Novel Group of Tyrosyl-DNA-phosphodiesterase 1 Inhibitors Based on Disaccharide Nucleosides As Drug Prototypes for Anti-cancer Therapy

Overview

Journal J Enzyme Inhib Med Chem

Specialty Biochemistry

Date 2018 Sep 8

PMID 30191738

Citations 14

Authors

Anastasia O Komarova

Mikhail S Drenichev

Nadezhda S Dyrkheeva

Irina V Kulikova

Vladimir E Oslovsky

Olga D Zakharova

Alexandra L Zakharenko

Sergey N Mikhailov

Olga I Lavrik

Affiliations

Soon will be listed here.

Abstract

A new class of tyrosyl-DNA phosphodiesterase 1 (TDP1) inhibitors based on disaccharide nucleosides was identified. TDP1 plays an essential role in the resistance of cancer cells to currently used antitumour drugs based on Top1 inhibitors such as topotecan and irinotecan. The most effective inhibitors investigated in this study have IC values (half-maximal inhibitory concentration) in 0.4-18.5 µM range and demonstrate relatively low own cytotoxicity along with significant synergistic effect in combination with anti-cancer drug topotecan. Moreover, kinetic parameters of the enzymatic reaction and fluorescence anisotropy were measured using different types of DNA-biosensors to give a sufficient insight into the mechanism of inhibitor's action.

Citing Articles

Natural Products and Their Derivatives as Inhibitors of the DNA Repair Enzyme Tyrosyl-DNA Phosphodiesterase 1.

Zakharenko A, Luzina O, Chepanova A, Dyrkheeva N, Salakhutdinov N, Lavrik O Int J Mol Sci. 2023; 24(6).

PMID: 36982848 PMC: 10051138. DOI: 10.3390/ijms24065781.

Synthesis and Biological Activities of 11- and 12-Substituted Benzophenanthridinone Derivatives as DNA Topoisomerase IB and Tyrosyl-DNA Phosphodiesterase 1 Inhibitors.

Yang H, Qin C, Wu M, Wang F, Wang W, Agama K ChemMedChem. 2023; 18(10):e202200593.

PMID: 36932053 PMC: 10233710. DOI: 10.1002/cmdc.202200593.

The Lipophilic Purine Nucleoside-Tdp1 Inhibitor-Enhances DNA Damage Induced by Topotecan In Vitro and Potentiates the Antitumor Effect of Topotecan In Vivo.

Chernyshova I, Zakharenko A, Kurochkin N, Dyrkheeva N, Kornienko T, Popova N Molecules. 2023; 28(1).

PMID: 36615517 PMC: 9822400. DOI: 10.3390/molecules28010323.

In Vitro and In Silico Studies of Human Tyrosyl-DNA Phosphodiesterase 1 (Tdp1) Inhibition by Stereoisomeric Forms of Lipophilic Nucleosides: The Role of Carbohydrate Stereochemistry in Ligand-Enzyme Interactions.

Dyrkheeva N, Chernyshova I, Ivanov G, Porozov Y, Zenchenko A, Oslovsky V Molecules. 2022; 27(8).

PMID: 35458631 PMC: 9024977. DOI: 10.3390/molecules27082433.

New Hybrid Compounds Combining Fragments of Usnic Acid and Thioether Are Inhibitors of Human Enzymes TDP1, TDP2 and PARP1.

Dyrkheeva N, Filimonov A, Luzina O, Orlova K, Chernyshova I, Kornienko T Int J Mol Sci. 2021; 22(21).

PMID: 34768766 PMC: 8583042. DOI: 10.3390/ijms222111336.

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