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New antitumor anthra[2,3-b]furan-3-carboxamides: Synthesis and structure-activity relationshipстатья
Статья опубликована в высокорейтинговом журнале
Информация о цитировании статьи получена из
Web of Science,
Scopus
Статья опубликована в журнале из списка Web of Science и/или Scopus
Дата последнего поиска статьи во внешних источниках: 10 августа 2018 г.
- Авторы: Tikhomirov Alexander S., Chia-Yang Lin, Volodina Yulia L., Dezhenkova Lyubov G., Tatarskiy Victor V., Dominique Schols, Shtil Alexander A., Punit Kaur, Chueh Pin Ju, Shchekotikhin Andrey E.
- Журнал: European Journal of Medicinal Chemistry
- Том: 148
- Год издания: 2018
- Издательство: Elsevier BV
- Местоположение издательства: Netherlands
- Первая страница: 128
- Последняя страница: 139
- DOI: 10.1016/j.ejmech.2018.02.027
- Аннотация: Chemical modifications of the anthraquinone scaffold are aimed at optimization of this exceptionally productive class of antitumor drugs. In particular, our previously reported anthra[2,3-b]furan-3- carboxamides demonstrated a high cytotoxic potency in cell culture and in vivo. In this study, we expanded our series of anthra[2,3-b]furan-3-carboxamides by modifying the key functional groups and dissected the structure-activity relationship within this chemotype. The majority of new compounds inhibited the growth of mammalian tumor cell lines at submicromolar to low micromolar concentrations. We found that 4,11-hydroxy groups as well as the carbonyl moiety in the carboxamide fragment were critical for cytotoxicity whereas the substituent at the 2-position of anthra[2,3-b]furan was not. Importantly, the new derivatives were similarly potent against wild type cells and their variants resistant to doxorubicin due to P-glycoprotein (Pgp) expression or p53 inactivation. The most cytotoxic derivatives 6 and 9 attenuated plasmid DNA relaxation by topoisomerase 1. Finally, we demonstrated that 6 and 9 at 1 mM induced intracellular oxidative stress, accumulation in G2/M phase of the cell cycle, and apoptosis in gastric carcinoma cell lines regardless of their p53 status. These results further substantiate the potential of anthra[2,3-b]furan-3-carboxamides as antitumor drug candidates.
- Добавил в систему: Тихомиров Александр Сергеевич