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

Konstantin Yu Ponomarev, Evgeniy V. Suslov, Alexandra L. Zakharenko, Olga D. Zakharova, Artem D. Rogachev, Dina V. Korchagina, Ayesha Zafar, Jóhannes Reynisson, Andrey A. Nefedov, Konstantin P. Volcho, Nariman F. Salakhutdinov, Olga I. Lavrik

Результат исследования: Научные публикации в периодических изданияхстатья

20 Цитирования (Scopus)

Аннотация

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 µM, respectively. These compounds proved to have low cytotoxicity in colon HCT-116 and lung A-549 human tumor cell lines (CC50 > 50 µM). It was demonstrated that compound 4a at 10 µM 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.

Язык оригиналаанглийский
Страницы (с-по)392-399
Число страниц8
ЖурналBioorganic Chemistry
Том76
DOI
СостояниеОпубликовано - 1 фев 2018

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  • Цитировать

    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. (2018). Aminoadamantanes containing monoterpene-derived fragments as potent tyrosyl-DNA phosphodiesterase 1 inhibitors. Bioorganic Chemistry, 76, 392-399. https://doi.org/10.1016/j.bioorg.2017.12.005