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

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

Journal

European Journal of Medicinal Chemistry
ISSN: 0223-5234 , E-ISSN: 1768-3254

Output data

Year: 2019, Volume: 161, Pages: 581-593 Pages count : 13 DOI: 10.1016/j.ejmech.2018.10.055

Tags

Tyrosyl-DNA phosphodiesterase 1 (Tdp1); Campthotecin; Topotecan; Usnic acid; Molecular modelling; Lewis lung carcinoma

Authors

Zakharenko A.L. ¹ , Luzina O.A. ² , Sokolov D.N. ² , Kaledin V.I. ³ , Nikolin V.P. ³ , Popova N.A. ^3,4 , Patel J. ⁵ , Zakharova O.D. ¹ , Chepanova A.A. ¹ , Zafar A. ⁵ , Reynisson J. ⁵ , Leung E. ^6,7 , Leung I.K.H. ⁵ , Volcho K.P. ^2,4 , Salakhutdinov N.F. ^2,4 , Lavrik O.I. ^1,4

Affiliations

1	(Данные Web of science) Russian Acad Sci, Siberian Branch, Novosibirsk Inst Chem Biol & Fundamental Med, 8 Akad Lavrentieva Ave, Novosibirsk 630090, Russia
2	(Данные Web of science) Russian Acad Sci, Siberian Branch, NN Vorozhtsov Novosibirsk Inst Organ Chem, 9 Akad Lavrentieva Ave, Novosibirsk 630090, Russia
3	(Данные Web of science) Russian Acad Sci, Siberian Branch, Inst Cytol & Genet, 10 Akad Lavrentieva Ave, Novosibirsk 630090, Russia
4	(Данные Web of science) Novosibirsk State Univ, Pirogova str 1, Novosibirsk 630090, Russia
5	(Данные Web of science) Univ Auckland, Sch Chem Sci, Auckland, New Zealand
6	(Данные Web of science) Univ Auckland, Auckland Canc Soc Res Ctr, Auckland, New Zealand
7	(Данные Web of science) Univ Auckland, Dept Mol Med & Pathol, Auckland, New Zealand

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.

Zakharenko A.L. , Luzina O.A. , Sokolov D.N. , Kaledin V.I. , Nikolin V.P. , Popova N.A. , Patel J. , Zakharova O.D. , Chepanova A.A. , Zafar A. , Reynisson J. , Leung E. , Leung I.K.H. , Volcho K.P. , Salakhutdinov N.F. , Lavrik O.I.
Novel tyrosyl-DNA phosphodiesterase 1 inhibitors enhance the therapeutic impact of topotecan on in vivo tumor models
European Journal of Medicinal Chemistry. 2019. V.161. P.581-593. DOI: 10.1016/j.ejmech.2018.10.055 WOS Scopus РИНЦ

Published print:

Jan 1, 2019

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