The paper with the participation of NIOCh's researchers O.A.Luzina, , D.N.Sokolov, K.P.Volcho, N.F.Salakhutdinov (international collaboration) is published in the journal European Journal of Medicinal Chemistry Volume 161, 1 January 2019, Pages 581-593 (IF=4,816)
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.LavrikFirst published: 05 October 2018
Volume 130, January 2019, Pages 581-593
https://doi.org/10.1016/j.ejmech.2018.10.055
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.
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