Cited by 19 publications

(21 citation statements)

References 74 publications

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“…This compound is now entering the preclinical trial phase. This group also used semisynthetic derivatives of bile acids and disaccharide nucleosides as a scaffold for the development of Tdp1 catalytic inhibitors [68,69] . The bile acid derivatives were tested by in silico-docking and in a catalytic assay showing inhibition in the 300 to 500 nmol/L ranges with N -(2”-(3’,5’-Di-tret-buthyl-4’-hydroxyphenyl)-ethyl)-3a,12a-diacetoxy-5b-cholan-24-amide as the most promising compound [69] .…”

Section: Catalytic Inhibitorsmentioning

confidence: 99%

Targeting Tyrosyl-DNA phosphodiesterase I to enhance toxicity of phosphodiester linked DNA-adducts

Brettrager

Waardenburg

2019

CDR

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Our genomic DNA is under constant assault from endogenous and exogenous sources, which needs to be resolved to maintain cellular homeostasis. The eukaryotic DNA repair enzyme Tyrosyl-DNA phosphodiesterase I (Tdp1) catalyzes the hydrolysis of phosphodiester bonds that covalently link adducts to DNA-ends. Tdp1 utilizes two catalytic histidines to resolve a growing list of DNA-adducts. These DNA-adducts can be divided into two groups: small adducts, including oxidized nucleotides, RNA, and non-canonical nucleoside analogs, and large adducts, such as (drug-stabilized) topoisomerase-DNA covalent complexes or failed Schiff base reactions as occur between PARP1 and DNA. Many Tdp1 substrates are generated by chemotherapeutics linking Tdp1 to cancer drug resistance, making a compelling argument to develop small molecules that target Tdp1 as potential novel therapeutic agents. Tdp1's unique catalytic cycle, which is centered on the formation of Tdp1-DNA covalent reaction intermediate, allows for two principally different targeting strategies: (1) catalytic inhibition of Tdp1 catalysis to prevent Tdp1-mediated repair of DNA-adducts that enhances the effectivity of chemotherapeutics; and (2) poisoning of Tdp1 by stabilization of the Tdp1-DNA covalent reaction intermediate, which would increase the half-life of a potentially toxic DNA-adduct by preventing its resolution, analogous to topoisomerase targeted poisons such as topotecan or etoposide. The catalytic Tdp1 mutant that forms the molecular basis of the autosomal recessive neurodegenerative disease spinocerebellar ataxia with axonal neuropathy best illustrates this concept; however, no small molecules have been reported for this strategy. Herein, we concisely discuss the development of Tdp1 catalytic inhibitors and their results.

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Section: Catalytic Inhibitorsmentioning

confidence: 99%

Targeting Tyrosyl-DNA phosphodiesterase I to enhance toxicity of phosphodiester linked DNA-adducts

Brettrager

Waardenburg

2019

CDR

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“…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].…”

Section: Introductionmentioning

confidence: 99%

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

Khomenko

Zakharenko

Chepanova

et al. 2019

IJMS

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Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is an important DNA repair enzyme in humans, and a current and promising inhibition target for the development of new chemosensitizing agents due to its ability to remove DNA damage caused by topoisomerase 1 (Top1) poisons such as topotecan and irinotecan. Herein, we report our work on the synthesis and characterization of new Tdp1 inhibitors that combine the arylcoumarin (neoflavonoid) and monoterpenoid moieties. Our results showed that they are potent Tdp1 inhibitors with IC50 values in the submicromolar range. In vivo experiments with mice revealed that compound 3ba (IC50 0.62 µM) induced a significant increase in the antitumor effect of topotecan on the Krebs-2 ascites tumor model. Our results further strengthen the argument that Tdp1 is a druggable target with the potential to be developed into a clinically-potent adjunct therapy in conjunction with Top1 poisons.

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“…It has been shown earlier that disaccharide nucleosides with lipophilic groups inhibit Tdp1 in a submicromolar range of concentrations and are only weakly toxic to cancerous and healthy cells [ 19 ]. On the other hand, disaccharide nucleosides tend to inhibit PARP1 [ 20 , 22 ], and this activity may reduce their selectivity toward Tdp1 in the cell.…”

Section: Discussionmentioning

confidence: 99%

“…The literature describes Tdp1 inhibitors of various structures based on different classes of natural and synthetic compounds [ 3 , 4 ]; these inhibitors have half-maximal inhibitory concentrations (IC 50 ) in the range 0.015–10.000 µM. Recently, a novel group of Tdp1 inhibitors effective in the submicromolar range of concentrations was found among disaccharide nucleosides with lipophilic groups [ 19 ]. The current work represents a continuation of our earlier studies on the inhibition of DNA repair enzymes by nucleoside compounds [ 19 , 20 , 21 , 22 , 23 , 24 ].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Tyrosyl-DNA Phosphodiesterase 1 by Lipophilic Pyrimidine Nucleosides

et al. 2020

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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.

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Novel group of tyrosyl-DNA-phosphodiesterase 1 inhibitors based on disaccharide nucleosides as drug prototypes for anti-cancer therapy

Cited by 19 publications

References 74 publications

Targeting Tyrosyl-DNA phosphodiesterase I to enhance toxicity of phosphodiester linked DNA-adducts

Targeting Tyrosyl-DNA phosphodiesterase I to enhance toxicity of phosphodiester linked DNA-adducts

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

Inhibition of Tyrosyl-DNA Phosphodiesterase 1 by Lipophilic Pyrimidine Nucleosides

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