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

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

Journal

Bioorganic Chemistry
ISSN: 0045-2068 , E-ISSN: 1090-2120

Output data

Year: 2018, Volume: 76, Pages: 392-399 Pages count : 8 DOI: 10.1016/j.bioorg.2017.12.005

Tags

Natural products; Fluorescent assay; Tdp1, molecular modelling; Chemical space; Amine; Cytotoxicity; Adamantanes

Authors

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

Affiliations

1	(Данные Web of science) Russian Acad Sci, Siberian Branch, NN Vorozhtsov Novosibirsk Inst Organ Chem, 9 Akad Lavrentieva Ave, Novosibirsk 630090, Russia
2	(Данные Web of science) Russian Acad Sci, Siberian Branch, Novosibirsk Inst Chem Biol & Fundamental Med, 8 Akad Lavrentieva Ave, Novosibirsk 630090, Russia
3	(Данные Web of science) Novosibirsk State Univ, 2 Pirogova Str, Novosibirsk 630090, Russia
4	(Данные Web of science) Univ Auckland, Sch Chem Sci, Auckland, New Zealand

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.

Ponomarev K.Y. , Suslov E.V. , Zakharenko A.L. , Zakharova O.D. , Rogachev A.D. , Korchagina D.V. , Zafar A. , Reynisson J. , Nefedov A.A. , Volcho K.P. , Salakhutdinov N.F. , Lavrik O.I.
Aminoadamantanes containing monoterpene-derived fragments as potent tyrosyl-DNA phosphodiesterase 1 inhibitors
Bioorganic Chemistry. 2018. V.76. P.392-399. DOI: 10.1016/j.bioorg.2017.12.005 WOS Scopus РИНЦ

Published print:

Feb 1, 2018

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