Novel tyrosyl-DNA phosphodiesterase 1 inhibitors enhance the therapeutic impact of topoteсan on in vivo tumor models

A. L. Zakharenko, O. A. Luzina, D. N. Sokolov, V. I. Kaledin, V. P. Nikolin, N. A. Popova, J. Patel, O. D. Zakharova, A. A. Chepanova, A. Zafar, J. Reynisson, E. Leung, I. K.H. Leung, K. P. Volcho, N. F. Salakhutdinov, O. I. Lavrik

Research output: Contribution to journalArticlepeer-review

15 Citations (Scopus)

Abstract

The druggability of the tyrosyl-DNA phosphodiesterase 1 (Tdp1) enzyme was investigated in conjunction with topoisomerase 1 inhibition. A novel class of thiazole, aminothiazole and hydrazonothiazole usnic acid derivatives was synthesized and evaluated as Tdp1 inhibitors and their ability to sensitize tumors to topotecan, a topoisomerase inhibitor in clinical use. Of all the compounds tested, four hydrazinothiazole derivatives, 20c, 20d, 20h and 20i, inhibited the enzyme in the nanomolar range. The activity of the compounds was verified by affinity experiments as well as supported by molecular modelling. The most effective Tdp1 inhibitor, 20d, was ton-toxic and increased the effect of topotecan both in vitro and in vivo in the Lewis lung carcinoma model. Furthermore, 20d showed significant increase in the antitumor and antimetastatic effect of topotecan in mice. The results presented here justify compound 20d to be considered as a drug lead for antitumor therapy. (C) 2018 Elsevier Masson SAS. All rights reserved.

Original languageEnglish
Pages (from-to)581-593
Number of pages13
JournalEuropean Journal of Medicinal Chemistry
Volume161
DOIs
Publication statusPublished - 1 Jan 2019

Keywords

  • Campthotecin
  • Lewis lung carcinoma
  • Molecular modelling
  • Topotecan
  • Tyrosyl-DNA phosphodiesterase 1 (Tdp1)
  • Usnic acid
  • STRAND BREAK REPAIR
  • HUMAN-CELLS
  • EMPIRICAL SCORING FUNCTIONS
  • TOPOISOMERASE-I
  • IDENTIFICATION
  • CAMPTOTHECIN
  • PROTEIN-LIGAND DOCKING
  • TDP1
  • BIOLOGICAL EVALUATION
  • USNIC ACID
  • Humans
  • Structure-Activity Relationship
  • Topotecan/chemical synthesis
  • Dose-Response Relationship, Drug
  • Quantum Theory
  • Neoplasms, Experimental/drug therapy
  • Lung Neoplasms/drug therapy
  • Molecular Structure
  • Cell Proliferation/drug effects
  • Mice, Inbred C57BL
  • Models, Molecular
  • Topoisomerase I Inhibitors/chemical synthesis
  • Antineoplastic Agents/chemical synthesis
  • Phosphoric Diester Hydrolases/metabolism
  • Animals
  • Cell Line, Tumor
  • Mice
  • Drug Screening Assays, Antitumor

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