TY - JOUR

T1 - Effective Inhibitors of Tyrosyl-DNA Phosphodiesterase 1 Based on Monoterpenoids as Potential Agents for Antitumor Therapy

AU - Chepanova, A. A.

AU - Li-Zhulanov, N. S.

AU - Sukhikh, A. S.

AU - Zafar, A.

AU - Reynisson, J.

AU - Zakharenko, A. L.

AU - Zakharova, O. D.

AU - Korchagina, D. V.

AU - Volcho, K. P.

AU - Salakhutdinov, N. F.

AU - Lavrik, O. I.

N1 - Publisher Copyright: © 2019, Pleiades Publishing, Ltd.

PY - 2019/11/1

Y1 - 2019/11/1

N2 - Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is one of the important DNA repair enzymes responsible for the repair of DNA damage caused by anticancer drugs, such as topotecan. In this regard, enzyme activity is one of the possible causes of tumor resistance to chemotherapy, and the use of inhibitors of this enzyme is considered as a promising adjuvant therapy. We have obtained a number of new isomeric naphthyl derivatives of thiophenyl octahydro-2H-chromene, the structure of one of which is confirmed by X-ray structural analysis. Based on molecular modeling data, the structure of the ligand-Tdp1 complex has been proposed. All compounds obtained inhibit Tdp1 at a concentration of about 2 μM. Low toxicity of three compounds was shown, which makes them promising candidates for the development of accompanying cancer therapy.

AB - Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is one of the important DNA repair enzymes responsible for the repair of DNA damage caused by anticancer drugs, such as topotecan. In this regard, enzyme activity is one of the possible causes of tumor resistance to chemotherapy, and the use of inhibitors of this enzyme is considered as a promising adjuvant therapy. We have obtained a number of new isomeric naphthyl derivatives of thiophenyl octahydro-2H-chromene, the structure of one of which is confirmed by X-ray structural analysis. Based on molecular modeling data, the structure of the ligand-Tdp1 complex has been proposed. All compounds obtained inhibit Tdp1 at a concentration of about 2 μM. Low toxicity of three compounds was shown, which makes them promising candidates for the development of accompanying cancer therapy.

KW - cytotoxicity

KW - octahydro-2H-chromene

KW - topotecan

KW - tyrosyl-DNA phosphodiesterase 1 inhibitors

KW - ASSAY

KW - EMPIRICAL SCORING FUNCTIONS

KW - IDENTIFICATION

KW - ENHANCE

KW - PROTEIN-LIGAND DOCKING

KW - TDP1

KW - IN-VIVO

KW - BIOLOGICAL EVALUATION

KW - BINDING

UR - http://www.scopus.com/inward/record.url?scp=85077900104&partnerID=8YFLogxK

U2 - 10.1134/S1068162019060104

DO - 10.1134/S1068162019060104

M3 - Article

AN - SCOPUS:85077900104

VL - 45

SP - 647

EP - 655

JO - Russian Journal of Bioorganic Chemistry

JF - Russian Journal of Bioorganic Chemistry

SN - 1068-1620

IS - 6

ER -