Antitumor activity of endoperoxide-iron chelator conjugates―design, synthesis and biological evaluation

•These endoperoxide and iron chelator conjugates inhibited cancer cell proliferation.•These compounds displayed 2–4 fold selectivity against cancer cell vs normal cell.•Both endoperoxide and iron-chelating moiety contributed to the biological ability.

The effort to pursue effective anti-cancer drugs with novel mechanism of action has been continued for decades. As an antimalarial agent, artemisinin is well-known for its endoperoxide moiety, which is activated by the cellular iron. Meanwhile, the anti-cancer activity of artemisinin is recognized and reported. Herein, we report on the design, synthesis and evaluation of a series of endoperoxide and iron chelating moiety conjugates. Our study demonstrated that the endoperoxide-quinoline conjugates displayed effective antiproliferative capability and good selectivity against certain cancer cells, while both hydroxamate and catechol-endoperoxide conjugates shown no significant inhibitory activity. Preliminary mechanism investigation suggested that the antiproliferative activity of these conjugates is related to the endoperoxide moiety as well as their iron-chelating ability. These compounds are expected to be used as prototype for further development of selective anti-cancer drug candidate.

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