New antitumor anthra[2,3-b]furan-3-carboxamides: Synthesis and structure-activity relationshipстатья
Статья опубликована в высокорейтинговом журнале
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Дата последнего поиска статьи во внешних источниках: 10 августа 2018 г.
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.