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

被引：11

作者：

Chepanova, A. A. ^{[1
]}

Li-Zhulanov, N. S. ^{[2
,3
]}

Sukhikh, A. S. ^{[3
,6
]}

Zafar, A. ^{[4
]}

Reynisson, J. ^{[5
]}

Zakharenko, A. L. ^{[1
]}

Zakharova, O. D. ^{[1
]}

Korchagina, D., V ^{[2
]}

Voleho, K. P. ^{[2
,3
]}

Salakhutdinov, N. F. ^{[2
,3
]}

Lavrik, O., I ^{[1
,3
]}

机构：

[1] Russian Acad Sci, Inst Chem Biol & Fundamental Med, Novosibirsk 630090, Russia

[2] Russian Acad Sci, Vorozhtsov Novosibirsk Inst Organ Chem, Siberian Branch, Novosibirsk 630090, Russia

[3] Novosibirsk State Univ, Novosibirsk 630090, Russia

[4] Univ Auckland, Sch Chem Sci, Auckland 1010, New Zealand

[5] Keele Univ, Sch Pharm, Hornbeam Bldg, Keele ST5 5BG, Staffs, England

[6] Russian Acad Sci, Nikolaev Inst Inorgan Chem, Siberian Branch, Novosibirsk 630090, Russia

来源：

RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY | 2019年 / 45卷 / 06期

基金：

俄罗斯基础研究基金会;

关键词：

tyrosyl-DNA phosphodiesterase 1 inhibitors; topotecan; octahydro-2H-chromene; cytotoxicity; EMPIRICAL SCORING FUNCTIONS; PROTEIN-LIGAND DOCKING; BIOLOGICAL EVALUATION; IN-VIVO; TDP1; IDENTIFICATION; ENHANCE; BINDING; ASSAY;

D O I：

10.1134/S1068162019060104

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 mu M. Low toxicity of three compounds was shown, which makes them promising candidates for the development of accompanying cancer therapy.

引用

页码：647 / 655

页数：9

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