Cucurbitacin B (CuB),
a highly cytotoxic constituent of the Cucurbitaceae
plant, was identified to exhibit potent inhibitory activity against
human cancer cells as well as normal cells. This disadvantage hampers
the possibility of developing this compound into an anticancer drug
candidate. In this work, several bioreductive prodrugs of CuB were
designed to reduce toxicity to normal cells while maintaining the
cytotoxic effect to cancer cells. Embedded with a bioreductive delivery
and cleavable system in cancer tissues, cucurbitacin B-based prodrugs 1, 2, and 3 were synthesized and
evaluated by in vitro and in vivo experiments. Compared with the parent CuB, prodrug 1 was found to significantly reduce the toxicity down to 310-fold
lower against noncancerous cells. LC-MS analyses show that prodrug 1 efficiently releases the parent compound in the reductase-overexpressed
MCF-7 cells. In addition, prodrug 1 shows satisfactory
and comparable effectiveness in controlling tumor growth as that by
tamoxifen in the 4T1 xenograft mice model.
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