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

Результат исследования: Научные публикации в периодических изданияхстатья

15 Цитирования (Scopus)

Аннотация

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.

Язык оригиналаанглийский
Страницы (с-по)581-593
Число страниц13
ЖурналEuropean Journal of Medicinal Chemistry
Том161
DOI
СостояниеОпубликовано - 1 янв 2019

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