TY - JOUR

T1 - Novel tyrosyl-DNA phosphodiesterase 1 inhibitors enhance the therapeutic impact of topoteсan on in vivo tumor models

AU - Zakharenko, A. L.

AU - Luzina, O. A.

AU - Sokolov, D. N.

AU - Kaledin, V. I.

AU - Nikolin, V. P.

AU - Popova, N. A.

AU - Patel, J.

AU - Zakharova, O. D.

AU - Chepanova, A. A.

AU - Zafar, A.

AU - Reynisson, J.

AU - Leung, E.

AU - Leung, I. K.H.

AU - Volcho, K. P.

AU - Salakhutdinov, N. F.

AU - Lavrik, O. I.

N1 - Publisher Copyright: © 2018 Elsevier Masson SAS

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

KW - Campthotecin

KW - Lewis lung carcinoma

KW - Molecular modelling

KW - Topotecan

KW - Tyrosyl-DNA phosphodiesterase 1 (Tdp1)

KW - Usnic acid

KW - STRAND BREAK REPAIR

KW - HUMAN-CELLS

KW - EMPIRICAL SCORING FUNCTIONS

KW - TOPOISOMERASE-I

KW - IDENTIFICATION

KW - CAMPTOTHECIN

KW - PROTEIN-LIGAND DOCKING

KW - TDP1

KW - BIOLOGICAL EVALUATION

KW - USNIC ACID

KW - Humans

KW - Structure-Activity Relationship

KW - Topotecan/chemical synthesis

KW - Dose-Response Relationship, Drug

KW - Quantum Theory

KW - Neoplasms, Experimental/drug therapy

KW - Lung Neoplasms/drug therapy

KW - Molecular Structure

KW - Cell Proliferation/drug effects

KW - Mice, Inbred C57BL

KW - Models, Molecular

KW - Topoisomerase I Inhibitors/chemical synthesis

KW - Antineoplastic Agents/chemical synthesis

KW - Phosphoric Diester Hydrolases/metabolism

KW - Animals

KW - Cell Line, Tumor

KW - Mice

KW - Drug Screening Assays, Antitumor

UR - http://www.scopus.com/inward/record.url?scp=85055914808&partnerID=8YFLogxK

U2 - 10.1016/j.ejmech.2018.10.055

DO - 10.1016/j.ejmech.2018.10.055

M3 - Article

C2 - 30396105

AN - SCOPUS:85055914808

VL - 161

SP - 581

EP - 593

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

SN - 0223-5234

ER -