Aminoadamantanes containing monoterpene-derived fragments as potent tyrosyl-DNA phosphodiesterase 1 inhibitors

被引：36

作者：

Ponomarev, Konstantin Yu. ^{[1
]}

Suslov, Evgeniy V. ^{[1
]}

Zakharenko, Alexandra L. ^{[2
]}

Zakharova, Olga D. ^{[2
]}

Rogachev, Artem D. ^{[1
,3
]}

Korchagina, Dina V. ^{[1
]}

Zafar, Ayesha ^{[4
]}

Reynisson, Johannes ^{[4
]}

Nefedov, Andrey A. ^{[1
,3
]}

Volcho, Konstantin P. ^{[1
,3
]}

Salakhutdinov, Nariman F. ^{[1
,3
]}

Lavrik, Olga I. ^{[1
,2
,3
]}

机构：

[1] Russian Acad Sci, Siberian Branch, NN Vorozhtsov Novosibirsk Inst Organ Chem, 9 Akad Lavrentieva Ave, Novosibirsk 630090, Russia

[2] Russian Acad Sci, Siberian Branch, Novosibirsk Inst Chem Biol & Fundamental Med, 8 Akad Lavrentieva Ave, Novosibirsk 630090, Russia

[3] Novosibirsk State Univ, 2 Pirogova Str, Novosibirsk 630090, Russia

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

来源：

BIOORGANIC CHEMISTRY | 2018年 / 76卷

关键词：

Natural products; Fluorescent assay; Tdp1; molecular modelling; Chemical space; Amine; Cytotoxicity; Adamantanes; EMPIRICAL SCORING FUNCTIONS; PROTEIN-LIGAND DOCKING; BIOLOGICAL EVALUATION; TOPOISOMERASE-I; 2-AMINOADAMANTANE DERIVATIVES; ADAMANTANE DERIVATIVES; TDP1; INHIBITORS; DATA-BANK; CANCER; CAMPTOTHECINS;

D O I：

10.1016/j.bioorg.2017.12.005

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：

The ability of a number of nitrogen-containing compounds that simultaneously carry the adamantane and monoterpene moieties to inhibit Tdp1, an important enzyme of the DNA repair system, is studied. Inhibition of this enzyme has the potential to overcome chemotherapeutic resistance of some tumor types. Compound (+)-3c synthesized from 1-aminoadamantane and (+)-myrtenal, and compound 4a produced from 2-aminoadamantane and citronellal were found to be most potent as they inhibited Tdp1 with IC50 values of 6 and 3.5 mu M, respectively. These compounds proved to have low cytotoxicity in colon HCT-116 and lung A-549 human tumor cell lines (CC50 > 50 mu M). It was demonstrated that compound 4a at 10 mu M enhanced cytotoxicity of topotecan, a topoisomerase 1 poison in clinical use, against HCT-116 more than fivefold and to a lesser extent of 1.5 increase in potency for A-549. (C) 2017 Elsevier Inc. All rights reserved.

引用

页码：392 / 399

页数：8

共 49 条

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