Structure optimization of an F-indole-chalcone (FC116) on 4-methoxy-phenyl group and therapeutic potential against colorectal cancers with low cytotoxicity

Advanced metastatic colorectal cancers (CRCs) are regarded as a challenge in clinical cancer therapy. Our previous studies have demonstrated that a representative fluoro-substituted indole-chalcone (FC116), was ob-tained to display highly potent activity against CRC using multiple in vitro and in vivo mouse models by targeting microtubules. However, several problems, such as low dose tolerance and highly toxic to the brain and colon, low solubility unsuitable for intravenous (i.v.) administration, are still existed and limit further development. Herein, we developed two series of FC116 derivatives on the 4-methoxyphenyl group by a structure-based design strategy. Among them, FC11619 with an amino terminus maintained the in vitro cytotoxicity against HCT-116 CRC in a low nanomolar range. This compound could induce G2/M phase arrest via regulating cyclin B1 expression, produce excess reactive oxygen species (ROS), and target tubulin in CRC cells. In vivo, FC11619 significantly suppressed tumor growth, achieving 65.3 and 73.4 % at doses of 5 and 10 mg/kg/d (i.v., 21 d), which were much better than 54.1% of Taxol at 7 mg/kg. In addition, this compound showed better in vivo tolerance compared to that of FC116 (only 3 mg/kg tolerance, intraperitoneal, i.p.), and no major organ-related toxicity, especially no apparent degenerated neurons, intestinal obstruction in clinical Taxol standard therapy. Taken together, the 4-amino-substitutedphenyl indole-chalcones represent lead compounds as chemotherapy of CRC for further drug development in this field.

Automated summary

Two series of 4-methoxyphenyl derivatives of FC116 were developed, among which FC11619 exhibited potent in vitro cytotoxicity against HCT-116 colorectal cancer cells in the low nanomolar range. This compound induced G2/M phase arrest, produced excess reactive oxygen species, and targeted tubulin in CRC cells. In vivo, FC11619 significantly suppressed tumor growth, achieving superior inhibition rates compared to Taxol. Additionally, FC11619 showed better in vivo tolerance and no major organ-related toxicity, making it a promising lead compound for further drug development in colorectal cancer therapy.