@article{7b8cfd0e25464a22ba4db1c42ad113d1,
title = "Novel tyrosyl-DNA phosphodiesterase 1 inhibitors enhance the therapeutic impact of topoteсan on in vivo tumor models",
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.",
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",
author = "Zakharenko, {A. L.} and Luzina, {O. A.} and Sokolov, {D. N.} and Kaledin, {V. I.} and Nikolin, {V. P.} and Popova, {N. A.} and J. Patel and Zakharova, {O. D.} and Chepanova, {A. A.} and A. Zafar and J. Reynisson and E. Leung and Leung, {I. K.H.} and Volcho, {K. P.} and Salakhutdinov, {N. F.} and Lavrik, {O. I.}",
note = "Copyright {\textcopyright} 2018 Elsevier Masson SAS. All rights reserved.",
year = "2019",
month = jan,
day = "1",
doi = "10.1016/j.ejmech.2018.10.055",
language = "English",
volume = "161",
pages = "581--593",
journal = "European Journal of Medicinal Chemistry",
issn = "0223-5234",
publisher = "Elsevier Masson SAS",
}